bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–05–31
79 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A transport-independent role for SLC25A12 in mitochondrial stress signalling.
  2. MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
  3. Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.
  4. Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
  5. Mitochondrial extracellular vesicles between pathology and regeneration.
  6. Mitochondrial myopathy biomarkers.
  7. Mitochondrial drivers of stem cell aging and inflammaging.
  8. A multilayered stress-response circuit: The mammalian mitochondrial UPR.
  9. Cholesterol in Mitochondrial Diseases-Friend or Foe?
  10. The Hidden Culprit in Optic Neuritis: Mitochondrial Complex I Deficiency Due to a Novel NDUFS1 Mutation.
  11. Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
  12. A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
  13. Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.
  14. MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
  15. Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.
  16. Detection of mitochondrial bioenergetics using a novel bimodal 3D microelectrode array (MEA)-based biosensor.
  17. Disruption of Fructose 1,6-Bisphosphatase 2 Proximity to MIC60 Correlates with Mitochondrial Ultrastructural Changes.
  18. Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
  19. Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
  20. PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.
  21. MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
  22. Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
  23. Hippocampal CA1 and CA2 dendritic compartment-specific differences in mitochondrial form and function.
  24. CSDE1 Associates with TOM20 and Mitochondrial Protein-Encoding mRNAs in Sensory Neurons.
  25. Transmembrane domain switching controls PINK1 import and fate in mitochondria.
  26. Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.
  27. Progressive Visual Recovery in a Patient with Leber Hereditary Optic Neuropathy Harboring a Rare Heteroplasmic (MT-ND5):m.13042G>A, p(Ala236Thr) Variant with Low Mutant Load: A Case Report.
  28. MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
  29. Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
  30. Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.
  31. Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.
  32. Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.
  33. Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
  34. Clinical and biochemical footprints of inherited cofactor disorders.
  35. Aspartate-Glutamate Carrier 1 (SLC25A12) Deficiency: Malate-Aspartate Shuttle Failure, Neurodevelopmental Epileptic Encephalopathy, and Ketone-Based Metabolic Therapy.
  36. A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.
  37. The pyruvate generator is a common phenomenon in mitochondria from different rat and mouse brain regions.
  38. Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
  39. Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
  40. Alternative organelle targeting of OPA1 mediates fatty acid release from lipid droplets.
  41. Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging.
  42. The Evidence Aggregator: AI reasoning applied to rare disease diagnostics.
  43. ROS-HIF1α-driven glycolytic reprogramming sustains ATP production in Huntington's disease.
  44. Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
  45. Targeting NAD Homeostasis: Compartmentalization, Quantification, and Modulation.
  46. Light-Activated Isolation of High-Quality Mitochondria for Therapeutic Transplantation.
  47. Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
  48. Platelet Mitochondria: A Promising Target for Antiplatelet Therapy.
  49. Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.
  50. Mechanism of age-related accumulation of mtDNA mutations in human blood.
  51. Mitochondrial genetic variation across tissues of the human body.
  52. Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.
  53. Intramuscular mitochondria transplantation ameliorates paclitaxel-induced peripheral neuropathy by restoring neuronal mitochondrial homeostasis and function.
  54. Dehydration promotes intracellular lipid synthesis and accumulation.
  55. NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
  56. Sestrin regulates cellular homeostasis through modulating mitochondrial function.
  57. Intercellular Mitochondrial Transfer as Endogenous Neuroprotection: Mechanisms and Therapeutic Implications in Ischemic Stroke.
  58. Redefining ocular safety assessment: retinal organoids as platforms for predicting human ocular toxicology.
  59. Histopathological findings and knowledge gaps in glaucomatous neurodegeneration.
  60. Mitigating Excessive Mitochondrial Fission Through the Development of a Selective Macrocyclic Inhibitor Targeting Fis1/Mid51 Signaling.
  61. Plasma membrane mediated GLUT10 mitochondrial targeting regulates intracellular ascorbic acid homeostasis.
  62. Characterization of a new mitophagy reporter uncovers requirement of BNIP3 for hypoxia-induced mitophagy in Drosophila.
  63. Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
  64. Lactylation landscape of mitochondrial proteins in myocardial infarction.
  65. Mitochondrial transfer in sepsis: Dual role, mechanistic networks, and translational strategies.
  66. Brucella Omp25c Modulates Host NAD+/NADH Homeostasis via Interaction with the Mitochondrial Complex I Assembly Factor Ndufaf2.
  67. Renal gluconeogenesis: a key metabolic hub in health and kidney disease.
  68. A genome-wide deletion map in 125,730 individuals for novel rare disease gene and variant discovery.
  69. Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
  70. Mitochondria-ER contact sites (MERCS) in the cell cycle: molecular architecture and functional remodeling across cellular states.
  71. Glutathione peroxidase 3 preserves hepatocyte mitochondrial quality control to enhance macrophage pro-regenerative phenotype during liver regeneration.
  72. Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
  73. The Use of Single-Cell Mitochondrial DNA SNP Combinations for Distinguishing Organ-Specific Cell Types.
  74. Unveiling C1QBP: A New Guardian of Dopaminergic Neuron in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
  75. Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice.
  76. Phenylalanyl-tRNA synthetase FARS-1/FARSA balances longevity and immunity by downregulating endogenous mitochondrial double-stranded RNAs.
  77. Genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort: insights from whole-exome sequencing.
  78. Time-restricted feeding enhances cross-tissue temporal coordination of mitochondrial-associated transcripts.
  79. Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.
  1. Nat Cell Biol. 2026 May 27.
    A transport-independent role for SLC25A12 in mitochondrial stress signalling.
    Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.
      Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-01973-1
  2. Protein Sci. 2026 Jun;35(6): e70653
    MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
    Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.
      Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.
    Keywords:  cristae; membrane organization; metabolism; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1002/pro.70653
  3. Protein Sci. 2026 Jun;35(6): e70631
    Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.
    Sahana Shankar, Chris Meisinger.
      The translocase of the outer mitochondrial membrane (TOM complex) serves as the central entry gate for more than 1000 nuclear-encoded precursor proteins imported into the organelle. Recently, the human import receptor TOM70 has been identified as a substrate of the serine/threonine kinase DYRK1A. DYRK1A activates the metabolite carrier import pathway, and its impairment triggers a transcriptional adaptive response that induces remodeling of the TOM complex. This compensatory mechanism activates additional import pathways to mitigate reduced DYRK1A signaling. Patients with dysfunctional DYRK1A signaling exhibit clinical manifestations that resemble classical features of mitochondriopathies. The emerging DYRK1A-TOM70 axis therefore represents a central signaling platform coordinating mitochondrial protein import pathways in health and disease.
    Keywords:  DYRK1A; DYRK1A‐related syndrome; Down syndrome; TOM complex; mitochondrial protein import; organellar signaling
    DOI:  https://doi.org/10.1002/pro.70631
  4. Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):
    Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
    Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.
      To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.
    Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response
    DOI:  https://doi.org/10.3390/muscles5020039
  5. Neural Regen Res. 2026 May 14.
    Mitochondrial extracellular vesicles between pathology and regeneration.
    Paola Margutti, Silvia Zamboni.
      Mitochondria are central regulators of cellular energy production, metabolic homeostasis, and stress responses, and their dysfunction represents a critical hallmark of neurodegenerative and neuroinflammatory diseases. To preserve mitochondrial integrity, cells rely on an intricate mitochondrial quality control system encompassing mitochondrial dynamics, mitophagy, biogenesis, and vesicle-mediated pathways. Emerging evidence highlights the pivotal role of mitochondria-derived vesicles as vehicles for trafficking mitochondrial components within cells, thereby contributing significantly to intracellular communication and mitochondrial quality control. In parallel, mitochondrial extracellular vesicles have been identified as dynamic mediators of intercellular communication, enabling the transfer of mitochondrial proteins, lipids, and even mitochondrial DNA between cells. Mitochondria-derived vesicles selectively remove damaged mitochondrial components and coordinate intracellular stress responses, whereas mitochondrial extracellular vesicles can transfer mitochondrial material, including proteins, mitochondrial DNA, and even intact mitochondria, between cells, thereby modulating inflammation, immune activation, and cellular bioenergetics. Interestingly, mitochondrial extracellular vesicles play a dual, context-dependent role: they can exacerbate pathology when carrying damaged or dysfunctional mitochondrial cargo, or promote cellular resilience when delivering healthy, functional mitochondrial components. Likewise, extracellular vesicles derived from mesenchymal stem cells, including larger extracellular vesicle populations capable of transferring functional mitochondria, are emerging as promising cell-free therapeutic candidates with the potential to restore mitochondrial function and promote tissue repair across multiple diseases, including neurodegenerative disorders. Collectively, these insights establish mitochondrial vesicular trafficking as a transformative frontier for diagnostic innovation, biomarker development, and novel therapeutic strategies in neurodegenerative and mitochondria-related central nervous system disorders. Implications for the field include: the recognition of mitochondrial vesicular pathways as fundamental regulators of central nervous system homeostasis highlights their crucial roles in sustaining neuronal function, cellular resilience, and overall brain health. When enriched with dysfunctional mitochondrial cargo, mitochondrial extracellular vesicles are emerging as key contributors to the etiopathogenesis of neurodegenerative and neuroinflammatory diseases, thereby driving disease initiation and progression. In parallel, their ability to reflect mitochondrial status positions mitochondrial extracellular vesicles - particularly those containing mitochondrial DNA and mitochondrial proteins - as promising biomarkers for monitoring mitochondrial stress, disease activity, and therapeutic response. At the translational level, advancing mitochondrial extracellular vesicles and mitochondrial vesicular pathways as therapeutic tools opens new opportunities to restore mitochondrial integrity, modulate neuroinflammation, and potentially modify disease trajectories. The objectives of this review are to: (1) delineate the mechanisms of mitochondrial dysfunction and mitochondrial quality control failure in neurodegenerative and neuroinflammatory diseases; (2) comprehensively characterize the biogenesis, trafficking pathways, and functional roles of mitochondria-derived vesicles; (3) evaluate experimental and clinical evidence supporting the role of mitochondrial extracellular vesicles as mediators of neuroimmune communication and mitochondrial transfer; (4) critically assess the therapeutic potential of mesenchymal stem cell-derived mitochondrial extracellular vesicles.
    Keywords:  autophagy; extracellular vesicles; lysosome; mesenchymal stem cells; mitochondria; mitochondrial damage-associated molecular patterns; mitochondrial transfer; mitophagy; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00964
  6. Adv Clin Chem. 2026 ;pii: S0065-2423(26)00021-1. [Epub ahead of print]133 161-216
    Mitochondrial myopathy biomarkers.
    Marco Refrigeri, Alessandra Tola, Rosangela Mogavero, Maria Michela Pietracupa, Giulia Gionta, Roberto Scatena.
      Mitochondrial myopathies comprise a heterogeneous group of disorders arising from structural or functional mitochondrial impairments that disrupt oxidative phosphorylation and cellular ATP production. The resulting energy deficit manifests not only in muscle but frequently leads to multi-systemic disease involving the brain, heart, kidneys, and endocrine system, creating a complex and often confounding clinical presentation. A critical, often overlooked aspect of their pathophysiology is that mitochondrial dysfunction extends far beyond bioenergetics. These organelles are vital hubs for biosynthetic pathways, calcium homeostasis, thermogenesis, apoptosis, and redox-sensitive signaling pathways that govern gene expression. The disruption of these integrated functions, whose molecular consequences are still being elucidated, is central to the disease's progression and heterogeneity. This clinical and molecular complexity contributes to significant diagnostic delay, with many remaining undiagnosed. Therefore, the development and strategic implementation of reliable biomarkers are essential. This review critically evaluates current and emerging biomarkers, proposing a diagnostic framework designed to improve diagnostic accuracy, limit unnecessary procedures, and ensure timely access to therapeutic interventions and genetic counseling.
    Keywords:  Biomarkers; Cell-free circulating mtDNA; Creatine; Diagnosis; Exercise intolerance; FGF21; GDF-15; Genetics; Mitochondrial disease; Mitochondrial medicine; Mitochondrial myopathy; Neurofilaments; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/bs.acc.2026.01.007
  7. NPJ Aging. 2026 May 28.
    Mitochondrial drivers of stem cell aging and inflammaging.
    Jhommara Bautista, Andrés López-Cortés.
      Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.
    DOI:  https://doi.org/10.1038/s41514-026-00422-5
  8. FEBS J. 2026 May 29.
    A multilayered stress-response circuit: The mammalian mitochondrial UPR.
    Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.
      Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.
    Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.1111/febs.70607
  9. Int J Mol Sci. 2026 May 13. pii: 4353. [Epub ahead of print]27(10):
    Cholesterol in Mitochondrial Diseases-Friend or Foe?
    Mila Taylor, Michal Halicki, Paul Chazot.
      Serving as central signalling organelles and hubs of metabolism, mitochondria are essential for cellular homeostasis. Mitochondrial disease can arise from mutations to nuclear or mitochondrial DNA, which result in disruptions to normal mitochondrial function. This generates a suite of rare disorders which are multi-system and often fatal. Variable tissue distribution of mitochondria, alongside a high degree of heterogeneity in associated phenotype, has resulted in an inadequate understanding and characterisation of mitochondrial disease. Addressing this issue is therefore crucial for better clinical management and patient outcomes. Cholesterol dyshomeostasis is a potential pathological hallmark of numerous mitochondrial diseases. Cholesterol is an essential lipid and bioactive compound involved in numerous mitochondrial and cellular processes. A growing number of studies have reported perturbations to cholesterol biosynthesis, cholesterol import, and cholesterol ratios in cell and animal models and individuals with mitochondrial disease, suggesting it could be a unifying feature of these disparate and variable disorders. This review summarises the current experimental evidence for the role of cholesterol dyshomeostasis in mitochondrial disease. It will further discuss reports of statin intolerance, generally attributed to off-target action on mitochondrial structures, in the context of this evidence. Ultimately, the necessity of further integrative clinical and experimental studies exploring the potential of cholesterol dyshomeostasis as a pathological hallmark of mitochondrial disease will be highlighted.
    Keywords:  cholesterol; dyshomeostasis; lipid; mitochondria; statin
    DOI:  https://doi.org/10.3390/ijms27104353
  10. J Neuroophthalmol. 2026 May 28.
    The Hidden Culprit in Optic Neuritis: Mitochondrial Complex I Deficiency Due to a Novel NDUFS1 Mutation.
    Prabhjit Kaur, Arushi Saini, Aastha Takkar, Sanjhi Paliwal, Gayatri Lal, Vikas Bhatia, Jaspreet Sukhija, Vivek Lal.
      
    DOI:  https://doi.org/10.1097/WNO.0000000000002475
  11. BMC Bioinformatics. 2026 May 25.
    Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
    Kohta Nakamura, Naoyuki Matsumoto, Yasushi Okazaki.
       BACKGROUND: Mitochondrial DNA heteroplasmy plays a crucial role in mitochondrial function, aging, and a wide range of human diseases. Recent advances in high-throughput sequencing have enabled large-scale detection of heteroplasmic variants; however, effective cohort-level integration, comparison, and visualization of Mutant Allele Frequency (MAF) values remain challenging. Existing tools often focus on single-sample visualization or require substantial manual preprocessing, limiting their scalability and usability for large cohorts. To address these challenges, we developed Mito_Plot, an open-source computational pipeline designed for standardized quantification and intuitive visualization of Mitochondrial DNA (mtDNA) heteroplasmy across multiple samples.
    RESULTS: Mito_Plot accepts standard mitochondrial VCF files and automatically calculates MAF based on allelic depth information. MAF data from multiple samples are aggregated into a unified matrix aligned by genomic position, enabling direct cross-sample comparison. The pipeline provides interactive two-dimensional circular plots that map MAF onto the mitochondrial genome with gene-level annotations, facilitating rapid identification of mutation hotspots and sample-specific patterns. In addition, Mito_Plot offers optional three-dimensional visualizations that enhance exploration of large cohorts by separating variant distributions across samples and genomic regions. Application of Mito_Plot to multi-sample mitochondrial sequencing datasets demonstrated robust handling of both variants with low and high MAF values, efficient processing of large cohorts, and improved interpretability compared with static or single-sample visualizations.
    CONCLUSIONS: Mito_Plot is a scalable, user-friendly software pipeline for cohort-scale quantification and visualization of mtDNA MAF. By integrating standardized MAF calculation with interactive 2D and 3D visualizations, Mito_Plot facilitates comprehensive exploration of mitochondrial variant landscapes across large datasets. The open-source and modular design of the software supports reproducible research and flexible integration into existing analysis workflows, making Mito_Plot a practical resource for mitochondrial genomics research and clinical investigations.
    Keywords:  Circular genome; Cohort-scale analysis; Data visualization; Mitochondrial DNA; Mitochondrial heteroplasmy; Variant analysis
    DOI:  https://doi.org/10.1186/s12859-026-06476-2
  12. Int J Mol Sci. 2026 May 14. pii: 4387. [Epub ahead of print]27(10):
    A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
    Yung Wu, Hongyun Tang.
      Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPRmt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPRmt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPRmt.
    Keywords:  Caenorhabditis elegans; GLDI-8; electron transport chain dysfunction; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27104387
  13. Mol Biomed. 2026 May 28. pii: 78. [Epub ahead of print]7(1):
    Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.
    Yan Tong, Jing Na He, Linbin Zhou, Jiaxin Zhang, Bo Man Ho, Lin Du, Yolanda Wong Ying Yip, Hemlata Bisnauthsing, Poemen P Chan, Clement C Tham, Chi Pui Pang, Wai Kit Chu.
      Mitochondrial dysfunction is a core pathogenic mechanism underlying a broad spectrum of neurodegenerative disorders, from Alzheimer's and Parkinson's diseases to inherited optic neuropathies and mitochondrial ataxias. This review provides a comprehensive analysis of how defects in mitochondrial and nuclear DNA converge to disrupt oxidative phosphorylation, mitochondrial dynamics, calcium homeostasis, and quality control pathways, leading to energy depletion, oxidative stress, and neuronal degeneration across multiple disease contexts. Building on this mechanistic foundation, we examine how these shared pathogenic principles manifest distinctly in major neurodegenerative diseases, while also discussing representative mitochondrial optic neuropathies as tractable disease models that have yielded critical mechanistic and therapeutic insights. We further review recent advances in diagnostic technologies that enhance our ability to detect and stratify mitochondrial pathologies for therapeutic intervention. On the therapeutic front, we provide a comprehensive evaluation of the rapidly evolving landscape, analyzing strategies ranging from metabolic modulators and antioxidants to pioneering gene-targeted therapies, organelle replacement approaches, and emerging epitranscriptomic interventions. Finally, we identify persistent challenges in clinical translation and outline pivotal future directions essential for developing effective, mechanism-informed combination therapies against mitochondrial dysfunction in neurodegeneration.
    Keywords:  Clinical translation; Gene therapy; Mitochondrial dynamics; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s43556-026-00480-x
  14. Neurol Sci. 2026 May 26. pii: 521. [Epub ahead of print]47(6):
    MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
    Yuan Xia, Yufen She, Ruiqi Zhao, Yan Zhang.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem mitochondrial disorder caused by thymidine phosphorylase (TYMP) deficiency, leading to toxic nucleoside accumulation and mitochondrial DNA instability. Pathogenic variants in POLG, encoding mitochondrial DNA polymerase γ, have been associated with overlapping mitochondrial syndromes. However, the coexistence of TYMP-related MNGIE and a concurrent heterozygous POLG variant has not been reported.
    CASE PRESENTATION: A 57-year-old woman presented with a 10-year history of recurrent dizziness, chronic diarrhea, and 20 kg weight loss. Laboratory investigations revealed chronic anemia, hypoproteinemia, and positivity for anti-centromere protein B and anti-mitochondrial M2 antibodies. Abdominal CT revealed multiple small-bowel diverticula, splenomegaly, and a retained capsule endoscope, whereas brain MRI showed diffuse white-matter hyperintensities. Electromyography showed sensorimotor neuropathy, and neurological examination revealed bilateral ptosis, ophthalmoplegia, and distal weakness. Whole-exome sequencing confirmed a homozygous TYMP variant (c.708C>A, p.Phe236Leu) and a heterozygous POLG variant (c.1781 T>C, p.Leu594Pro). Surgical removal of the retained capsule together with supportive therapy, including enteral nutrition and coenzyme Q10, resulted in clinical improvement. To our knowledge, this is the first reported case of MNGIE with a homozygous TYMP variant and a concurrent heterozygous POLG variant.
    CONCLUSION: While the homozygous TYMP variant provides the primary molecular basis for the diagnosis, the concurrent heterozygous POLG variant may represent a potential phenotypic modifier. This case expands the genotypic context of MNGIE and highlights the importance of early genetic testing and multidisciplinary management in patients with unexplained gastrointestinal and neurological manifestations.
    Keywords:  Capsule endoscopy; Mitochondrial disease; Mitochondrial neurogastrointestinal encephalomyopathy; POLG; TYMP
    DOI:  https://doi.org/10.1007/s10072-026-09131-z
  15. Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00791-4. [Epub ahead of print]253 221-237
    Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.
    Ehsaneh Khodadadi, Bingwei Lu.
      Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In addition to driving ATP synthesis through oxidative phosphorylation (OxPhos), MCI is a dynamic redox regulator that couples bidirectional catalysis with redox signaling. MCI conducts electron transfer in both the forward and reverse directions. While forward electron transport (FET) is essential for OxPhos and ATP synthesis, reverse electron transport (RET), driven by high membrane potential and ubiquinol pool, transfers electrons from ubiquinol to NAD+ and produces excessive ROS. MCI-derived ROS and NAD+/NADH changes act as physiologically regulated signals mediating hypoxia sensing, immune activation, stem-cell metabolism, but they can also contribute to pathology when dysregulated as in ischemia-reperfusion, cancer, neurodegeneration, and aging. Recent cryo-EM structures, time-resolved studies, and multiscale molecular dynamics (MD) simulations have provided near-atomic views of MCI architecture and operational mechanics. Here we review these developments from a redox-centered perspective. By positioning MCI as a dynamic redox regulator within a spatially organized mitochondrial network, we aim to provide a unifying framework for understanding how directional electron transfer, proton translocation, and redox signaling are intertwined in mitochondrial biology.
    Keywords:  Mitochondrial Complex I; Proton-coupled electron transfer; Reactive oxygen species (ROS); Redox signaling; Reverse electron transport (RET)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.311
  16. Microsyst Nanoeng. 2026 May 28. pii: 208. [Epub ahead of print]12(1):
    Detection of mitochondrial bioenergetics using a novel bimodal 3D microelectrode array (MEA)-based biosensor.
    Randall K James, Tatiana C Hostios, Ji Chang, Aakash Patel, Faisal Bin Kashem, Isaac Johnson, Jorge Manrique Castro, James Hickman, Swaminathan Rajaraman.
      Developing new label-free paradigms for functional assays in biomedical research has the potential to catalyze efforts in drug discovery and improve the understanding of complex disorders. Mitochondria are an essential organelle in nearly every eukaryotic organism that perform vital functions such as adenosine triphosphate (ATP) production, redox signaling, reactive oxygen species (ROS) homeostasis and regulation of programmed cell death. These activities are regulated by electrophysiological processes that occur in the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) in response to metabolic demands, making them an important physiological marker for bioenergetic studies. Mitochondria dysfunction is an early pathological biomarker of complex diseases, such as diabetes, neurodegeneration, myopathy, cancer, and cardiovascular disease. Built atop a novel microfabrication strategy for 3D Microelectrode Arrays (MEAs), we demonstrate a 3D mitochondria biosensor capable of bimodal sensing of mitochondrial electrophysiology from the OMM and IMM using electrochemical impedance spectroscopy (EIS) and electrophysiology recordings. Data obtained using EIS displays impedance magnitude and phase characterization of mitochondria isolated from NIH3T3 and induced pluripotent stem cells (iPSC) models, these measurements represent the major functional outputs of cellular respiration and electron transport chain (ETC) activity through the detection of conductive and capacitive properties of the IMM. Additionally, time-resolved electrophysiological recordings from an NIH3T3 derived mitochondrial pellet captured sub-millisecond voltage transients, establishing a complementary real-time electrophysiological profile of mitochondrial membrane activity that can be attributed voltage dependent anion channel (VDAC) gating or IMM potential dynamics.
    DOI:  https://doi.org/10.1038/s41378-026-01275-4
  17. Cells. 2026 May 20. pii: 942. [Epub ahead of print]15(10):
    Disruption of Fructose 1,6-Bisphosphatase 2 Proximity to MIC60 Correlates with Mitochondrial Ultrastructural Changes.
    Łukasz Pietras, Marta Migocka-Patrzałek, Bartosz Budziak, Dariusz Rakus, Agnieszka Gizak.
      Fructose 1,6-bisphosphatase 2 (FBP2) is a multifunctional protein whose cellular functions depend on its oligomeric state. Forced FBP2 tetramerization has been linked to microtubule disruption and impaired mitochondrial trafficking, accompanied by abnormal mitochondrial morphology. Here, we identify MIC60 (mitofilin), a core element of the mitochondrial contact site and cristae organizing system (MICOS), as a potential mediator of these effects. Using proximity ligation assay, protein crosslinking combined with mass spectrometry, and ultrastructural analysis, we demonstrate that FBP2 is in close proximity to MIC60 under basal conditions and this proximity is reduced upon FBP2 tetramerization or partial FBP2 depletion. Loss of this proximity coincides with marked remodeling of inner-membrane ultrastructure. These findings are consistent with a working model in which dimeric FBP2 contributes to the coordination of microtubule-dependent mitochondrial positioning with MICOS-linked intramitochondrial organization, providing a plausible mechanistic bridge between metabolic cues (AMP/NAD+) and mitochondrial structural integrity.
    Keywords:  FBP2; MIC60; cardiomyocyte; mitochondria; mitofilin; ultrastructure
    DOI:  https://doi.org/10.3390/cells15100942
  18. bioRxiv. 2026 May 17. pii: 2026.05.15.725497. [Epub ahead of print]
    Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
    Yaw Akosah, Ioannis Azoidis, Dane Jensen, Paolo Bernardi, Evgeny Pavlov.
      Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and cristae dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the sub-organellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K + ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K + influx leads to increase of mitochondrial matrix volume while stimulation of K + efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.
    DOI:  https://doi.org/10.64898/2026.05.15.725497
  19. Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]
    Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
    Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.
      The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.
    Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
  20. bioRxiv. 2026 May 13. pii: 2026.05.11.724378. [Epub ahead of print]
    PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.
    Julia F Riley, Charity V Robbins, Erika L F Holzbaur.
      Astrocytes directly influence neuronal survival and increasingly are understood to contribute to the progression of neurodegenerative diseases including Parkinson's disease (PD). Mitochondrial damage is a hallmark of PD pathology in both neurons and astrocytes. Damaged mitochondria are cleared by PINK1/Parkin-mediated mitophagy; loss-of-function mutations in either PINK1 or Parkin are sufficient to cause PD. Neuronal mitophagy is well-studied, but far less is known about how mitochondrial dysfunction in astrocytes affects neural health. While microglial release of pro-inflammatory cytokines has been shown to induce astrocytes to mount their own inflammatory response, we hypothesize that a more direct pathway is involved, and that mitochondrial damage to astrocytes directly triggers release of proinflammatory cytokines. To address these questions, we treated primary murine cortical astrocytes with oxidative phosphorylation (OXPHOS) inhibitors antimycin A (AA) and oligomycin A (OA) and observed the PINK1-dependent accumulation of Parkin on damaged mitochondria, leading to phospho-ubiquitination of proteins in the outer mitochondrial membrane and the recruitment of the autophagy receptor SQSTM1/p62. To identify transcriptional changes caused by mitochondrial damage and the resulting activation of mitophagic machinery, we performed bulk RNA-sequencing on astrocytes isolated from WT, PINK1 -/- , or Parkin -/- mice treated with AA/OA or a vehicle control. In WT astrocytes, TNF-α signaling via NF-κB was the most significantly upregulated pathway following OXPHOS inhibition. OXPHOS inhibitor treatment also stimulated p62 expression, while NF-κB inhibition prevented this upregulation. Astrocytic secretion of cytokines, including TNF-α, was increased following mitochondrial damage; this secretion was dependent on NF-κB activation and occurred at levels sufficient to induce mitochondrial depolarization in hippocampal neurons. Compared to WT astrocytes, PINK1 -/- astrocytes showed a significant reduction in transcriptional signatures associated with TNF-α signaling following mitochondrial damage, while Parkin -/- astrocytes exhibited upregulation of both IFN-γ and IFN-α signaling. These findings indicate altered inflammatory responses to mitochondrial damage in the absence of functional PINK1 or Parkin. Finally, we analyzed scRNA-sequencing data from substantia nigra astrocytes harvested from human brain tissue from PD-positive or control samples. Distinct clusters comprised predominantly of PD-positive or control astrocytes emerged. Astrocytes in the PD-positive cluster were enriched for NF-κB, IFN-α and IFN-γ responses, consistent with the signaling observed in vitro post-OXPHOS inhibition. Together, these findings identify inflammatory signatures activated by mitochondrial damage in astrocytes, and establish this pathway as a potential contributor to neuroinflammation in PD.
    DOI:  https://doi.org/10.64898/2026.05.11.724378
  21. Nanomedicine. 2026 May 25. pii: S1549-9634(26)00060-2. [Epub ahead of print]75 102959
    MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
    Nishad Keethedeth, Goutam Chandra, B Prakash Kumar, G Ganga Anand, Rajesh A Shenoi.
      Mitochondrial dysfunction is a key contributor to the pathogenesis of major neurodegenerative diseases such as Parkinson's disease. Targeted drug delivery to neuronal mitochondria is often limited by the inherent toxicity and inefficiency of drug carriers. Here we report the mitochondrial targeting ability of MitoPG, a novel nanocarrier based on dendritic polyglycerol (PG) conjugated with triphenylphosphonium (TPP+). Among a library of MitoPGs studied, MitoPG3 demonstrated superior mitochondrial localization and minimal cytotoxicity, without adverse effects on mitochondrial functions. Notably, it retained high mitochondrial targeting efficiency even under MPP+-induced mitochondrial dysfunction in neuronal cells. MitoPG 3 exhibited excellent blood brain permeability in vitro. To the best of our knowledge, this is the first report of a dendritic polymer-based nanocarrier with high mitochondrial localization and reduced toxicity and without impairing mitochondrial functions. These results highlight MitoPG as a safe and effective platform for delivering therapeutics to neuronal mitochondria, with the potential for clinical translation.
    Keywords:  Mitochondria targeting; Mitochondrial dysfunction; Polyglycerol; Targeted drug delivery; Triphenyl phosphonium
    DOI:  https://doi.org/10.1016/j.nano.2026.102959
  22. Commun Biol. 2026 May 27.
    Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
    Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.
    DOI:  https://doi.org/10.1038/s42003-026-10312-x
  23. Prog Neurobiol. 2026 May 26. pii: S0301-0082(26)00057-2. [Epub ahead of print] 102931
    Hippocampal CA1 and CA2 dendritic compartment-specific differences in mitochondrial form and function.
    Mayd Alsalman, Lucy Turner, Katy Pannoni, Renesa Tarannum, Rutvi Desai, Sharon A Swanger, Shannon Farris.
      Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found that CA2 dendritic mitochondria were larger than in CA1. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for MFF and OPA1, which showed a general enrichment in distal relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerability to disease.
    Keywords:  calcium; dendrite; entorhinal cortex; heterogeneity; hippocampus; mitochondria
    DOI:  https://doi.org/10.1016/j.pneurobio.2026.102931
  24. Antioxidants (Basel). 2026 May 11. pii: 608. [Epub ahead of print]15(5):
    CSDE1 Associates with TOM20 and Mitochondrial Protein-Encoding mRNAs in Sensory Neurons.
    Hoyong Jin, Eunsu Jang, Eunhye Park, Ju Yeon Lee, Ju Hwan Song, Yongcheol Cho.
      Mitochondrial proteostasis in neurons relies on the coordinated expression, targeting, and import of a predominantly nuclear-encoded proteome to meet high metabolic demands. Here, we identify the RNA-binding protein cold shock domain containing E1 (CSDE1) as a TOM20-associated factor linked to mitochondrial protein-encoding mRNAs in sensory neurons. CSDE1 immunoprecipitation followed by sequencing from naïve dorsal root ganglion tissue revealed association with nuclear-encoded mitochondrial mRNAs enriched for inner membrane/matrix and oxidative phosphorylation pathways. A subset of CSDE1 localized to mitochondria and associated with the outer mitochondrial membrane import receptor TOM20 via its N-terminal region in an RNA-independent manner. In cultured sensory neurons, CSDE1 depletion reduced the mitochondrial-fraction abundance of representative nuclear-encoded electron transport chain mRNAs and decreased the abundance of selected mitochondrial proteins in the mitochondrial fraction. CSDE1 depletion reduced TMRM-positive mitochondrial puncta density along sensory neurites, without significantly increasing MitoSOX-detectable mitochondrial superoxide signals under either basal or oxidative challenge conditions. These findings identify CSDE1 as a TOM20-associated RNA-binding protein linked to mitochondrial protein-encoding transcripts in sensory neurons and support a model in which CSDE1 contributes to mitochondria-associated post-transcriptional regulation.
    Keywords:  CSDE1; OXPHOS; RNA-binding proteins; TOM20; mitochondrial mRNA; mitochondrial proteostasis; oxidative stress; protein import; sensory neurons; translation-import coupling
    DOI:  https://doi.org/10.3390/antiox15050608
  25. EMBO J. 2026 May 26.
    Transmembrane domain switching controls PINK1 import and fate in mitochondria.
    James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.
      Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.
    DOI:  https://doi.org/10.1038/s44318-026-00789-x
  26. Nat Commun. 2026 May 25.
    Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.
    I-Chi Lee, Po-Hsuan Lai, Chen-Wei Tsai, Yung-Chi Tu, Yu-Chen Huang, Wei-Chen Chen, Ming-Feng Tsai.
      The mitochondrial Ca2+ uniporter mediates mitochondrial Ca2+ uptake to regulate cellular bioenergetics, Ca2+ signaling and survival, but excessive activity triggers Ca2+ overload and tissue injury. Cells counter this threat by expressing MCUb, a paralog of the uniporter's pore-forming MCU subunit, to attenuate uniporter activity. Despite harboring the conserved Ca2+-coordinating DIME motif, MCUb paradoxically lacks conductance, a defining yet enigmatic feature underlying its uniporter-inhibitory role. Here, we demonstrate that MCUb's non-conductivity stems from its inability to bind EMRE, a subunit essential for uniporter function, and that its N-terminal domain (NTD) exerts autoinhibition. Reinstating EMRE binding and relieving NTD-mediated inhibition rebuild Ca2+ conductance in MCUb, reaching ~80% of MCU activity. Wild-type MCUb exhibits ~30% of the inhibitory capacity of a pore-disrupting E249A variant, indicating that MCUb is a modest, rather than potent, negative regulator. These findings reveal how MCU-MCUb paralog divergence endows the uniporter with regulatory plasticity to fine-tune mitochondrial Ca2+ homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-73711-y
  27. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 423-432
    Progressive Visual Recovery in a Patient with Leber Hereditary Optic Neuropathy Harboring a Rare Heteroplasmic (MT-ND5):m.13042G>A, p(Ala236Thr) Variant with Low Mutant Load: A Case Report.
    Tom Buelens, Audrey Meunier, Sara Seneca, François Willermain.
       Introduction: The majority of Caucasian patients with Leber hereditary optic neuropathy (LHON) harbor one of three primary pathogenic mitochondrial DNA (mtDNA) variants, which are usually present in homoplasmy in leukocytes. Most of the remaining cases have been linked to rare heteroplasmic pathogenic variants, which typically require a mutational load of more than 60% to result in phenotypic expression.
    Case Presentation: An 18-year-old Caucasian man presented with sudden visual loss in the left eye. Eye examination revealed hyperemic optic discs with retinal vascular tortuosity and subtle peripapillary telangiectasia, reminiscent of LHON, but initial mtDNA analysis was negative. Best corrected visual acuity (BCVA) continued to decrease despite systemic corticotherapy and subsequent treatment with plasma exchange. The patient then experienced visual loss in the fellow eye, with BCVA in both eyes deteriorating to "counting fingers". Subsequent screening of complete mtDNA by massive parallel sequencing of leukocyte DNA identified a variant NC_012920.1(MT-ND5):m.13042G>A, p.(Ala236Thr), in heteroplasmy, with a variant load of around 23.8%. Progressive visual recovery was observed in both eyes, resulting in BCVA of 20/29 in both eyes after 4 years of follow-up.
    Conclusion: In patients with a strong clinical suspicion of LHON, complete mitochondrial genome sequencing should be considered when initial testing, typically limited to the three primary mutations, is negative. Furthermore, the diagnosis of LHON should not be dismissed if "low" blood mutant loads are found, as important discrepancies of heteroplasmy levels between different tissues have been reported for variants located in the mitochondrial ND5 gene.
    Keywords:  Case report; Heteroplasmy; Leber hereditary optic neuropathy; MT-ND5; Optic neuropathy
    DOI:  https://doi.org/10.1159/000551571
  28. bioRxiv. 2026 May 17. pii: 2026.05.13.724988. [Epub ahead of print]
    MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
    Allison R Hanaford, Elizaveta A Olkhova, Ryan Liao, Ashley Ching, Alvin Huang, Erin Shien Hsieh, Kino Watanabe, Yihan Chen, Megan Wichman, Noelle Hwang, Katerina James, Michael Mulholland, Vivian Truong, Holly Coulson, Kerry Gibbins, Owen Cairns, Anastasia Dimitriou, Bernhard Kayser, Brittany M Johnson, Surojit Sarkar, Vandana Kalia, Simon C Johnson.
      Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the Ndufs4 (-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient Ndufs4 (-/-)/ MyD88 (-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of MyD88 in Ndufs4 (-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that Myd88 -mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient MyD88 (-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.
    DOI:  https://doi.org/10.64898/2026.05.13.724988
  29. Neural Regen Res. 2026 May 14.
    Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
    Yao Wang, Zitong Wang, Jie Zhao, Yimin Zhou, Dong Wei, Jingjing Zhao, Zhongqing Sun, Wen Jiang.
      Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.
    Keywords:  artificial cells; biomaterial-assisted transplantation; extracellular vesicles; mesenchymal stem cells; mitochondrial dysfunction; mitochondrial surface modification; mitochondrial transfer; mitochondrial transplantation; neurological disorders; tunneling nanotubes
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01156
  30. J Mol Neurosci. 2026 May 25. pii: 89. [Epub ahead of print]76(2):
    Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.
    Ahmed M Abdelaziz, Mustafa M Shokr, Mohamed K Fathy, Mohamed N Fawzy.
      Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca²⁺ signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca²⁺ overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.
    Keywords:  Alzheimer’s disease; Astrocyte; Bioenergetics; CD38; Calcium signaling; Miro1; Mitochondrial transfer; Neurodegeneration; Therapeutic target; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/s12031-026-02531-y
  31. Physiol Res. 2026 May 12. 75(2): 293-299
    Clinical and Genetic Characteristics of Mitochondrial DNA Depletion Syndrome Associated with SUCLG1 Variants in China.
    G-X Zhang, K-J Ji, Z-W Wang, N-N Wang.
      This study aimed to summarize the genetic variants and clinical characteristics of mitochondrial DNA depletion syndrome (MDS) associated with SUCLG1 mutations in children from China. A systematic review of cases reported in a Chinese literature database was conducted. Clinical data and genetic findings of children with MDS caused by SUCLG1 mutations were analyzed. A total of 13 cases from 9 articles were identified. The primary clinical features included hypotonia, psychomotor retardation, feeding difficulties, growth retardation, hearing impairment, and liver function impairment. Urine organic acid analysis demonstrated a mild increase in methylmalonic acid, while plasma concentrations of propionylcarnitine and/or butyrylcarnitine were elevated. Additionally, increased lactate and pyruvic acid levels were observed in both plasma and cerebrospinal fluid. Brain magnetic resonance imaging identified basal ganglion lesions and/or cerebral atrophy. A total of 14 SUCLG1 variants were identified: c.550G>A, c.751C>T, c.809A>C, c.961C>G, c.826-2A>G, c.713T>C, c.916G>T, c.619T>C, c.980dupT, c.40A>G, c.142C>T, c.601A>G, c.871G>C, and c.721_c.722delGA. Among these, the c.826-2A>G variation was the most frequently detected, present in 4 children, followed by c.550G>A. No significant correlation was found between genotype and phenotype. All 13 children were treated with vitamin B complex and coenzyme Q10. Among them, 2 died, while the remaining children exhibited clinical improvement. MDS associated with SUCLG1 mutations presents with nonspecific clinical manifestations and can affect multiple organ systems. Genetic testing is necessary for diagnosis, and no definitive treatment is currently available.
  32. Cell Rep. 2026 May 28. pii: S2211-1247(26)00541-3. [Epub ahead of print]45(6): 117463
    Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.
    Jing Yang, Yitian Ying, Huiwen Ye, Meiyi Chen, Xia Liu, Ganlu Wei, Jiayue She, Xinyu Lin, Muyang Wan, Xun Tan.
      Mitophagy and xenophagy, two selective autophagy pathways sharing common E3 ligases, have been proposed to intersect in host defense against invading pathogens. Here, we show that mitochondrial damage, but not mitophagy, is essential for triggering xenophagy via the inner mitochondrial membrane protein prohibitin 2 (PHB2). Upon bacteria-induced disruption of the outer mitochondrial membrane, PHB2 bridges mitochondria to bacteria by binding bacterial surface proteins, while concurrently interacting with either auto-ubiquitinated E3 ligase ARIH1 or Parkin, two well-characterized mitophagy-associated E3 ligases. This interaction positions polyubiquitin chains near PHB2-targeted bacteria to recruit selective autophagy receptors for initiating xenophagy, leading to the co-autophagic degradation of bacteria and mitochondria, a process unaffected by mitophagy inhibition. Our findings establish an uncovered mechanism of mitochondria-dependent antibacterial autophagy, positioning mitochondrial PHB2 as both a bacterial sensor and an E3 ligase scaffold, and unveiling a previously unidentified process governing the recruitment of mitophagy-associated E3 ligases to intracellular bacteria.
    Keywords:  ARIH1; CP: cell biology; CP: molecular biology; Listeria; PHB2; Salmonella; Staphylococcus aureus; mitochondria; mitophagy; parkin; ubiquitin; xenophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117463
  33. Cell Death Differ. 2026 May 27.
    Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
    Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.
      Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-026-01769-8
  34. Mol Genet Metab. 2026 May 18. pii: S1096-7192(26)00446-4. [Epub ahead of print]148(3): 110163
    Clinical and biochemical footprints of inherited cofactor disorders.
    Ivano Di Meo, Carlos R Ferreira, Thomas Opladen, Günter Schwarz, Valeria Tiranti, Clara van Karnebeek, Eva van Walree, Nenad Blau.
      Inherited metabolic disorders (IMDs) affecting cofactor biosynthesis, recycling, transport, or utilization cause characteristic combinations of biochemical abnormalities and multi-system clinical signs. Here, we describe footprints of 29 ICIMD-curated cofactor disorders: tetrahydrobiopterin (BH4; n = 6), molybdenum cofactor (MoCo; n = 5), vitamin B6 (pyridoxal-5'-phosphate; n = 6), niacin/nicotinamide adenine dinucleotide (NAD; n = 7), and pantothenate/coenzyme A (n = 5), by integrating disorder-specific biomarker panels with a structured symptom matrix. Across domains, heat map-based profiling highlights recurrent neurologic hot spots (seizures, movement disorders, neurodevelopmental impairment) while also revealing pathway-anchored signatures that can rapidly narrow the differential diagnosis, such as hyperphenylalaninemia with monoamine deficiency in several BH4 disorders, sulfite intoxication markers in classic MoCo deficiency, a B6-responsive neonatal epileptic encephalopathy pattern, an ocular-predominant footprint in nicotinamide mononucleotide adenylyltransferase 1 NMNAT1-related NAD disease, and cardio-metabolic failure in multiple CoA biosynthesis defects. We summarize pathomechanisms and current treatment options, emphasizing time-critical, treatable conditions (e.g., cyclic pyranopterin monophosphate (cPMP; fosdenopterin) replacement in MoCo-A; neurotransmitter and vitamin replacement strategies). This harmonized framework is intended to support early, pathway-informed testing and management in suspected cofactor-related IMDs. By aligning clinical-system patterns with biochemical 'anchors', this framework complements genomic diagnostics, guides surveillance, and prioritizes interventions in neonatal encephalopathy, childhood movement disorders, and recurrent acute metabolic crises. While newborn screening is well established for disorders of BH4 metabolism, screening for several other disorders, such as PDE-ALDH7A1 deficiency, is still in the pilot phase and available only in a few specialized centers. In contrast, genomic screening, with all its benefits and pitfalls, is emerging as a complement to classic newborn screening.
    Keywords:  Biomarkers; Coenzyme a; Cofactor; Inherited metabolic disorders; Molybdenum cofactor; NAD; Phenotype; Tetrahydrobiopterin; Vitamin B(6)
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110163
  35. Int J Mol Sci. 2026 May 15. pii: 4455. [Epub ahead of print]27(10):
    Aspartate-Glutamate Carrier 1 (SLC25A12) Deficiency: Malate-Aspartate Shuttle Failure, Neurodevelopmental Epileptic Encephalopathy, and Ketone-Based Metabolic Therapy.
    Manuela Murano, Giorgia Natalia Iaconisi, Magnus Monné, Amer Ahmed, Giuseppe Fiermonte, Loredana Capobianco, Vincenza Dolce.
      Aspartate-glutamate carrier 1 (AGC1) deficiency is a rare neurometabolic disorder caused by biallelic pathogenic variants in SLC25A12. Clinically, it is characterized by early-onset developmental and epileptic encephalopathy, often associated with hypomyelination and reduced brain N-acetylaspartate. AGC1 loss reduces malate-aspartate shuttle flux, limiting cytosolic NAD+ regeneration and impairing neuronal redox coupling, ATP supply, and aspartate-dependent biosynthesis during brain development. We integrate human genetics with mechanistic evidence from mammalian, Drosophila melanogaster, and Saccharomyces cerevisiae models to describe conserved transport principles and species-specific regulation underlying selective central nervous system vulnerability. We review the management of AGC1 deficiency, focusing on ketogenic therapy. Published reports show reproducible seizure reduction and, in some patients, improved myelination and N-acetylaspartate. However, these responses are heterogeneous and appear to depend on the timing, duration, and stability of ketosis. Preclinical evidence suggests that β-hydroxybutyrate may contribute to metabolic support in AGC1 deficiency. Prospective studies should test disease modification using standardized endpoints plus MRI/1H-MRS and ketosis measures.
    Keywords:  N-acetylaspartate (NAA); SLC25A12; aspartate/glutamate carrier 1 (AGC1); epilepsy; ketogenic diet; myelination
    DOI:  https://doi.org/10.3390/ijms27104455
  36. bioRxiv. 2026 May 15. pii: 2026.05.13.724793. [Epub ahead of print]
    A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.
    Sean McCracken, Minglei Zhao, Kyler Squirrell, Christopher Zhao, Saman Behboodi Tanourlouee, Michelle Aum, Philip R Williams.
      Retinal ganglion cells (RGCs) degenerate in optic neuropathies like glaucoma and traumatic optic nerve injury leading to irreversible vision loss. Higher levels of homeostatic Ca 2+ and canonical Ca 2+ regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca 2+ homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca 2+ levels (mito-Ca 2+ ). We find that mito-Ca 2+ is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca 2+ levels. Mitochondrial dysfunction was observed where mito-Ca 2+ was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca 2+ in surviving RGCs by altering mito-Ca 2+ levels and Ca 2+ transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca 2+ increased survival to ONC. We then manipulated mito-Ca 2+ permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca 2+ to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca 2+ and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca 2+ levels.
    DOI:  https://doi.org/10.64898/2026.05.13.724793
  37. FEBS Lett. 2026 May 23.
    The pyruvate generator is a common phenomenon in mitochondria from different rat and mouse brain regions.
    Grazyna Debska-Vielhaber, Niki Karavasili, Matthias Kunz, Zemfira Gizatullina, Timur Gainutdinov, Stefan Vielhaber, Wolfram S Kunz, Frank N Gellerich.
      The finding of the pyruvate generator ('mitochondrial gas pedal') arose from the observation that cytosolic Ca2+ accelerates glutamate-driven respiration. Here, we show that glutamate respiration of isolated rat brainstem mitochondria appears to be insensitive to extra-mitochondrial Ca2 +. This raises the question: Do these mitochondria lack a pyruvate generator, or is its detection masked? By reconstituting the complete malate-aspartate shuttle (MAS), we demonstrate that brainstem mitochondria possess a pyruvate generator, just like mitochondria from other brain regions. Direct measurement, however, is hindered by the high rate of Ca2+-insensitive glutamate utilization by glial mitochondria. We therefore conclude that the pyruvate generator is a universal mechanism in all tissues that contain a functional MAS and pyruvate-generating enzymes.
    Keywords:  extra‐mitochondrial calcium; glutamate respiration; malate–aspartate shuttle; oxidative phosphorylation; rat brain mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.70370
  38. J Lipid Res. 2026 May 22. pii: S0022-2275(26)00081-7. [Epub ahead of print] 101055
    Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
    Meagan S Kingren, Daniel G Sadler, Elijah Bolin, Izak Harville, James Sikes, Renny Lan, Elisabet Børsheim, Craig Porter.
       BACKGROUND: Carnitine plays an obligatory role in energetics owing to its role in the translocation of long-chain fatty acids into the mitochondrion for oxidation. Here, we determined the metabolic and behavioral consequences of systemic carnitine deficiency (SCD) in mice.
    METHODS: Female C57BL/6J mice were randomized to receive normal drinking water (control, n = 8) or drinking water supplemented with mildronate 4g.L-1 (mildronate, n = 8) for 21 days. Body composition was assessed at baseline and post treatment. Metabolic and behavioral phenotyping was performed continuously over 72 hours following 14 days of control or mildronate treatment. Stable isotope were used to assess whole-body substrate oxidation. Carnitine subfractions were quantified in skeletal muscle and liver, as was mitochondrial respiratory function. Liver and muscle samples also underwent proteomic analysis.
    RESULTS: Mildronate treatment depleted total carnitine in muscle and liver by ∼97% (P < 0.001) and ∼90% (P < 0.001), respectively. Carnitine depletion was accompanied by lower total energy expenditure (P = 0.01), attributable to lower voluntary wheel running (P = 0.01). Oxidation rates of palmitate (P < 0.01) but not octanoate were lower whereas rates of glucose oxidation were greater in carnitine depleted mice (P < 0.01). Mitochondrial respiratory capacity was unaltered by carnitine deficiency. Carnitine deficiency remodeled muscle and liver proteomes to support lipid oxidation and energy production.
    Keywords:  Carnitine; Energetics; Fat oxidation; Mildronate; Mitochondria; Skeletal muscle; Stable Isotopes; glucose oxidation
    DOI:  https://doi.org/10.1016/j.jlr.2026.101055
  39. Nat Commun. 2026 May 26.
    Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
    Kritarth Singh, Hormos Salimi Dafsari, Olivia Gillham, Haoyu Chi, Ivet Mandzhukova, Ioanna Kourouzidou, Preethi Sheshadri, Chih-Yao Chung, Valeria Pingitore, Fleur Vansenne, David L Selwood, Diana Pendin, Gyorgy Szabadkai, Manolis Fanto, Heinz Jungbluth, Michael R Duchen.
      The autophagy-tethering factor ectopic P-granule 5 autophagy protein (EPG5) plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 causes a rare devastating multisystem disorder known as Vici syndrome, which features neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are only partially understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we find that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological cytosolic Ca2+ transients result in unexpected mitochondrial Ca2+ overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca2+ signals cause mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we identify a pathophysiological cascade driving disease progression associated with EPG5 deficiency, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-73538-7
  40. bioRxiv. 2026 May 11. pii: 2026.05.07.723579. [Epub ahead of print]
    Alternative organelle targeting of OPA1 mediates fatty acid release from lipid droplets.
    Xiao Li, Dennis Voronin, Rikshita Bhattacharyya, Jonathon Klein, MaryEllen Haas, Woo Jung Cho, Camenzind G Robinson, Robert E Throm, Gang Wu, Chang Li, Yadav Sapkota, Natalie M Niemi, Shondra M Pruett-Miller, Joseph T Opferman, Chi-Lun Chang.
      Mitochondria and lipid droplets (LDs) are functionally coupled to coordinate fatty acid utilization and storage. However, a comprehensive understanding of mitochondria-LD alliances remains elusive. We have identified a previously unrecognized role for optical atrophy 1 (OPA1), a mitochondrial fusion factor, in the regulation of fatty acid release from LDs. We demonstrated that OPA1's exon 4 adapts an amphipathic helix to target OPA1 to LDs. OPA1 localized to LDs promote fatty acid release by facilitating the recruitment of lipases to LDs. In addition, OPA1's residence on LDs competes with its mitochondrial entry, influencing mitochondria fusion and connectivity. Furthermore, the S158N polymorphism within OPA1's exon 4 exhibiting attenuated fatty acid release from LDs is associated with changes in metabolic traits in pediatric cancer survivors. Altogether, our findings reveal that OPA1 actively mediates fatty acid release from LDs and provide a mechanistic link between OPA1 and human metabolism.
    DOI:  https://doi.org/10.64898/2026.05.07.723579
  41. NPJ Aging. 2026 May 26.
    Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging.
    Beatriz Escobar-Doncel, Xiaoyi Zhang, Åsne Ljøstad, Mario Fernández de la Puebla, Shreyas Balachandra Rao, Synnøve Algrøy Fjeldstad, Maja Tvedt Dahle, Mahmood Amiry-Moghaddam, Magnar Bjørås, Evandro Fei Fang, Wannan Tang.
      Mitochondrial homeostasis is majorly maintained through mitochondrial autophagy (mitophagy). Recent research highlights the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving male mice across two age groups, including 2-3-month-old (early-aged) and 18-20-month-old (old-aged) mice. We show reduced mitophagy in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons at the same age, in both age groups. Pharmacological augmentation of NAD+, a pivotal metabolite that induces mitophagy but normally declines in the aging brain, increased cellular mitophagy in both neurons and astrocytes in old-aged male mice at the dose and method of administration tested. Collectively, our data support an age-dependent reduction of mitophagy in neurons and astrocytes, at least in mouse somatosensory cortex, while NAD+ repletion offsets such reduction.
    DOI:  https://doi.org/10.1038/s41514-026-00414-5
  42. Genet Med. 2026 May 27. pii: S1098-3600(26)00930-5. [Epub ahead of print] 102612
    The Evidence Aggregator: AI reasoning applied to rare disease diagnostics.
    Hope Twede, Lynn Pais, Samantha Bryen, Emily O'Heir, Greg Smith, Ron Paulsen, Christina A Austin-Tse, Alex Bloemendal, Cas Simons, Amanda K Hall, Scott Saponas, Miah Wander, Daniel G MacArthur, Heidi L Rehm, Ashley Mae Conard.
       PURPOSE: Variant assessment of rare disease diagnostics depends on using domain knowledge in the time-intensive process of retrieving, reviewing, and synthesizing clinical and technical information.
    METHODS: To address these challenges, we developed the Evidence Aggregator (EvAgg), an open-source, generative-AI-based tool designed to support rare disease diagnosis that systematically extracts relevant information from the scientific literature for any human gene. Further, we constructed an expert-curated dataset and evaluated EvAgg's performance for the tasks of relevant paper selection, finding observations of human genetic variation within those papers, and extracting specific details about those observations (e.g. zygosity, variant inheritance, variant type, functional study. phenotype, and study type). A user study evaluated utility and user experience in rare disease case analysis.
    RESULTS: Our evaluation study revealed that EvAgg achieved 92% recall in identifying relevant papers, 96% recall in detecting instances of genetic variation within those papers, and ∼80% accuracy in extracting individual case and variant-level content. Our subsequent user study evaluated the utility and user experience in rare disease case analysis. We found that EvAgg reduced review time by 34% (p-value < 0.002) and increased the number of papers, variants, and cases evaluated per unit time.
    CONCLUSION: EvAgg provides a thorough and current summary of observed genetic variants and their associated clinical features, supporting the process of manual literature review and enabling rapid synthesis of evidence concerning gene-disease relationships. The demonstrated time savings have the potential to reduce diagnostic latency and increase solve rates for challenging rare disease cases.
    Keywords:  entity recognition and linking; evidence aggregation; generative AI; information retrieval; rare disease
    DOI:  https://doi.org/10.1016/j.gim.2026.102612
  43. Neurobiol Dis. 2026 May 25. pii: S0969-9961(26)00204-4. [Epub ahead of print]226 107459
    ROS-HIF1α-driven glycolytic reprogramming sustains ATP production in Huntington's disease.
    Ching-Wen Wu, Ching-Pang Chang, Dennis W Hwang, Yu-Wen Chen, Yan Hua Lee, Jian Jing Siew, Hui-Mei Chen, Yijuang Chern.
      Huntington's disease (HD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and impaired energy metabolism contribute to disease pathogenesis. Surprisingly, we find that ATP levels are not diminished but instead elevated in the striatum of R6/2 HD mice despite impaired TCA cycle intermediates and mitochondrial deficits. Integrative metabolomics, gene expression profiling, and pharmacological perturbation reveal that increased reactive oxygen species stabilize hypoxia-inducible factor-1α (HIF1α), driving enhanced glucose uptake and glycolytic flux. In vivo dynamic glucose-enhanced (DGE) MRI further supports altered glucose handling in the living R6/2 brain. Inhibition of either glycolysis or HIF1α abolishes ATP elevation, suggesting that HIF1α-dependent glycolysis compensates for mitochondrial impairment. Single-nucleus RNA sequencing further uncovers coordinated metabolic reprogramming across neuronal and glial populations. These findings reveal an oxidative stress-triggered metabolic switch that sustains ATP production in HD, redefining bioenergetic adaptation in neurodegenerative diseases.
    Keywords:  Energy metabolism; Glucose uptake; Glycolysis; HIF1α; Huntington's disease; Metabolic resilience; Oxidative stress
    DOI:  https://doi.org/10.1016/j.nbd.2026.107459
  44. EMBO J. 2026 May 27.
    Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
    Tanveer Ahmed, Hui Zhang, Ghulam M Mushraf, Yongzhang Pan, Zeyu Zhang, Zhenzhu Sun, Mengran Yin, Xueting Xu, Xinyu Wu, Yin Gao, Yan Li, Peizhi Li, Liang Ding, Qiang Zhang, Runxia Lin, Khair Ullah, Yinghua Huang, Bushra Mirza, Yifeng Huang, Abdul Sammad, Xiangqian Kong, Dajiang Qin, Miguel A Esteban, Lulu Wang, Baoming Qin.
      The electron transport chain (ETC) is essential for NAD+ regeneration and proliferation. While many cell types tolerate ETC inhibition when pyruvate or aspartate is supplied, pluripotent stem cells (PSCs) enter a reversible paused state even at abundant pyruvate levels. Here, we show that ETC inhibition triggers severe NADH reductive stress in mouse embryonic stem cells (mESCs), driven mainly by threonine dehydrogenase (TDH). TDH-derived NADH establishes a metabolic environment that disfavors cells with compromised mitochondrial function, maintains inhibition of pyruvate dehydrogenase (PDH), and is associated with increased genomic and epigenetic stability at the cellular population level. ETC inhibition similarly induces pausing in early mouse embryos and in human pluripotent stem cells (hPSCs). In hPSCs, combined inhibition of the one-carbon metabolism enzymes serine hydroxymethyltransferase (SHMT1/2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) effectively reduced reductive stress and rescued the paused phenotype. Together, these findings support a model in which limited mitochondrial redox adaptability represents a conserved metabolic feature of pluripotent stem cells and in which NADH reductive stress is associated with genomic and epigenetic stability.
    DOI:  https://doi.org/10.1038/s44318-026-00784-2
  45. Metabolites. 2026 May 18. pii: 338. [Epub ahead of print]16(5):
    Targeting NAD Homeostasis: Compartmentalization, Quantification, and Modulation.
    Marta Nobile, Veronica Fontanini, Simone Serrao, Johannes Burtscher, Francesca Re, Giuseppe Paglia.
      Nicotinamide adenine dinucleotide (NAD+) and its reduced form, NADH, are essential coenzymes that play central roles in cellular redox homeostasis, energy metabolism, DNA repair, and signaling. Cellular NAD+ levels are maintained by a dynamic balance between the de novo Preiss-Handler, and salvage synthesis pathways, and consumption by enzymes like sirtuins, PARPs, and CD38. Among these, the nicotinamide Phosphoribosyltransferase (NAMPT)-driven salvage pathway represents the predominant route of NAD+ synthesis. The specific regulation of NAD (NAD+ and NADH) levels across distinct subcellular compartments has emerged as a critical determinant of cellular function but it remains poorly understood. Dysregulation of NAD metabolism is a hallmark of aging and various pathologies, including cancer, neurodegenerative disorders, and metabolic diseases, making strategies to modulate NAD levels a promising therapeutic frontier. This review provides the first integrated overview of NAD concentrations across cellular compartments (cytosol, mitochondria, nucleus, endoplasmic reticulum, Golgi, peroxisomes, and the extracellular space) together with measurement and modulation strategies. We summarize current knowledge on NAD distribution within organelles, address key challenges in accurate quantification, and highlight established and emerging approaches for both global and compartment-specific analysis. Finally, we discuss therapeutic strategies, from NAD+ precursor supplementation to enzyme modulators and gene therapy, highlighting both their translational potential and current limitations in treating diverse diseases and prolonging life and health span.
    Keywords:  NAD metabolism; NAD modulation; NAD quantification; NAD+/NADH; metabolic regulation; subcellular compartmentalization
    DOI:  https://doi.org/10.3390/metabo16050338
  46. Angew Chem Int Ed Engl. 2026 May 28. e7935890
    Light-Activated Isolation of High-Quality Mitochondria for Therapeutic Transplantation.
    Hui Liu, Yuxin Jiao, Ting Zhang, Haiwei Wang, Yufei Xue, Jiayu Ding, Yang Ding, Meiling Wang, Weisen Zhang, Hua Bai, Bo Peng, Nicolas H Voelcker, Lin Li.
      Artificial mitochondrial transplantation (AMT) holds great promise for reprogramming cellular metabolism and restoring cell function. Its clinical translation, however, relies on access to mitochondria that are both of high purity and metabolically active, requirements that current isolation techniques struggle to meet. Conventional differential centrifugation (DC) method yields heterogeneous and low-activity mitochondria, whereas magnetic bead (MB)-based immuno-isolation leaves non-biodegradable beads permanently attached. Herein, we present a Light-Activated Mitochondrial Isolation (LAMI) platform comprising programmable mitochondria-targeting MBs and a photo-responsive release mechanism for the selective, efficient, and non-destructive extraction of high-quality mitochondria. LAMI employs magnetic nanoparticles decorated with a branched, modular probe architecture that supports systematic variation in mitochondria-targeting ligand type, ligand density, and optical tracking elements. Incorporation of a photo-cleavable linker allows on-demand, mild, and reagent-free release of captured mitochondria. Compared with DC method, LAMI produces mitochondria with markedly improved purity, structural integrity, and functionality. In an ischemia-reperfusion injury (IRI) model, LAMI-isolated mitochondria-based AMT exhibits superior therapeutic performance. Together, LAMI provides a non-destructive, efficient, and versatile mitochondrial isolation strategy that overcomes long-standing limitations of current methods, offering a robust platform to advance AMT and its future biomedical applications.
    Keywords:  ischemia‐reperfusion injury; mitochondrial isolation; mitochondrial transplantation; multifunctional modular design; photo‐responsive release
    DOI:  https://doi.org/10.1002/anie.7935890
  47. Neurol Genet. 2026 Jun;12(3): e200394
    Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    Gianpaolo Cicala, Elisa Rolleri, Beatrice Berti, Marco Luigetti, Nicola Forcina, Marianna Villa, Anna Capasso, Chiara Arpaia, Martina Malaspina, Fabiana Fattori, Luca Bosco, Guido Primiano, Antonio Novelli, Teresa Rizza, Enrico Bertini, Marika Pane, Eugenio Mercuri.
       Objectives: Variants in COA7 (cytochrome c oxidase assembly factor 7) are a rare cause of mitochondrial disease, with limited clinical descriptions and phenotypic variability. We describe 2 siblings carrying compound heterozygous COA7 variants, one of which (c.457C>T; p.Leu153Phe) is novel. Both presented with early-onset, slowly progressive axonal sensorimotor neuropathy, with differences in severity and associated features.
    Methods: Patients were identified based on clinical presentation and evaluated through longitudinal neurologic, neurophysiologic, genetic, biochemical, and neuroimaging assessments.
    Results: The elder brother developed symptoms at age 12, including muscle cramps, tremors, and falls, whereas the sister showed motor impairment with difficulty walking and running from age 5, along with more prominent cerebellar involvement. Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother. Nerve conduction studies demonstrated axonal sensorimotor polyneuropathy. Genetic analysis identified 2 compound heterozygous COA7 variants. Skin biopsy revealed reduced mitochondrial complex IV activity. Brain MRI findings were unremarkable in both siblings.
    Discussion: These cases expand the clinical spectrum of COA7-related disorders and illustrate the potential for intrafamilial phenotypic variability. The identification of a novel variant and extended clinical follow-up provide further insight into the features associated with COA7 variants.
    DOI:  https://doi.org/10.1212/NXG.0000000000200394
  48. Antioxid Redox Signal. 2026 May 27. 15230864261452350
    Platelet Mitochondria: A Promising Target for Antiplatelet Therapy.
    Yan-Zhu Yao, Tong Yin, Yong-Ming Yao.
       SIGNIFICANCE: Platelet mitochondria drive platelet activation and thrombosis by fueling energy demands via metabolic reprogramming, regulating calcium-mediated procoagulant signaling, and maintaining functional integrity through quality control mechanisms. Current antiplatelet agents, including P2Y12 antagonists, cyclooxygenase-1 inhibitors, glycoprotein IIb/IIIa blockers, and protease-activated receptor-1 antagonists, effectively prevent thrombosis but increase bleeding risk, underscoring the need for metabolism-targeting strategies.
    RECENT ADVANCES: Here, we summarize key platelet mitochondrial mechanisms driving platelet activation: metabolic reprogramming through oxidative phosphorylation (OXPHOS)-to-glycolysis shifts, calcium flux mediated by the mitochondrial calcium uniporter controlling coagulation, quality control through dynamics and mitophagy, and mitochondrial genome (mtDNA) regulation linked to relevant diseases.
    CRITICAL ISSUES: The variable role of OXPHOS in thrombosis remains incompletely understood. Metabolic flexibility complicates therapeutic intervention, while the cytotoxic effects of mitochondrial modulators and technical limitations in the quantification of circulating mtDNA present significant translational challenges.
    FUTURE DIRECTIONS: Development of therapies based on mitochondria-targeted antioxidants and metabolic enzyme modulators is proposed as a promising antiplatelet strategy. Transplantation of platelet-derived mitochondria and standardized detection of mtDNA warrant further exploration for thrombotic diseases. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  antiplatelet targets; platelet activation; platelet mitochondria
    DOI:  https://doi.org/10.1177/15230864261452350
  49. Nat Neurosci. 2026 May 26.
    Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.
    Chensi Liang, Yulan Zhou, Kai Zhuang, Shuzhong Wang, Li Zhong, Dan Can, Aiyu Lei, Huifang Li, Jie Zhang, Lige Leng.
      Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.
    DOI:  https://doi.org/10.1038/s41593-026-02317-w
  50. Nature. 2026 May 27.
    Mechanism of age-related accumulation of mtDNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Masahiro Kanai, Md Mesbah Uddin, Wenhan Lu, M Austin Argentieri, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
    DOI:  https://doi.org/10.1038/s41586-026-10569-6
  51. Nucleic Acids Res. 2026 May 20. pii: gkag513. [Epub ahead of print]54(10):
    Mitochondrial genetic variation across tissues of the human body.
    Nathaniel Fisher, Liying Xue, Karan K Smith, Brian Tao, Jason A Cunha, Scott Ladenheim, Jesse D Moreira-Bouchard, Zachary J Milstone, Anna Zhebrun, Xiaoling Zhang, Gyungah R Jun, Thor D Stein, Ting Fang Alvin Ang, Lindsay A Farrer, Melissa G Farb, Robert F Padera, Emelia J Benjamin, Daniel Levy, Deepa M Gopal, R Stefan Isaac, Marc E Lenburg, Seung Hoan Choi, Jessica L Fetterman.
      Each mitochondrion contains 2-10 copies of the mitochondrial genome. Multiple mitochondria in a cell allow for mitochondrial genomes carrying different variants to co-exist within a cell or tissue, termed heteroplasmy. The extent to which mitochondrial genetic variation differs across tissues of the human body and the origins of heteroplasmic variants is largely unknown. Using next-generation sequencing of 47 paired tissues from 947 donors in the Genotype-Tissue Expression dataset, we found that 39% of unique mitochondrial DNA variants identified were present in one tissue (tissue-specific) and 7% of unique variants were found in several but not all tissues of a donor. Tissue-specific variants were more likely to be transversions, nonsynonymous, deleterious, and present at lower variant allele fractions compared to variants shared across all tissues within a donor. Tissues primarily composed of proliferative cell types had the most tissue-specific variants, while highly energetic tissues had the least. The number of tissue-specific variants was associated with donor age for the tissues with the most tissue-specific variants. We determined that most of the heteroplasmic variants likely arise de novo after tissue differentiation. Our study suggests that mitochondrial DNA variants arise throughout an individual's lifetime in a tissue-dependent manner, which may have disease implications.
    DOI:  https://doi.org/10.1093/nar/gkag513
  52. Antioxid Redox Signal. 2026 May 28. 15230864261455714
    Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.
    Xiaorong Wang, Yuxin Li, Jinhua Tan, Xiaona Sun, Qidi Zhou, Rui Xu, Xiaoqi Song, Yu Cui, Zhaolong Zhang.
       AIMS: Cerebral ischemia-reperfusion (I/R) injury is a leading cause of neurological disability and is characterized by mitochondrial dysfunction and oxidative stress. Although depletion of nicotinamide adenine dinucleotide (NAD+) is a hallmark of ischemic injury, therapeutic strategies aimed at NAD+ replenishment have shown limited efficacy. Whether impaired mitochondrial NAD+ import contributes to neuronal vulnerability after I/R remains poorly understood.
    RESULTS: We found that cerebral I/R disrupts the balance of NAD+ distribution between the cytoplasm and mitochondria in the cortex due to upregulated expression of SLC25A51. Augmenting SLC25A51 expression restored mitochondrial NAD+ pools, improved mitochondrial respiratory function, reduced oxidative lipid damage, and attenuated neuronal injury. In contrast, SLC25A51 deficiency exacerbated mitochondrial dysfunction and heightened susceptibility to I/R stress. These effects occurred independently of global NAD+ biosynthesis, indicating that mitochondrial NAD+ transport rather than NAD+ availability per se is a critical determinant of neuronal survival.
    INNOVATION: This study reveals the subcellular distribution change of NAD+-mediated by SLC25A51 and its neuroprotective effects via modulating mitochondrial function after cerebral I/R injury.
    CONCLUSION: This study identifies defective mitochondrial NAD+ import as a previously underrecognized mechanism of cerebral I/R injury. By establishing SLC25A51-dependent NAD+ trafficking as a key regulator of mitochondrial redox balance and neuronal resilience, our findings shift the therapeutic paradigm from NAD+ supplementation to restoration of subcellular NAD+ distribution, highlighting mitochondrial NAD+ transport as a promising target for ischemic brain injury. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  NAD+; SLC25A51; ischemic-reperfusion injury; mitochondria; neurons; oxidative stress
    DOI:  https://doi.org/10.1177/15230864261455714
  53. Life Sci. 2026 May 22. pii: S0024-3205(26)00288-2. [Epub ahead of print]400 124479
    Intramuscular mitochondria transplantation ameliorates paclitaxel-induced peripheral neuropathy by restoring neuronal mitochondrial homeostasis and function.
    Sheng-Hua Wu, Ying-Chun Wang, Ching-Hsiang Ku, Shih-Ming Yang, Chen-Fuh Lam, Ming-Hong Tai, Shu-Hung Huang.
       AIMS: Paclitaxel-induced peripheral neuropathy (PIPN) is a significant, dose-limiting side effect of chemotherapy characterized by neuronal dysfunction stemming from mitochondrial damage. This study investigates the therapeutic potential of mitochondria transplantation for mitigating PIPN.
    MATERIALS AND METHODS: PIPN was induced in rats via intraperitoneal paclitaxel injections (2 mg/kg, four doses). Allogeneic mitochondria from donor soleus muscles were injected into the vastus lateralis muscle of recipient rats. Sensory and motor functions were evaluated using behavioral tests. Mitochondrial biodistribution was tracked utilizing MitoTracker™ dye and lentiviral Mito-GFP labeling. Mechanistic evaluations included mitochondrial complex I-V activity assays, biogenesis marker quantification (TFAM, Nrf2), and histological assessments of sciatic nerve myelination, intraepidermal nerve fibers (IENFs), and neuromuscular junctions (NMJs).
    KEY FINDINGS: Exogenous mitochondria successfully underwent retrograde transport from the muscle into the sciatic nerve and spinal cord, significantly alleviating paclitaxel-induced neuropathic pain and motor impairments. Mechanistically, transplantation restored mitochondrial complex activities and biogenesis markers in the peripheral nervous system, improved neuronal redox balance, and reduced microglial infiltration. Furthermore, mitochondrial transplantation promoted sciatic nerve remyelination and normalized target-tissue innervation by rescuing IENF and NMJ densities.
    SIGNIFICANCE: Intramuscular mitochondria transplantation effectively counteracts paclitaxel-induced mitochondrial damage, suppresses neuroinflammation, and restores neuronal homeostasis, offering a promising therapeutic strategy for managing PIPN.
    Keywords:  Chemotherapy-induced peripheral neuropathy; Mitochondria transplantation; Paclitaxel
    DOI:  https://doi.org/10.1016/j.lfs.2026.124479
  54. Nat Commun. 2026 May 25.
    Dehydration promotes intracellular lipid synthesis and accumulation.
    Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don A Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter K Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.
      Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.
    DOI:  https://doi.org/10.1038/s41467-026-73534-x
  55. Autophagy. 2026 May 24. 1-19
    NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
    Jie Cui, Shifeng Ren, Bingjie Wang, Nan Zhang, Shanshan Zhu, Yajun Zhang, Xiangqing Qi, Weixue Meng, Liwei Shao, Shan Gao, Lijie Xing, Zengjun Li, Xiaodong Mu.
      The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.
    Keywords:  Cellular senescence; cytoskeleton; innate immunity; mechanical stress; mitochondrial damage; mitophagy dysfunction
    DOI:  https://doi.org/10.1080/15548627.2026.2677181
  56. FEBS J. 2026 May 27.
    Sestrin regulates cellular homeostasis through modulating mitochondrial function.
    Alexander Haidurov, Andrei Budanov.
      For years, the function of Sestrin proteins has been assigned to antioxidant protection and regulation of mTOR complexes 1 and 2. However, recent data demonstrate that Sestrins have a new role in the regulation of mitochondrial functions through incompletely understood mechanisms. These include Sestrin involvement in the control of mitochondrial biogenesis, respiration and mitophagy. Machado et al. describe a key role of Sestrin2 in the regulation of mitochondrial function in myoblast C2C12 cells. Sestrin2 supports mitochondrial biogenesis and respiration through control of mitochondrial protein expression and tuning up mitophagy. These discoveries expand our understanding of the potential role of Sestrins in supporting muscle function through mitochondrial signalling.
    Keywords:  ageing; mTOR; mitochondria; myoblasts; sestrin
    DOI:  https://doi.org/10.1111/febs.70604
  57. Transl Stroke Res. 2026 May 28. pii: 60. [Epub ahead of print]17(3):
    Intercellular Mitochondrial Transfer as Endogenous Neuroprotection: Mechanisms and Therapeutic Implications in Ischemic Stroke.
    Yun-Fan Zhang, Di Zhao, Jing-Jing Wei, Xiao Liang, Liu-Ding Wang, Jia-Wei Wang, Li-Bin Jiang, Ju-Ying Chen, Yun-Ling Zhang, Yue Liu.
      Ischemic stroke remains a leading cause of mortality and disability worldwide. Current reperfusion therapies are limited by narrow therapeutic time windows and the risk of secondary reperfusion injury, underscoring the urgent need for novel translatable neuroprotective targets. Mitochondrial dysfunction serves as a central hub in the ischemic cascade, contributing to energy failure, oxidative stress, calcium dysregulation, and various forms of programmed cell death. Recently, intercellular mitochondrial transfer has emerged as a crucial form of metabolic communication within the neurovascular unit (NVU). In the context of ischemia-reperfusion, donor cells can transfer functional mitochondria to compromised cells, facilitating metabolic rescue and remodeling the local microenvironment. Extensive in vivo and in vitro studies have shown that astrocytes, mesenchymal stem cells (MSCs), and pericytes can deliver mitochondria to neurons or brain microvascular endothelial cells (BMECs) through mechanisms such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), and gap junctions. This transfer helps maintain blood-brain barrier (BBB) integrity and promotes neurological recovery. The process is finely regulated by inflammatory signaling, metabolic reprogramming, and epigenetic modulation, all of which influence the directionality and functional outcomes of the transfer. As a result, pharmacotherapies, non-pharmacological interventions, and direct mitochondrial transplantation have demonstrated considerable neuroprotective potential in experimental models and early-stage clinical research. However, challenges related to transfer selectivity, the durability of effects, delivery efficiency, and immune safety still hinder clinical translation. Future efforts must prioritize elucidating the underlying mechanisms, standardizing protocols, and developing precise stratification strategies to advance mitochondrial transfer-based interventions from proof-of-concept to a controllable and evaluable therapeutic option for stroke treatment.
    Keywords:  Intercellular Mitochondrial Transfer; Ischemic Stroke; Mitochondrial Dysfunction; Mitochondrial Transplantation; Neuroprotection; Neurovascular Unit; Tunneling Nanotubes
    DOI:  https://doi.org/10.1007/s12975-026-01446-5
  58. Genes Genomics. 2026 May 26.
    Redefining ocular safety assessment: retinal organoids as platforms for predicting human ocular toxicology.
    Yung Hyun Choi, Sun-Hee Leem.
      Despite the substantial progress in drug discovery and precision therapeutics, the predictive power of current ocular safety assessments remains limited owing to the lack of human experimental models. Conventional two-dimensional cell cultures lack the complex laminar organization, multicellular interactions, and functional electrophysiological properties of the human retina. Additionally, animal models frequently exhibit species-specific differences in retinal development, metabolism, and stress responses that hinder translational accuracy. Human induced pluripotent stem cell-derived retinal organoids are transformative microphysiological platforms that recapitulate key aspects of the human retinal architecture, including photoreceptor differentiation, synaptic connectivity, and neuronal functionality within a three-dimensional and human-derived context. In addition to structural resemblance, these systems enable multidimensional and mechanism-related toxicity assessments of oxidative stress, mitochondrial dysfunction, lysosomal impairment, ferroptotic signaling, synaptic dysregulation, and adaptive cytoprotective pathways. Therefore, retinal organoids can be incorporated into quantitative and regulatory toxicological frameworks using concentration-response modeling, benchmark dose derivation, and adverse outcome pathway mapping. Notably, these models identify the reactive oxygen species-mitochondria-lysosome axis as a central vulnerability hub that mechanistically links diverse exposure modalities, including small-molecule drugs, biologics, gene therapies, and nanomaterials, to photoreceptor degeneration. Ongoing advances in maturation, vascular-like integration, microfluidic coupling, and interline reproducibility have further enhanced their translational value. Collectively, retinal organoids are redefining ocular safety assessments by shifting the paradigm from hazard identification to predictive, mechanism-based, and human toxicology.
    Keywords:  Mitochondrial dysfunction; Oxidative stress; Predictive toxicology; Quantitative risk assessment; Retinal organoids
    DOI:  https://doi.org/10.1007/s13258-026-01778-4
  59. Am J Pathol. 2026 May 28. pii: S0002-9440(26)00157-4. [Epub ahead of print]
    Histopathological findings and knowledge gaps in glaucomatous neurodegeneration.
    Flora Hui, Pete A Williams.
      Glaucoma is the leading cause of irreversible blindness globally, characterized by progressive retinal ganglion cell dysfunction and death resulting in remodeling of the optic nerve head and optic nerve degeneration. Whilst substantial progress has been made in understanding basic mechanisms of glaucomatous neurodegeneration in animal models, significant knowledge gaps remain regarding the histopathological substrate of this disease in human tissue. This review synthesizes current understanding of established histopathological findings in glaucomatous eyes, including retinal ganglion cell degeneration, synaptic pathology, axonal transport dysfunction, lamina cribrosa remodeling, glial cell responses, extracellular matrix changes, and structure-function relationships. We end by identifying major gaps in our knowledge regarding cellular heterogeneity in retinal ganglion cell vulnerability, circuit-level retinal remodeling, the temporal sequence of pathological events, the functional consequences of astrocyte and microglial activation, and the mechanisms linking structural pathology to functional vision loss. Addressing these gaps requires integrated approaches combining classical histology with modern molecular profiling, greater access to human post-mortem tissue with rigorous disease staging, and systematic investigation of retinal ganglion cell subtype-specific pathology in the human retina and optic nerve.
    Keywords:  axon degeneration; glaucoma; gliosis; histopathology; knowledge gaps; lamina cribrosa; neurodegeneration; neuropathology; optic nerve; retinal ganglion cells
    DOI:  https://doi.org/10.1016/j.ajpath.2026.04.020
  60. J Med Chem. 2026 May 23.
    Mitigating Excessive Mitochondrial Fission Through the Development of a Selective Macrocyclic Inhibitor Targeting Fis1/Mid51 Signaling.
    Mulate Zerihun, Sayan Chakraborty, Ayetenew Abita, Suchismita Dey, Ivan Lopez, Rani Wainer Shlomo, Mahesh Kumar Cinthakunta Sridhar, Liron Davis, Offir Ertracht, Shaul Atar, Deborah E Shalev, Marta De Zotti, Bereketeab Haileselassie, Nir Qvit.
      Mitochondrial fission protein 1 (Fis1) and mitochondrial dynamics protein of 51 kDa (Mid51) regulate stress-induced mitochondrial fragmentation implicated in cardiovascular disease. Using homologous sequence analysis and structure-guided design, we identified a linear peptide inhibitor (CVP-240) targeting the Fis1/Mid51 protein-protein interaction (PPI) and optimized it into a macrocyclic derivative (CVP-764). Both compounds bind Mid51 with high affinity, selectively disrupt Fis1/Mid51 signaling over Drp1-dependent interactions, and exhibit nanomolar binding in fluorescence polarization assays using FAM-conjugated tracers. In H9c2 cardiomyocytes, CVP-240 and CVP-764 preserve mitochondrial membrane potential, reduce reactive oxygen species, maintain mitochondrial network integrity, and improve cell viability under stress. Macrocyclization enhances proteolytic and serum stability and confers intrinsic cell permeability without the need for a cell-penetrating sequence. In silico ADMET profiling and preliminary in vivo toxicity studies support a favorable safety profile, establishing CVP-764 as a promising lead for targeting pathological mitochondrial fission.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00333
  61. iScience. 2026 Jun 19. 29(6): 115891
    Plasma membrane mediated GLUT10 mitochondrial targeting regulates intracellular ascorbic acid homeostasis.
    Anu Chirackal Jose, Yu-Wei Syu, Hao-Wen Lai, Ming-Yuan Tsai, Yi-Fan Jiang, Shao-Chun Hsu, Po-Yen Lin, Wan-Chen Huang, Wei-Chen Chu, Chi-Yu Fu, Yi-Ching Lee.
      Intracellular ascorbic acid (AA) regulation is essential for connective tissue homeostasis; however, the precise mechanisms governing AA homeostasis during cellular stress remain poorly understood. Here, we identify an oxidative stress-induced glucose transporter 10 (GLUT10) intracellular trafficking mechanism that regulates AA homeostasis via a noncanonical route from the endoplasmic reticulum (ER) to the plasma membrane (PM) and ultimately to mitochondria. This mechanism bridges the traditionally considered spatially and mechanistically distinct pathways of endomembrane system trafficking and mitochondria targeting. Using live-cell imaging and complementary biochemical approaches, we demonstrate that oxidative stress drives this redistribution. Increased PM localization of GLUT10 enhances the uptake of dehydroascorbic acid (DHA), the oxidized form of AA, thereby sustaining intracellular AA levels. The disruption of this trafficking pathway impairs AA homeostasis. Our findings reveal previously unrecognized localization of GLUT10 at the PM and endosomes and uncover endomembrane-mitochondria communication that maintains intracellular AA homeostasis and supports adaptation to oxidative stress.
    Keywords:  biochemistry; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115891
  62. Res Sq. 2026 May 11. pii: rs.3.rs-9407058. [Epub ahead of print]
    Characterization of a new mitophagy reporter uncovers requirement of BNIP3 for hypoxia-induced mitophagy in Drosophila.
    Hubert Osei Acheampong, Emily Rozich, Ryan Insolera.
       BACKGROUND: Mitophagy is the cellular removal of unwanted mitochondria via the lysosome. Given the importance of this process to energy demanding tissues, mitophagy defects have been linked to various metabolic and neurodegenerative diseases. Mitophagy assessment tools are important for evaluating and quantifying mitophagy flux, which are useful in studying mitophagy pathways, mechanisms, and dysfunction. Mitophagy reporters are commonly used reagents to examine endpoint mitophagy flux. Following the generation of a new mitophagy reporter, mitoSRAI (mitochondrial Signal Retaining Autophagy Indicator), we introduced this reporter as a transgene into Drosophila melanogaster (Dm). We hypothesized that mitoSRAI will be capable of measuring mitophagic flux through microscopic visualization of the TOLLES:YPet fluorescence ratios, and biochemically through the relative persistence of TOLLES proteins in the lysosomes following YPet degradation.
    RESULTS: We found that when we express the mitoSRAI reporter in the Dm larval muscle wall and examine mitoSRAI flux by inducing mitophagy via hypoxia, we observe a significant increase in TOLLES only fluorescent signals and bands by confocal imaging and western blotting respectively. Complementarily, the readout of mitoSRAI is sensitive to conditions of mitophagy inhibition under hypoxia. To validate our results, we compared mitoSRAI to a similarly constructed reporter, matrix-QC, and found that mitoSRAI is less responsive to neuronal and fat body mitophagy flux manipulations.
    CONCLUSION: Overall, our work characterizes the strengths and weaknesses of the application of the mitoSRAI reporter in Dm. We demonstrate with the mitoSRAI reporter that BNIP3 is an important mediator for hypoxia-induced mitophagy in Dm.
    DOI:  https://doi.org/10.21203/rs.3.rs-9407058/v1
  63. Antioxidants (Basel). 2026 May 03. pii: 580. [Epub ahead of print]15(5):
    Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
    Dong-Bin Back, Gen Hamanaka, Ji-Hyun Park, Shin Ishikane, Masayoshi Tanaka, Takafumi Nakano, Yoshihiko Nakamura, Kazuhide Hayakawa.
      Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H2O2-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat-mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without the normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. The removal of mitochondrial surface-associated ribosomes or the inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. The restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress.
    Keywords:  MitoCoat; lipid modification; mRNA; mitochondria
    DOI:  https://doi.org/10.3390/antiox15050580
  64. Redox Biol. 2026 May 18. pii: S2213-2317(26)00224-7. [Epub ahead of print]94 104226
    Lactylation landscape of mitochondrial proteins in myocardial infarction.
    Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.
      Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently discovered lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we mapped the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocyte-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
    Keywords:  AZD3965; Lactate; Lactylation; MCT1; Mitochondria; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.redox.2026.104226
  65. Tissue Cell. 2026 May 22. pii: S0040-8166(26)00324-1. [Epub ahead of print]102 103631
    Mitochondrial transfer in sepsis: Dual role, mechanistic networks, and translational strategies.
    Yingyu Li, Yuhang Fan, Kangkai Wang, Nian Wang.
      Sepsis is a life-threatening clinical syndrome characterized by dysregulated host response, metabolic disturbance, and multiple organ dysfunction. Mitochondrial damage and bioenergetic failure are core pathological events driving sepsis progression. As a critical intercellular communication mechanism, mitochondrial transfer (MT) participates in mitochondrial quality control, energy homeostasis, and inflammatory regulation under septic stress. This review systematically summarizes the structural and functional mitochondrial injury in sepsis and endogenous quality control pathways. We focus on the four major MT routes, their crosstalk, and regulatory networks. The dual role of MT in sepsis is highlighted: functional MT supports tissue repair and organ protection, while damaged MT amplifies inflammation and exacerbates organ injury. We further outline current strategies to optimize MT-based therapy, including donor cell preconditioning, carrier engineering, and direct mitochondrial modification, as well as biosafety and translational challenges. This review provides an integrated theoretical framework and practical strategies for mitochondria-targeted interventions in sepsis.
    Keywords:  Mitochondrial quality control; Mitochondrial transfer; Mitochondrial transplantation; Sepsis
    DOI:  https://doi.org/10.1016/j.tice.2026.103631
  66. Curr Issues Mol Biol. 2026 May 01. pii: 472. [Epub ahead of print]48(5):
    Brucella Omp25c Modulates Host NAD+/NADH Homeostasis via Interaction with the Mitochondrial Complex I Assembly Factor Ndufaf2.
    Lina Wang, Lian Wu, Kexin Zhang, Rui Ma, Shurong Chen, Tong Ji, Min Zhou, Jiayi Xie, Lingli Zheng, Qingshan Bill Fu.
      Brucellosis, acting as a typical chronic zoonotic disease, is caused by the invasion of Brucella into the human body. Outer membrane protein 25 (Omp25), specifically localized on the Brucella membrane, is the main virulence factor of Brucella and participates in multiple links of the damage process. Omp25c, a porin protein of Brucella, is a paralog of Omp25 with high sequence identity. NADH dehydrogenase [ubiquinone] complex I assembly factor 2 (Ndufaf2) has a key function in cell energy metabolism, particularly in the formation and activity of the mitochondrial respiratory chain. Loss of Ndufaf2 results in oxidative stress and mitochondrial DNA (mtDNA) deletion. However, the functional relationship between Omp25c and Ndufaf2, the underlying mechanism of the proteins, remains unclear. In this work, we purified the Omp25c and Ndufaf2proteins. Our data revealed that Omp25c directly interacts with Ndufaf2, as determined using Biacore analysis. In addition, assays revealed that Ompa2c reshapes the host cell's redox environment by decreasing the oxidized nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratioand adenosine triphosphate (ATP) production, whereas Ndufaf2 exerts an opposing regulatory effect; Co-expression results further revealed an antagonistic relationship between the two during metabolic processes. These findings provide a new perspective for elucidating the mechanisms of mitochondrial functional regulation in Brucella-host interactions and lay the theoretical and experimental foundation for drug development targeting metabolic interventions to eliminate intracellular pathogens.
    Keywords:  NAD+/NADH; NADH dehydrogenase (ubiquinone) complex I assembly factor 2; brucellosis; outer membrane protein 25c
    DOI:  https://doi.org/10.3390/cimb48050472
  67. Nephrol Dial Transplant. 2026 May 28. pii: gfag092. [Epub ahead of print]
    Renal gluconeogenesis: a key metabolic hub in health and kidney disease.
    Sihem Sellami, Thomas Verissimo, Delal Dalga, Sophie de Seigneux.
      Gluconeogenesis, responsible for maintaining systemic glucose availability during fasting, has long been thought to be a process mainly performed by the liver. Over the past decades, physiological and molecular studies have established the kidney as a major site of endogenous glucose production. Renal gluconeogenesis occurs mainly in proximal tubular epithelial cells, where it integrates substrate utilization, hormonal signaling, and acid-base regulation to support systemic homeostasis. The kidney relies on distinct regulatory inputs and dynamically adapts gluconeogenic flux to nutritional state, metabolic acidosis, and inter-organ metabolite exchange. As a highly metabolically active organ, it sustains the important energetic demands and differentiated state of proximal tubular cells through a high mitochondrial density. Renal gluconeogenesis is tightly coupled to ammoniagenesis and tricarboxylic acid cycle dynamics in addition to its contribution to glucose homeostasis, thus being a key determinant of mitochondrial integrity. Increasing evidence indicates that disruption of this metabolic program is a consistent feature of acute and chronic kidney disease, where suppression of gluconeogenesis accompanies epithelial dedifferentiation, mitochondrial dysfunction, and fibrotic remodeling. In this review, we synthesize current knowledge on the regulation and function of renal gluconeogenesis and discuss its emerging role as a central determinant of mitochondrial integrity, tubular resilience, and kidney disease progression.
    Keywords:  ammoniagenesis; chronic kidney disease; gluconeogenesis; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/ndt/gfag092
  68. medRxiv. 2026 May 15. pii: 2026.05.13.26352722. [Epub ahead of print]
    A genome-wide deletion map in 125,730 individuals for novel rare disease gene and variant discovery.
    Anthony McGuigan, Alistair T Pagnamenta, Laura E Covill, Jacob Samson, Carme Camps, Yuyang Chen, Tanishi Moitra, Kartik Chundru, Emily O'Heir, Kirsten Allan, Gavin Arno, Alexander Broomfield, Martin Delatycki, Siying Lin, Michel Michaelides, Rocio Rius, Tony Roscioli, Cas Simons, Andrew Webster, Susan M White, Louise Wilson, Stephan J Sanders, Anne O'Donnell-Luria, Jamie M Ellingford, Jenny C Taylor, Nicola Whiffin.
      Structural variants (SVs) can disrupt gene function and contribute to pathogenesis of rare disorders. Here, we created a genome-wide knockout dataset across 125,730 individuals with genome sequencing data in the UK's National Genomic Research Library by leveraging the distinct read-depth signal associated with homozygous deletions. We curated 535,699 rare high-confidence homozygous deletion SVs, of which 48,735 were rare. These deletions collectively covered 213Mb or 6.92% of the human genome (4.58% of autosomal sequence), revealing substantial tolerance to complete sequence loss. From a subset of 58,022 individuals with rare disease, we identified 295 individuals with likely diagnostic homozygous deletions impacting protein-coding regions of known disease genes. A further 32 individuals had candidate non-coding SVs in or near to known disease genes, 19/32 (59.37%) of which disrupted 5'-UTR/promoter regions, revealing promoter deletion as an underappreciated cause of rare disorders. Finally, we identify 43 genes with no known rare-disease association but with exonic homozygous deletions in two or more individuals with consistent phenotypes. We describe in detail PDC (phosducin) in Leber Congenital Amaurosis, GCG (glucagon) for a syndromic neurodevelopmental disorder with gastrointestinal involvement, and ENTPD3 for intellectual disability with autism, as candidate novel disease-associated genes. Overall, we create a genome-wide map of homozygous deletions and demonstrate the power of this dataset for rare disease diagnosis and novel disease-gene discovery.
    DOI:  https://doi.org/10.64898/2026.05.13.26352722
  69. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2605194123
    Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
    Djamal Brahim Belhaouari, Anil Pant, Santiago Navarro-Forero, Fernando Cantu, Zhilong Yang.
      Induction of RNA degradation in infected cells is a strategy used by many viruses to promote efficient replication. Vaccinia virus, the prototype poxvirus and the vaccine platform for smallpox and mpox, encodes two decapping enzymes to accelerate mRNA and double-stranded RNA (dsRNA) degradation during infection, through functional coordination with host cell RNA exonuclease. Previous studies have largely focused on RNA degradation as a mechanism for regulating viral gene expression and evading innate immune sensing. Here, we show that impaired RNA degradation in vaccinia virus-infected cells, due to either depletion of viral decapping enzymes or cellular exonuclease, severely compromises mitochondrial respiration and integrity. We further demonstrated that accumulation of excess dsRNA and mRNA, including pseudouridine-modified RNAs, is sufficient to induce profound defects in mitochondrial respiration and integrity. Notably, this impairment occurs independently of interferon induction and dsRNA innate immune sensor Protein Kinase R. Moreover, excess RNA suppresses respiration in purified cell-free mitochondria and physically associates with mitochondria in cell-free and cellular contexts, supporting an immune-independent mechanism. Excess mRNA and dsRNA reduce mitochondrial membrane potential in both cells and purified mitochondria, indicating disruption of the proton gradient as the mechanism underlying impaired mitochondrial respiration and integrity. Together, these findings identify excess mRNA and dsRNA as perturbants of mitochondrial homeostasis in cells with dysfunctional RNA degradation during vaccinia virus infection, revealing a paradigm-shift concept linking RNA metabolism to mitochondrial function. The finding carries broad implications for understanding RNA and mitochondrial biology and RNA-based therapeutics and vaccines.
    Keywords:  RNA degradation; dsRNA; mRNA; mitochondrial respiration; poxvirus
    DOI:  https://doi.org/10.1073/pnas.2605194123
  70. BMC Biol. 2026 May 27.
    Mitochondria-ER contact sites (MERCS) in the cell cycle: molecular architecture and functional remodeling across cellular states.
    Eduardo Silva-Pavez, Bruno Torres-Gonzalez, Michelle Sotomayor, Benjamín Cartes-Saavedra, Dorian V Ziegler, Yessia Hidalgo-Fadic, Ulises Ahumada-Castro.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are nanoscopic, dynamic platforms integrating metabolism, signaling, and stress responses to regulate cell fate. These nanoscopic interfaces remodel continuously to meet the demands of proliferating, quiescent, and senescent cells. We synthesize evidence that MERCS actively coordinate local Ca2+ signaling, non-vesicular lipid transfer, and proteostasis to shape mitochondrial function and cellular homeostasis. We discuss how MERCS architecture changes across the cell cycle and during arrest, distinguishing adaptive from maladaptive remodeling, and consider therapeutic potential in aging and age-related disease.
    Keywords:  Calcium signaling; Cell-cycle regulation; Cellular senescence; Lipid transfer; Mitochondria–ER contact sites
    DOI:  https://doi.org/10.1186/s12915-026-02645-0
  71. Clin Transl Med. 2026 Jun;16(6): e70695
    Glutathione peroxidase 3 preserves hepatocyte mitochondrial quality control to enhance macrophage pro-regenerative phenotype during liver regeneration.
    Yuechen Wang, Jian Xu, Zeyu Zhu, Ye Zhang, Haoran Hu, Yiyun Gao, Yuting Tao, Feifan Yao, Suiqing Zhou, Weizhe Zhong, Zhuqing Rao, Haoming Zhou, Xuehao Wang.
       BACKGROUND: Precise regulation of mitochondrial function is critical for liver regeneration. However, the underlying regulatory mechanism remains elusive. Here, we aimed to investigate the role of hepatocellular glutathione peroxidase 3 (GPX3) in liver regeneration.
    METHODS: In a 70% partial hepatectomy (PH) mouse model, immunostaining and single-cell RNA sequencing revealed significant enrichment but down-regulation of mitochondrial oxidative phosphorylation pathways post-PH, along with up-regulated hypoxia-inducible factor 1a (HIF-1a) and GPX3 in hepatocytes. Single-cell analysis confirmed peak GPX3 expression in hepatocytes at day 2 post-PH. Hepatocyte-specific GPX3 knockout impaired mitochondrial function and delayed liver regeneration.
    RESULTS: Mechanistically, immunoprecipitation-mass spectrometry and MitoCarta3.0 analysis identified voltage-dependent anion channel 1 (VDAC1) as a direct GPX3-binding partner. GPX3 interacted with VDAC1 via its A2 domain (residues 75-150), suppressing VDAC1 oligomerisation to restore mitochondrial Ca2+ homeostasis and preserve mitochondrial quality control (MQC). Notably, GPX3 deficiency promoted mitochondrial DNA (mtDNA) release, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Persistent STING hyperactivation increased interferon production while suppressing hepatocyte growth factor release, further inhibiting regeneration. Critically, GPX3 overexpression enhanced liver regeneration in both PH and hepatic ischemia-reperfusion injury models, underscoring its central role across regenerative stressors.
    CONCLUSIONS: In conclusion, GPX3 promotes liver regeneration by inhibiting VDAC1 oligomerisation to stabilise mitochondrial Ca2+ dynamics and MQC, while preventing mtDNA-mediated functional and phenotypic alterations in macrophages, positioning it as a therapeutic target for liver regeneration.
    KEY POINTS: GPX3 directly binds VDAC1 via its A2 domain to suppress VDAC1 oligomerisation, restoring mitochondrial Ca2 + homeostasis and preserving mitochondrial quality control during liver regeneration. GPX3 deficiency promotes mtDNA release, hyperactivating the cGAS-STING pathway in macrophages and suppressing hepatocyte growth factor (HGF) release. GPX3 overexpression enhances liver regeneration in both partial hepatectomy and hepatic ischemia-reperfusion injury models, highlighting its therapeutic potential.
    Keywords:  cGAS‐STING; hepatocyte; liver regeneration; macrophage; mitochondrial quality control
    DOI:  https://doi.org/10.1002/ctm2.70695
  72. Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]
    Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
    Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.
      Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.
    Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
  73. Cells. 2026 May 21. pii: 947. [Epub ahead of print]15(10):
    The Use of Single-Cell Mitochondrial DNA SNP Combinations for Distinguishing Organ-Specific Cell Types.
    Shuai Wang, Xinyue Tu, Haozhe Zhu, Ce Gao, Jianan Gao, Jinsong Wei, Hui Shi, Jinrong Peng.
      Cell lineage relationship studies in developmental and regenerative biology have been greatly advanced using techniques such as fluorescent labeling driven by cell-type-specific promoters. Nevertheless, unbiased non-invasive tools for distinguishing cell lineages are inevitably desired. Mitochondrial DNA (mtDNA) exhibits wide-range single-nucleotide polymorphisms (SNPs) among individual cells. Here, we aim to distinguish cell types in organs/tissues of the same individual and in the regenerated liver based on the use of mtDNA SNPs. For this, two approaches-"Mitochondrial Alteration Enrichment and Sequencing" (MAESTER) and "mitochondrial single-cell assay for transposase-accessible chromatin with sequencing" (mtscATAC-seq)-were adopted to facilitate the detection of mtDNA SNPs in single cells. With MAESTER, we show that specific cell types in the liver and spleen of the same individual can be successfully defined using collective individual-specific markers composed of panels of unique mtDNA SNP combinations. For its application, we performed partial hepatectomy (PH) on a Krt19:DreERT2/+;R26:Rox-ZsGreen-Stop-Rox-tdTomato/+ mouse harboring tdTomato-labeled cholangiocytes following tamoxifen injection and demonstrated that utilizing panels of unique mtDNA SNP combinations detected by mtscATAC-seq in the pre-PH cholangiocytes as markers can faithfully trace the cell fate in the post-PH liver samples. Hence, this approach may serve as an unbiased tool for investigating cell lineage relationships in relevant research areas such as liver regeneration.
    Keywords:  MAESTER; cell lineage; mitochondrial DNA; single nucleotide polymorphism (SNP); single-cell sequencing
    DOI:  https://doi.org/10.3390/cells15100947
  74. Free Radic Biol Med. 2026 May 22. pii: S0891-5849(26)00784-7. [Epub ahead of print]
    Unveiling C1QBP: A New Guardian of Dopaminergic Neuron in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
    Jing Li, Yihan Wang, Min Liu, Zhenlong Yu, Yan Wang, Peng Wang, Cong Guo, Minzhi Wang, Ruifeng Shi, Yulin Peng, Jing Tan, Yongzhong Lin.
      Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding protein (C1QBP) plays a crucial role in regulating mitophagy and maintaining mitochondrial homeostasis. This study aims to investigate the role of C1QBP in the pathogenesis of PD by employing bidirectional modulation of C1QBP expression in the PD models. Our results showed reduced C1QBP expression in PD models. C1QBP deficiency aggravated motor dysfunction and dopaminergic neuron degeneration induced by MPTP, while its overexpression exerts protective effects. Mechanistically, C1QBP ameliorates MPP+-induced mitochondrial dysfunction, thereby attenuating neuronal loss. Furthermore, C1QBP promotes mitophagy to maintain mitochondrial homeostasis in PD models. However, these neuroprotective effects of C1QBP were abolished upon UNC-51-Like Kinase 1 (ULK1) knockdown. Collectively, our study has identified C1QBP as a novel guardian for dopaminergic neurons in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
    Keywords:  C1QBP; Parkinson’s disease; ULK1; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.304
  75. J Hepatol. 2026 May 25. pii: S0168-8278(26)00288-6. [Epub ahead of print]
    Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice.
    Elena Barbon, Chiara Simoni, Amy Argabright, Molly Boettiger, Camilla Negri, Elisabetta Manta, Andrea Raimondi, Elena Vezzoli, Cesare Canepari, Mauro Biffi, Alessandro Nonis, Francesco Gazzo, Fabrizio Benedicenti, Eugenio Montini, Giancarlo la Marca, Francesca Sanvito, Julianne Smith, Angelo D'Alessandro, Alessio Cantore.
       BACKGROUND & AIMS: Isolated methylmalonic acidemia (MMA) is a severe inherited metabolic disorder caused by a deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase, encoded by the MMUT gene. Lentiviral vector (LV)-based liver gene therapy may offer sustained therapeutic benefits even in pediatric patients, whose livers are still growing, due to the stable genomic integration of the therapeutic transgene.
    METHODS: We evaluated the efficacy of liver-directed LV gene therapy in a mouse model of MMA and in patient-derived human fibroblasts.
    RESULTS: Systemic administration of an MMUT-expressing LV to 2-week-old MMA mice yielded a rapid, strong, and long-lasting (>1 year) therapeutic effect, with normalization of liver histology and mitochondrial ultrastructure. LV-mediated supraphysiological hepatic expression of MMUT promoted detoxification of the kidney and brain from methylmalonic acid and achieved broad correction of metabolomic, lipidomic, and proteomic profiles. Subsequently, we developed a codon-optimized MMUT transgene to increase expression and lower the minimal therapeutic dose. In 2-week-old MMA mice, this LV variant showed a dose-dependent improvement in metabolic biomarkers, clinical phenotype, and hepatocyte transduction efficiency (exceeding 80%). At the lower LV doses, corrected hepatocytes gained a selective proliferative advantage. Throughout all treated animals, LV integration site analysis revealed a high number of integrations without dominant clones, supporting a polyclonal profile. LV gene therapy provided metabolic improvement even in adult MMA mice, which had a more advanced disease stage than 2-week-old MMA mice. In vitro, LV delivery restored MMUT expression in patient-derived fibroblasts and partially corrected their metabolic abnormalities.
    CONCLUSION: These data provide preclinical proof-of-concept for the efficacy, safety, and extrahepatic therapeutic benefit of liver-directed LV gene therapy for MMA.
    IMPACT AND IMPLICATIONS: Methylmalonic acidemia (MMA) is a severe metabolic disorder with few treatment options. A liver-targeted gene therapy using integrating lentiviral vectors (LV) could allow treatment of pediatric patients with a single dose, due to the stable integration of the therapeutic transgene into the DNA of target cells. In this study, we showed that in a relevant MMA mouse model, systemic LV administration led to long-lasting expression of the therapeutic enzyme in hepatocytes, which corrected metabolic abnormalities and significantly improved the disease phenotype. Supranormal enzyme levels in the liver enabled systemic detoxification and widespread metabolic normalization without detectable LV-related toxicity. We provide a detailed LV dose-response study evaluating the efficiency of gene transfer to hepatocytes and its therapeutic outcomes. Overall, these findings offer strong preclinical evidence to support progressing to clinical trials for MMA patients and help guide the potential use of liver-directed LV gene therapy for other inherited metabolic diseases.
    Keywords:  lentiviral vector; liver gene therapy; metabolomics; methylmalonic acidemia; mitochondriopathy; mouse model
    DOI:  https://doi.org/10.1016/j.jhep.2026.05.011
  76. Mol Cell. 2026 May 25. pii: S1097-2765(26)00284-4. [Epub ahead of print]
    Phenylalanyl-tRNA synthetase FARS-1/FARSA balances longevity and immunity by downregulating endogenous mitochondrial double-stranded RNAs.
    Jooyeon Sohn, Moonhyeon Jeon, Hanseul Lee, JinA Lim, Seokjin Ham, JiSoo Park, Jongsun Lee, Yoonji Jung, Gee-Yoon Lee, Hyemin Min, Eunseok Kang, Yerim Jang, Yunhee Kong, Dajeong Bong, Yoosik Kim, Seung-Jae V Lee.
      Endogenous double-stranded RNAs (dsRNAs) are immunogenic self-molecules that drive aberrant immune activation under pathological conditions. Here, we show that dsRNAs and their regulation by RNA-binding proteins are key determinants of the fine balance between aging and immunity in Caenorhabditis elegans and cultured human cells. We find elevated levels of dsRNAs with organismal aging and cellular senescence. We identify a moonlighting function for phenylalanyl-tRNA synthetase, FARS-1/FARSA, as a key factor necessary and sufficient for extending lifespan by downregulating dsRNAs, in particular, mitochondrial dsRNAs. FARS-1/FARSA possesses a previously unrecognized dsRNA-binding domain and mediates dsRNA downregulation with the RNA helicase, RHA-2/DHX37, independently of its canonical role in translation. Notably, increased dsRNA expression resulting from genetic inhibition of fars-1/FARSA upregulates immune response-related genes and enhances innate immunity against pathogens. Our study establishes that FARS-1/FARSA is an evolutionarily conserved dsRNA-binding protein that delays aging and promotes longevity by suppressing dsRNA accumulation.
    Keywords:  Caenorhabditis elegans; FARS-1/FARSA; RNA-binding protein; double-stranded RNA; immunity; longevity; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.030
  77. Neurogenetics. 2026 May 30. pii: 42. [Epub ahead of print]27(1):
    Genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort: insights from whole-exome sequencing.
    Jasodhara Chaudhuri, Dipanwita Sadhukhan, Amrita Karmakar, Joydeep Mukherjee, Soma Gupta, Saranya Roy, Kallol Das, Shashi Shekhar Jayswal, Debasis Maity, Souvik Mondal, Bonny Sen, Akash Manna, Manamita Mandal, Kartik Chandra Ghosh, Samar Biswas, Amar Kumar Mishra, Gautam Gangully, Atanu Biswas, Priyankar Pal, Apurba Ghosh, Arindam Biswas.
      Rare neurogenetic and neurometabolic disorders comprise a clinically and genetically heterogeneous group of conditions, frequently presenting with overlapping neurological manifestations such as developmental delay, seizures, and cognitive impairment. Whole-exome sequencing (WES) has emerged as a robust approach for elucidating the molecular basis of these disorders. A total of 184 patients with suspected rare neurological disorders were enrolled in this study. Detailed demographic and clinical data were collected, and WES was performed to identify pathogenic and likely pathogenic variants. Variants were annotated and interpreted using standard guidelines, and inheritance patterns were determined. The cohort showed a slight male predominance, with the majority of cases presenting in early childhood (mean age at onset: 29.62 ± 27.69 months). The most common clinical features included developmental delay (82.06%), seizures (74.4%), and cognitive decline (41.3%), followed by dystonia (25%) and ataxia (17.9%). This study delineates the genetic spectrum of rare neurogenetic and neurometabolic disorders in a clinically heterogeneous cohort and underscores the diagnostic utility of WES. Early implementation of genomic testing can facilitate accurate diagnosis, guide clinical management, and improve genetic counseling in affected individuals.
    Keywords:  Indians; Movement disorders; Mutations; Rare diseases; Wilson’s disease
    DOI:  https://doi.org/10.1007/s10048-026-00912-4
  78. iScience. 2026 Jun 19. 29(6): 115957
    Time-restricted feeding enhances cross-tissue temporal coordination of mitochondrial-associated transcripts.
    Dylan C Sarver, Yaniv Maddahi, Christopher S Colwell, Aldons Jake Lusis.
      Coordinating metabolism with the day-night cycle is essential for health. Circadian rhythms synchronize cellular and tissue functions with the external environment. Nutrient timing is a potent circadian cue that entrains peripheral clocks across organs. Mitochondria exhibit daily rhythms in energy metabolism and redox regulation; however, the temporal organization of mitochondrial-associated transcriptional programs across tissues remains unknown. We hypothesized that time-restricted feeding (TRF) enhances the cross-tissue coordination of mitochondrial-associated transcripts (MATs). Using a 22-tissue, 24-h transcriptomic dataset from mice under ad libitum or TRF conditions, we applied correlation- and phase-based analyses to quantify the intra- and inter-tissue alignment of MAT expression. TRF markedly increased cross-tissue coordination, nearly quadrupling the number of globally aligned MATs. Among these, Coq10b emerged as the most rhythmically aligned gene across organs, highlighting it as a representative marker of coordinated MAT expression. Together, these findings reveal a previously unrecognized temporal organization of mitochondrial-associated gene networks shaped by nutrient timing.
    Keywords:  biological sciences; systems biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115957
  79. Commun Biol. 2026 May 23.
    Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.
    Satadeepa Kal, Venkat R Chirasani, Nilima Biswas, Sumana Mahata, Suborno Jati, Kechun Tang, Teresa Pasqua, Ennio Avolio, Ramamurthy Chitteti, Shrabastee Chakraborty, Gautam Bandyopadhyay, Brian P Head, Geert van den Bogaart, Hemal H Patel, Debashis Sahoo, Sanjib Senapati, Sushil K Mahata.
      Hypertension is a major risk factor for heart failure, characterized by impaired energy metabolism and mitochondrial dysfunction. The endogenous peptide catestatin (CST) has known cardiovascular protective effects, but its role in cardiac metabolism remains unclear. Here, we show that CST regulates cardiac metabolic pathways through integrated transcriptomic and network analyses, identifying cell-type-specific gene programs that are disrupted in its absence and restored with supplementation. Comparative analysis with human heart failure datasets reveals conserved alterations in glucose and fatty acid metabolism and mitochondrial function. Functional studies demonstrate that CST restores metabolic flexibility by shifting substrate utilization toward glucose oxidation. Mechanistically, CST enhances mitochondrial ATP production by interacting with ATP synthase and improving membrane potential and enzyme activity. These findings establish CST as a key regulator of cardiac energy metabolism and reveal an endocrine-mitochondrial signaling axis with therapeutic potential for hypertension-associated heart failure.
    DOI:  https://doi.org/10.1038/s42003-026-10310-z
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