bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–05–17
73 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial morphology in human fibroblasts and induced pluripotent stem cells in Leigh syndrome: A comparative analysis.
  2. Mitochondrial transfer technologies with molecular insights into clinical applications.
  3. Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
  4. In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
  5. Mammalian mtDNA gene expression: Concepts learned from in vivo models.
  6. MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
  7. 170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
  8. Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
  9. PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.
  10. Mitochondria and Qi: Merging Eastern and Western Medicine.
  11. Neurodegenerative Diseases in Children: A Comprehensive Review.
  12. Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
  13. Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization.
  14. Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
  15. MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
  16. Glyceroneogenesis has a new PEP in its step(s).
  17. Deciphering Bax Dynamics: Regulation, Retrotranslocation, and Mitochondrial Interplay in the Commitment to Apoptosis: A Narrative Review.
  18. Reply To: Comments on "Age-Associated Differences in Optic Disc Findings of Leber's Hereditary Optic Neuropathy".
  19. The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
  20. Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease.
  21. Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
  22. Strabismus as a primary presentation of combined OXPHOS deficiency: a case of GTPBP3 mutations.
  23. AMPK: a master regulator of mitochondrial quality and quantity.
  24. High-Resolution Imaging Reveals Mitochondrial Protein Imbalance in Sperm of Oligoasthenospermic Men.
  25. Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
  26. Genetic diagnosis of hereditary kidney disease in pediatric patients through whole-exome sequencing and mitochondrial DNA analysis.
  27. Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.
  28. Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria.
  29. ClpP Activation in High-Risk Medulloblastoma: ONC206 as a Potent Inducer of the Integrated Stress Response and Mitochondrial Damage for a Broader Therapeutic Window.
  30. Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.
  31. BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.
  32. FAM162A Is a Key Regulator of Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity.
  33. Therapeutic potential of mitochondrial transfer in reversing mutant-to-wild-type mtDNA ratio and improving mitochondrial dysfunction in 1555A>G mtDNA mutation-associated hearing loss.
  34. Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.
  35. Investigating how changes in the levels of kinesins impact neuronal health in Drosophila and human iPSC-derived neurons AD model.
  36. Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
  37. Gene Therapy for Leber Hereditary Optic Neuropathy (LHON): A Systematic Review and Meta-Analysis.
  38. Glutathione Decline Coordinates Mitochondria to License Histone Acetylation and Zygotic Genome Activation.
  39. Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.
  40. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
  41. Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.
  42. Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.
  43. Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.
  44. IFI204 drives gasdermin D-mediated mitochondrial permeabilization to amplify neuronal pyroptosis in ischemic stroke.
  45. Therapeutic Impact of Mitochondrial Transplants for Cardiovascular Diseases.
  46. Convergent effects of neurodevelopmental disorder-associated variants at mitochondria.
  47. Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.
  48. Flexible Data Integration for Genomics-Driven Decision Support in Rare Genetic Epilepsy.
  49. Universal conditional knockout approach to multiple species, from fish to human induced pluripotent stem cells.
  50. Whole-blood NAD+ levels do not reflect healthy ageing.
  51. Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
  52. A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis.
  53. Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
  54. Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer.
  55. Reverse electron transfer at mitochondrial complex I restrains dopaminergic neuron activity to promote early-life sleep in Drosophila.
  56. Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
  57. Mitochondrial dysfunction redirects proton transport and energy homeostasis in Saccharomyces cerevisiae under variable pH and glucose conditions.
  58. Recent advances in the design mechanisms of mitochondrial fluorescent probes: A review.
  59. Modeling human neurodegenerative disorders in Drosophila: strategies and translational opportunities.
  60. Genetic survey exposes flaws in widely used mouse models.
  61. PSG6: A mitochondrially-targeted gentisic acid derivative exerts antiplatelet action via mitochondrial complex I inhibition.
  62. Liver Disease Reveals KIF12 as a Critical Regulator of Mitochondria, Lysosome and Cilia Localization.
  63. Automated stem cell-derived organoid platforms for disease modeling.
  64. Environmental stress-induced mitochondrial metabolic reprogramming as a central driver of endocrine dysfunction: A food and chemical toxicology perspective.
  65. Mitochondrial ROS Production at Complexes I and III in Human Myocardium and Skeletal Muscle: A Distinct Pattern Compared with Rat Tissue.
  66. Adult-onset STING-associated vasculopathy.
  67. A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA.
  68. New developments and applications of human organoids.
  69. Generation of spinal cord organoids from human induced pluripotent stem cells caudalised to a lumbar fate.
  70. Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
  71. Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.
  72. m6A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.
  73. Assessing Mitochondrial Respiratory Complex-Associated Function From Previously Frozen Mouse Placental Tissue.
  1. Physiol Rep. 2026 May;14(9): e70911
    Mitochondrial morphology in human fibroblasts and induced pluripotent stem cells in Leigh syndrome: A comparative analysis.
    Fibi Meshrkey, Ajibola B Bakare, Raj R Rao, Shilpa Iyer.
      Mitochondria are dynamic organelles that regulate several vital cellular functions in both health and disease. Accurately quantifying different mitochondrial shapes using simple, affordable techniques remains challenging. We have previously developed a Mitochondrial Cellular Phenotype (MitoCellPhe) tool to quantify 24 different mitochondrial shapes, enabling sensitive analysis and quantification of mitochondrial phenotype in health, under stress, and in diseased conditions. This approach permits us to study the morphological changes, if any, associated with perturbations in the mitochondrial genome and function that contribute to mitochondrial diseases like Leigh Syndrome (LS), a fatal pediatric neurodegenerative and muscular disorder represented with different clinical phenotypes in infancy. Using images generated from normal and diseased fibroblasts and human induced pluripotent stem cells (hiPSCs) (undifferentiated), we have identified and characterized differences in morphologies between a healthy and diseased state in both undifferentiated hiPSCs and differentiated fibroblasts. These results will help us better understand the pathophysiology of devastating mitochondrial diseases like LS, especially in its early developmental stages.
    Keywords:  mitochondria; morphology; networks; stem cells; structure
    DOI:  https://doi.org/10.14814/phy2.70911
  2. Stem Cells. 2026 May 07. pii: sxag026. [Epub ahead of print]
    Mitochondrial transfer technologies with molecular insights into clinical applications.
    Vahan Martirosian, Berney Peng, Michael A Teitell.
      Mitochondria are essential cell signaling, survival, and bioenergetic organelles that uniquely harbor a maternally inherited, multicopy genome called mitochondrial DNA (mtDNA). The occurrence or accumulation of mtDNA mutations underlies a spectrum of inherited and acquired mitochondrial syndromes and diseases and is increasingly recognized as a source of metabolic plasticity, clonal fitness, and therapy tolerance in cancer. Recent studies have revealed mitochondrial transfer as a potential mode of intercellular communication that could compensate for mtDNA mutation-associated mitochondrial dysfunction. Transfer of mitochondria can restore homeostasis in stressed recipient cells by rebuilding respiratory capacity, rebalancing redox state, and reshaping cell fate. Reported mechanisms of transfer include tunneling nanotubes, extracellular vesicles, cell fusion, and others, such as macropinocytosis. Here, we review and evaluate emerging technologies developed for mitochondrial transfer studies and define the impact of transfer on cell physiology and pathology. We discuss translational opportunities for mitochondrial transfer-based interventions, as well as how mitochondrial exchange may represent a new framework for understanding tumor heterogeneity, adaptation, and aggressiveness.
    Keywords:  Mitochondria; Mitochondrial transfer; mtDNA; techniques; transplantation
    DOI:  https://doi.org/10.1093/stmcls/sxag026
  3. Bioessays. 2026 May;48(5): e70146
    Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
    Yi Sheng, Zachary Markovich, Sung Min Han, Rui Xiao.
      Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age-related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPRMT) and integrated stress response (ISR) are discussed, including their tissue-specific as well as non-cell-autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context-dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.
    Keywords:  aging; integrated stress response; mitochondria ROS; mitochondrial dynamics; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1002/bies.70146
  4. EMBO Rep. 2026 May 14.
    In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
    Lisa Dengler, Francesco Padovani, Bianca Lemke, Rebecca Brugger, Alissa Benedikt, Benedikt Westermann, Boris Maček, Kurt M Schmoller, Jennifer C Ewald.
      Mitochondrial biogenesis and inheritance must be tightly coordinated with cell division to maintain mitochondrial function and cell survival. The dynamics of the mitochondrial network, including fusion and fission, are essential for mitochondrial inheritance and quality control. In budding yeast, simultaneous inhibition of both processes compromises mitochondrial DNA (mtDNA) integrity, increasing the frequency of petite cells. Loss of fusion alone completely eliminates mtDNA. Although this has been known for decades, why mtDNA is lost remained unclear. Here, we examine the effects of impaired mitochondrial fusion by depleting the mitofusin Fzo1. By analyzing over thirty thousand single cells across their cell cycles, we show that Fzo1-depletion induces rapid mitochondrial fragmentation and loss of membrane potential, followed by progressive declines in mtDNA content and growth rate. During division, Fzo1-depleted daughters inherit disproportionately large mitochondrial amounts, leaving mothers with too little. This imbalance, combined with an inability to upregulate compensatory mtDNA synthesis, drives rapid mtDNA loss. Our results reveal how fusion defects cause mtDNA loss and mitochondrial dysfunction, which might have implications for diseases linked to impaired fusion.
    DOI:  https://doi.org/10.1038/s44319-026-00794-5
  5. Biochim Biophys Acta Mol Cell Res. 2026 May 13. pii: S0167-4889(26)00056-X. [Epub ahead of print] 120158
    Mammalian mtDNA gene expression: Concepts learned from in vivo models.
    Diana Rubalcava-Gracia, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) expression is essential for oxidative phosphorylation (OXPHOS) and its in vivo regulation requires significant refinement. Here, we review key insights from mouse models carrying genetic modifications to the mtDNA expression machinery. While in vitro studies defined the basic machinery, mouse models reveal that mitochondrial transcription often exceeds immediate needs and may not be the primary rate-limiting step for OXPHOS biogenesis. Instead, mitochondria produce a transcript surplus regulated by nucleoid compaction and post-transcriptional stabilization. This apparent excess capacity is uncoupled from protein output under basal conditions but becomes critical during physiological stress or pathology. Using current and emerging genetic tools, researchers are now deciphering how regulatory layers coordinate to sustain systemic energy demands. These lessons highlight the importance of in vivo systems for identifying regulatory control points of mtDNA expression and developing targeted therapies for mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120158
  6. Trends Cell Biol. 2026 May 13. pii: S0962-8924(26)00065-6. [Epub ahead of print]
    MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
    Nora Haggerty, Kentaro Nakamura, Hiromi Sesaki, Miho Iijima.
      Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed 'Mitochondrial Safeguard (MitoSafe)', in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.
    Keywords:  OMA1; PINK1; Parkin; dynamin-related GTPase; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.007
  7. J Clin Pharmacol. 2026 May;66(5): e70209
    170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
    Volkmar Weissig.
      One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.
    Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.1002/jcph.70209
  8. Dev Cell. 2026 May 13. pii: S1534-5807(26)00123-1. [Epub ahead of print]61(5): 1146-1161.e8
    Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
    Rajini Chandrasegaram, Sara Gottardo, Abhilesh Dhawanjewar, Antony M Hynes-Allen, Beitong Gao, Suvagata Roy Chowdhury, Luis-Carlos Tábara, Michele Frison, Stavroula Petridi, Patrick F Chinnery, Julien Prudent, Hansong Ma, Jelle van den Ameele.
      Mitochondrial DNA (mtDNA) exists in many copies per cell, with cell-to-cell variability in mutation load, which is known as heteroplasmy. Developmental and age-related expansion of heteroplasmic mtDNA mutations contributes to the pathogenesis of mitochondrial and neurodegenerative diseases. Here, we describe an approach for in situ sequence-specific detection of single mtDNA molecules (mtDNA-single-molecule fluorescent in situ hybridization [smFISH]). We apply this method to visualize and measure mtDNA and heteroplasmy levels in situ at single-cell resolution in whole-mount Drosophila tissue and cultured human cells. In Drosophila, we identify a somatic mtDNA bottleneck during neurogenesis. This amplifies heteroplasmy variability between neurons, as predicted by a mathematical bottleneck model, predisposing individual neurons to a high mutation load. However, both during neurogenesis and oogenesis, mtDNA segregation is accompanied by purifying selection, promoting wild-type (WT) over pathogenic mtDNA. mtDNA-smFISH thus elucidates how developmental cell-fate transitions, accompanied by changes in cell morphology, behavior, and metabolism, can shape the transmission and selection of deleterious mtDNA variants.
    Keywords:  Drosophila; bottleneck; heteroplasmy; mitochondria; mitochondrial DNA; mitochondrial disease; neurogenesis; oogenesis; purifying selection; single-molecule fluorescent in situ hybridization
    DOI:  https://doi.org/10.1016/j.devcel.2026.03.011
  9. J Cell Biol. 2026 Jun 01. pii: e202603198. [Epub ahead of print]225(6):
    PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.
    Sneha Hegde, Marc Germain.
      Mitochondrial dynamics regulate mitochondrial activity through several pathways, but their coordination remains unclear. Zhao et al. (https://doi.org/10.1083/jcb.202508040) show that endosomal PI(3)P promotes CDC42-dependent actin polymerization on mitochondria, providing insight into the upstream signals regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1083/jcb.202603198
  10. Pharmacol Res. 2026 May 11. pii: S1043-6618(26)00158-1. [Epub ahead of print] 108243
    Mitochondria and Qi: Merging Eastern and Western Medicine.
    Wanqing Xie, Deborah G Murdock, Douglas C Wallace.
      Since the discovery of mitochondrial DNA (mtDNA) diseases almost 40 years ago, large numbers of diseases have been linked to mutations in both mtDNA and nuclear DNA (nDNA) genes that perturb the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction is being implicated not only in rare primary mitochondrial diseases but also a wide range of common diseases, yet the availability of effective mitochondrial therapies remains limited. One potential source of mitochondrial therapeutic approaches is Traditional Chinese Medicine (TCM). TCM emphasizes the health-preservation philosophy and practical experience centered around the concept of "Qi", or vital force, and has generated Qi-oriented therapies over the past several thousand years. We propose that various properties and functions attributed to Qi may be explained by modulation of mitochondrial bioenergetics, the interplay between OXPHOS and fatty acid oxidation versus glycolysis and the pentose phosphate pathway (PPP), and the mitochondrial regulation of the immune system through mitochondrial reactive oxygen species (mROS). Hence, TCM therapeutics may provide approaches for treating the increasing spectrum of mitochondria associated diseases.
    Keywords:  Mitochondria; Qi; TCM; energy; mtDNA; therapy
    DOI:  https://doi.org/10.1016/j.phrs.2026.108243
  11. Int J Mol Sci. 2026 May 03. pii: 4096. [Epub ahead of print]27(9):
    Neurodegenerative Diseases in Children: A Comprehensive Review.
    Constantin Ailioaie, Laura Marinela Ailioaie, Cristinel Ionel Stan, Anca Sava, Dragos Andrei Chiran.
      Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a "rare-but-many" landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy-lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies.
    Keywords:  developmental regression; gene therapy; leukodystrophies; lysosomal storage disorders; mitochondrial diseases; neuroinflammation; oxidative stress; pediatric neurodegeneration; peroxisomal disorders; precision medicine
    DOI:  https://doi.org/10.3390/ijms27094096
  12. Mech Ageing Dev. 2026 May 08. pii: S0047-6374(26)00043-6. [Epub ahead of print]231 112191
    Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
    YiFan Yan, Yuetong Li, Heng Ma.
      Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.
    Keywords:  Aging; Lysosome; Membrane contact sites; Mitochondria-lysosome contacts; Mitochondrial quality control; Organelle homeostasis
    DOI:  https://doi.org/10.1016/j.mad.2026.112191
  13. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2533968123
    Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization.
    Xiaoyuan Yan, Chao Wei, Jeffrey M Mann, Guanyi Shang, Qianyi Wang, Huirong Xie, Elena Y Demireva, Liangliang Sun, Deqiang Ding, Chen Chen.
      Pachytene piRNAs are the least understood class of piRNAs in the mammalian male germ line. During meiosis, their biogenesis occurs near the mitochondrial outer membrane in germ granules known as intermitochondrial cement (IMC). However, how mitochondrial factors regulate the trafficking of PIWI proteins into and out of the IMC remain poorly understood. Here we show that the cytoplasmic PIWI proteins MILI and MIWI are recruited for pachytene piRNA biogenesis via distinct mitochondrial membrane proteins. Loss of the mitochondrial scaffold protein ASZ1 during meiosis in mice disrupts multiple downstream biogenesis steps, resulting in misregulation of MILI, MIWI, and MOV10L1, failure of IMC formation, and an almost complete loss of mature pachytene piRNAs. Strikingly, despite the drastic depletion of pachytene piRNAs, LINE1 transposon silencing remains unaffected. We identify three classes of pachytene piRNA pathway components that coordinate piRNA production and compartmentalization. Our findings reveal that chromatoid body precursors serve as a central hub for the accumulation of pachytene PIWI-piRNA complexes, thus establishing a connection between IMC-based biogenesis and downstream piRNA function.
    Keywords:  ASZ1; PIWI; pachytene; piRNA; spermatogenesis
    DOI:  https://doi.org/10.1073/pnas.2533968123
  14. FASEB J. 2026 May 31. 40(10): e71812
    Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
    Ranran Zhao, Jican Zhao, Weiyi Xia, Wanjuan Yu, Huihui Zhou, Xuan Wang, Kansen Mai, Gen He, Chengdong Liu.
      The Integrated Stress Response (ISR) is a vital cellular mechanism that regulates cell survival during various stress conditions, including hypoxia. Activating transcription factor 4 (ATF4) is recognized as a key regulator of ISR, however, its role in hypoxic stress responses remain underexplored. In the present study, we generated an Atf4a-deficient zebrafish model to investigate the role of Atf4a in hypoxia tolerance, mitochondrial homeostasis, and cellular stress adaptation. The results showed that atf4a knockout led to significant growth impairment, endoplasmic reticulum and mitochondrial dysfunction, and disrupted energy metabolism, particularly under hypoxic conditions. We observed an increase in mitochondrial DNA and impaired mitochondrial morphology in Atf4a-deficient zebrafish. Metabolomic analysis revealed significant alterations in the pentose phosphate pathway and TCA cycle following atf4a knockout. Additionally, we observed increased mitochondrial oxidative stress and reduced antioxidant capacity in atf4a mutants. Atf4a-deficiency also led to decreased expression of the mitophagy-related gene p62 and parkin. Atf4a transcriptionally regulates the expression of parkin, suggesting that Atf4a regulates mitochondrial homeostasis through parkin-mediated mitophagy in zebrafish. These results underscore the critical role of Atf4a in maintaining cellular homeostasis, mitochondrial integrity, and metabolic adaptation during hypoxic stress, highlighting its potential as a therapeutic target for stress-related diseases.
    Keywords:  ATF4; ISR; hypoxia; mitophagy; parkin
    DOI:  https://doi.org/10.1096/fj.202502855R
  15. Nat Metab. 2026 May 13.
    MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
    Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.
      Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.
    DOI:  https://doi.org/10.1038/s42255-026-01513-z
  16. Cell. 2026 May 14. pii: S0092-8674(26)00470-8. [Epub ahead of print]189(10): 2788-2790
    Glyceroneogenesis has a new PEP in its step(s).
    Alexandra E Jerrett, Nicolai R Hathiramani, Jessica B Spinelli.
      Mitochondria generate phosphoenolpyruvate (PEP), although its export mechanism and physiological roles were unknown. In this issue of Cell, Kajimura and colleagues identify SLC25A35 as the mitochondrial PEP exporter and uncover a previously unrecognized role for mitochondrial PEP synthesis in glyceroneogenesis in adipose tissue and upon development of fatty liver disease.
    DOI:  https://doi.org/10.1016/j.cell.2026.04.035
  17. Health Sci Rep. 2026 May;9 e72501
    Deciphering Bax Dynamics: Regulation, Retrotranslocation, and Mitochondrial Interplay in the Commitment to Apoptosis: A Narrative Review.
    Mehrin Haque Tanisha, Md Ayman Siddique, Zubaier Ahmed, Nashrah Mustafa, Fariha Tasneem.
       Background: The apoptotic pathway mediated by mitochondria depends on the activation of pro-apoptotic Bcl-2 proteins Bax and Bak. When they permeabilize the outer mitochondrial membrane (OMM), mitochondrial dysfunction occurs, leading to caspase activation. A recent study proposed that Bax accumulation on mitochondria increases apoptotic susceptibility, with adhesion-initiated signals regulating Bax. When adhesion signaling is inhibited, Bax translocates to the OMM, undergoes conformational change, and forms complexes that create pores. Although MOMP is well studied, mechanisms regulating Bax shuttling, non-canonical partners, and mitochondrial dynamics remain poorly understood.
    Aims: This review aims to provide insights by discussing the mechanisms through which Bax regulates its mitochondrial targeting, the mitochondrial dynamics associated with Bax translocation, and their influence to apoptosis. Understanding these processes could reveal new insights into the decision-making checkpoints that determine cell death.
    Methods: A comprehensive literature search was conducted across scientific databases for peer-reviewed publications up to 2025. Search terms included Bax retrotranslocation, mitochondrial dynamics, Bcl-2 family interactome, and apoptotic priming.
    Results: Recent evidence shows that Bax continuously retrotranslocates from mitochondria to the cytosol under survival conditions, a process driven by anti-apoptotic Bcl-2 proteins. When adhesion signaling or other survival cues are inhibited, this cycle is disrupted, leading to Bax accumulation on mitochondria, its oligomerization, and the onset of MOMP. Several mitochondrial proteins, including Drp1, MAVS, OCIAD1, PTPN1, and AKAP1, have also been linked to a mitochondrial interaction network that influences Bax localization and retrotranslocation. Proximity-labeling approaches such as BioID are further identifying new proteins that may regulate Bax's mitochondrial targeting and apoptotic priming.
    Conclusion: The mechanisms driving Bax accumulation on mitochondria and its retrotranslocation remain unclear, especially the role of mitochondrial proteins. Evidence suggests mitochondrial interaction networks influence Bax and Bak regulation. Further research is needed to define how these networks integrate with the Bcl-2 interactome to shape apoptotic decisions.
    Keywords:  Bax retrotranslocation; Bcl‐2 family proteins; apoptotic priming; cell death regulation; mitochondrial dynamics; mitochondrial outer membrane permeabilization (MOMP); protein–protein interaction networks; pro‐apoptotic signaling
    DOI:  https://doi.org/10.1002/hsr2.72501
  18. Neuroophthalmology. 2026 ;50(3): 294-295
    Reply To: Comments on "Age-Associated Differences in Optic Disc Findings of Leber's Hereditary Optic Neuropathy".
    Yasuyuki Takai, Akiko Yamagami, Mayumi Iwasa, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.
      
    Keywords:  Leber hereditary optic neuropathy; mitochondrial disease; optic disc; retinal nerve fiber layer
    DOI:  https://doi.org/10.1080/01658107.2026.2642123
  19. Aging Cell. 2026 05;25(5): e70534
    The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
    Prasanna Katti, Praveena Prasad, Sepiso K Masenga, Prasanna Venkhatesh, Zer Vue, Andrea G Marshall, Benjamin Rodriguez, Han Le, Edgar Garza-Lopez, Alexandria Murphy, Brenita Jenkins, Ashlesha Kadam, Jianqiang Shao, Amber Crabtree, Pamela Martin, Chantell Evans, Mark A Phillips, David Hubert, Nelson Wandira, Okwute M Ochayi, Dhanendra Tomar, Clintoria R Williams, Jennifer Gaddy, Briar Tomeau, LaCara Bell, Taneisha Gillyard, Markis' Hamilton, Vineeta Sharma, Mohd Mabood Khan, Elma Zaganjor, Olujimi A Ajijola, Estevão Scudese, Tyne W Miller Fleming, André Kinder, Chandravanu Dash, Anita M Quintana, Bret C Mobley, Julia D Berry, Pooja Jadiya, Dao-Fu Dai, Annet Kirabo, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Renata Oliveira Pereira, Debra D Murray, Joyonna Gamble-George, Melanie R McReynolds, Antentor Hinton.
      Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age-related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block face-scanning electron microscope and manual segmentation using the Amira software were employed to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health.
    Keywords:  3DEM; MICOS complex; kidney; metabolism; mitochondria
    DOI:  https://doi.org/10.1111/acel.70534
  20. Nat Commun. 2026 May 13.
    Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease.
    Dingyi Luo, Lvqin Zheng, Ming-Ao Lu, Ziyao Chen, Panpan Wang, Qiang Guo, Ning Gao.
      Mitochondrial function critically depends on protein quality control systems, with the m-AAA protease playing a key role at the inner mitochondrial membrane (IMM). The evolutionarily conserved prohibitins (PHBs) are essential modulators of this protease across species, yet the molecular mechanisms remain unclear. Here, we present the cryo-EM structure of the Chaetomium thermophilum PHB (CtPHB) complex, revealing a cage-like assembly composed of 11 copies of PHB1/PHB2 heterodimers. Electron microscopic and biochemical analyses suggest that m-AAA proteases are enclosed within the PHB complex through interactions mediated by their SPFH-interacting motif (SIM) exposed in the intermembrane space. Further in situ cryo-ET directly visualizes these cage-protease assemblies in native mitochondria. Disruption of their interface leads to elevated m-AAA protease activity and diminished mitochondrial stress resistance. These data establish PHB complexes as spatial organizers that compartmentalize m-AAA proteases in membrane microdomains to fine-tune proteolytic homeostasis. Our findings reveal the critical role of the PHB complex in maintaining mitochondrial proteostasis, providing a unified mechanistic model to explain and reconcile the pleiotropic and often contradictory phenotypes of PHB and m-AAA protease in mitochondrial physiology and various disease conditions.
    DOI:  https://doi.org/10.1038/s41467-026-73040-0
  21. Mitochondrion. 2026 May 12. pii: S1567-7249(26)00057-7. [Epub ahead of print]90 102167
    Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
    Ayumu Sugiura, Kohta Nakamura, Heidi M McBride, Yasushi Okazaki.
      Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.
    Keywords:  Lysosomes; Mitochondria; Mitochondrial-derived vesicles; Peroxisomes
    DOI:  https://doi.org/10.1016/j.mito.2026.102167
  22. Strabismus. 2026 Jun;34(2): 234-237
    Strabismus as a primary presentation of combined OXPHOS deficiency: a case of GTPBP3 mutations.
    Hennaav Kaur Dhillon, Nitya Raghu.
      
    Keywords:  Diplopia; GTPBP3 gene; OXPHOS deficiency; esotropia; extraocular muscle involvement; mitochondrial myopathy; pediatric strabismus
    DOI:  https://doi.org/10.1080/09273972.2025.2571777
  23. Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]
    AMPK: a master regulator of mitochondrial quality and quantity.
    Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.
    Keywords:  endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.008
  24. Mol Reprod Dev. 2026 05;93(5): e70110
    High-Resolution Imaging Reveals Mitochondrial Protein Imbalance in Sperm of Oligoasthenospermic Men.
    Pauline Teixeira, Magalie Boguenet, Florence Pascaretti-Grizon, Florence Manero, Solenn Plouzennec, Pierre-Emmanuel Bouet, Pascal Reynier, Arnaud Chevrollier, Pascale May-Panloup.
      Male infertility accounts for nearly half of global infertility cases and is often linked to poor sperm quality, such as oligospermia, asthenospermia, and teratospermia. Although the exact mechanisms remain unclear, mitochondria, which are critical for ATP production and reactive oxygen species generation during fertilization, are increasingly recognized as key players in male infertility but remain underexplored. ATP synthesis relies on respiratory chain complexes that establish a proton gradient across the inner mitochondrial membrane, powering the F0F1-ATP synthase. Proper stoichiometry of these complexes, encoded by both nuclear and mitochondrial DNA, is essential for efficient energy production. However, no previous studies have directly correlated mitochondrial protein expression with sperm quality. Due to the small size and helical structure of sperm mitochondria, imaging them is challenging, yet crucial for understanding sperm function. This study investigates the role of mitochondrial oxidative phosphorylation proteins in sperm quality using single-cell immunolabeling and high-resolution microscopy. It compares spermatozoa from oligoasthenospermic (OA) patients to normospermic controls. OA sperm show increased levels of mitochondrial genome encoded cytochrome c oxidase subunit 1 and significantly reduced F0F1-ATP synthase subunits. This imbalance may contribute to mitochondrial dysfunction and underscores the need for deeper exploration of the pathophysiological mechanisms involved, which could affect sperm function and fertility. These initial results suggest a potential pathway toward the identification of novel biomarkers of male infertility.
    Keywords:  OXPHOS; infertility; microscopy; mitochondria; sperm
    DOI:  https://doi.org/10.1002/mrd.70110
  25. J Neurol Sci. 2026 Apr 15. pii: S0022-510X(26)00202-9. [Epub ahead of print]487 125920
    Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
    Shubham, Abhishek Mathur.
      
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Cell-free mitochondrial DNA; Mitochondrial DNA; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.jns.2026.125920
  26. Kidney Res Clin Pract. 2026 May 15.
    Genetic diagnosis of hereditary kidney disease in pediatric patients through whole-exome sequencing and mitochondrial DNA analysis.
    Jiyoung Oh, Keumwha Lee, Dongju Won, Young-Mock Lee, Jae Il Shin.
       Background: Identifying the genetic cause of hereditary kidney disease is essential for appropriate management. However, pediatric patients often present with nonspecific renal symptoms such as proteinuria, hematuria, or both, making accurate diagnosis difficult. Mitochondrial diseases are also an important but underrecognized etiology of hereditary kidney disorders. This study aimed to assess the diagnostic utility of whole-exome sequencing (WES) combined with mitochondrial DNA (mtDNA) analysis and to describe the clinical and genetic features of pediatric patients presenting with isolated proteinuria, combined hematuria and proteinuria, or hematuria with a relevant family history.
    Methods: DNA was extracted from peripheral blood leukocytes of 77 pediatric patients with hematuria and/or proteinuria with or without family history. WES and mtDNA analyses were conducted to identify underlying genetic etiologies.
    Results: The overall molecular diagnostic yield was 54.5% (42/77) with COL4A-related nephropathy (29 cases) being the most prevalent diagnosis. Notably, one patient with no systemic symptoms except for renal manifestations was identified with the m.3243A>G variant in MT-TL1, which is associated with the MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome. This patient's initial and predominant presentation was gross and microscopic hematuria, diverging from typical MELAS-associated kidney disease.
    Conclusion: WES proved valuable in diagnosing hereditary kidney diseases in pediatric patients with nonspecific urinalysis findings. Incorporating mtDNA analysis further improved diagnostic yield and enabled identification of atypical presentations of mitochondrial disorders, such as MELAS, even when renal symptoms were isolated.
    Keywords:  Exome sequencing; Genetic testing; Kidney diseases; Mitochondrial DNA
    DOI:  https://doi.org/10.23876/j.krcp.25.394
  27. JIMD Rep. 2026 May;67 e70093
    Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.
    Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.
      Primary mitochondrial diseases frequently affect the central nervous system, yet the extent, distribution and progression of white matter hyperintensities (WMHs) remain insufficiently characterised, particularly in terms of quantitative volumetrics and longitudinal progression. Although WMHs are typically attributed to cerebral small-vessel disease, mitochondrial disorders may cause white matter injury through distinct vascular and metabolic mechanisms. We conducted a retrospective single-centre study at Turku University Hospital including 36 patients with mitochondrial disease, each with at least one brain MRI (73 images). Longitudinal data were available for 15 patients. Three-dimensional T1-weighted and FLAIR images (1.5/3 T) were analysed with the FDA-cleared cNeuro tool to obtain intracranial volume-normalised WMH and lesion volumes and an automated global Fazekas score. At baseline (median age 49 years), WMHs were present in all supratentorial regions. Over time, WMH volumes increased significantly in periventricular, deep and juxtacortical regions, while lesion progression was predominantly periventricular. Fazekas scores remained generally low and stable. In follow-up imaging, women and patients carrying the m.3243A>G variant showed a greater burden of WMHs and lesions, compared with men and those with other mitochondrial diagnoses. WMH load did not differ according to history of stroke-like episodes. Mitochondrial disease is associated with early and progressive WMH accumulation, particularly in individuals with the m.3243A>G variant, and the pattern exceeds what would be expected from conventional vascular risk factors alone. These findings support a disease-specific mechanism of white matter vulnerability and highlight the importance of quantitative MRI for monitoring progression in mitochondrial disease.
    Keywords:  disease progression; longitudinal imaging; mitochondrial disease; quantitative MRI; small‐vessel pathology; white matter hyperintensities
    DOI:  https://doi.org/10.1002/jmd2.70093
  28. Nano Lett. 2026 May 11.
    Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria.
    Jiafeng Zhong, Luyao Wang, Wenjing Xuan, Xuehan Xu, Xing Chang, Jianjun Cheng, Chengjie Sun.
      Mitochondria-targeted therapies hold great promise for treating metabolic syndrome, neurodegeneration, and cancers associated with mitochondrial dysfunction or genetic mutations. However, its advancement is significantly limited by the lack of effective and biocompatible targeted delivery systems. Here, we introduce mitofusin-decorated extracellular vesicles (MFNEVs) as a natural-sourced nanoplatform for efficient mitochondrial delivery of various cytoplasm-sensitive macromolecular cargos. The surface-displayed mitofusin proteins MFN1 and MFN2 direct MFNEVs to localize to mitochondria, as confirmed by confocal imaging and gel electrophoresis analysis. In both in vitro and in vivo models, siRNA-loaded MFNEVs effectively reduce the expression of mitochondrial DNA-encoded genes. Moreover, sgRNA-loaded MFNEVs can achieve CRISPR-based mitochondrial gene editing, resulting in a decreased mitochondrial DNA content. Mechanistic studies further reveal that the delivery is facilitated by the cooperation of the mitochondrial fusion machinery. These findings establish the feasibility and versatility of MFNEVs as a promising delivery solution for mitochondrial therapeutics.
    Keywords:  CRISPR; extracellular vesicles; mitochondria-targeted delivery; mitofusin; siRNA
    DOI:  https://doi.org/10.1021/acs.nanolett.6c00233
  29. Neuro Oncol. 2026 May 09. pii: noag105. [Epub ahead of print]
    ClpP Activation in High-Risk Medulloblastoma: ONC206 as a Potent Inducer of the Integrated Stress Response and Mitochondrial Damage for a Broader Therapeutic Window.
    Peter Hau.
      
    DOI:  https://doi.org/10.1093/neuonc/noag105
  30. Nutrients. 2026 Apr 28. pii: 1392. [Epub ahead of print]18(9):
    Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.
    Rafail C Christodoulou, Laura Lorentzen, Daniel Eller, Evros Vassiliou.
      Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.
    Keywords:  astrogliosis; immunometabolism; lipid peroxidation; long-chain fatty acids; microglia; neurodegeneration; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/nu18091392
  31. Aging Cell. 2026 May;25(5): e70539
    BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.
    Zhouyang Deng, Hailong Han, Caifang Wang, Wen Zhong, Zhengqing Wan, Dan Zhou, Ye Chen, Yanni Peng, Zongzhao Zhai, Kai Yuan, Ruoxi Wang, Zhuohua Zhang.
      Aging is a major risk factor for numerous diseases, including degenerative and metabolic disorders. Cumulative mitochondrial damage, elevated reactive oxygen species (ROS), and impaired mitophagy are hallmarks of aging. In this study, we generated a Drosophila version of the mito-SRAI reporter to monitor mitophagy in vivo and demonstrated an age-dependent decline in muscle mitophagy, accompanied by the accumulation of insoluble proteins, increased ROS levels, and mitochondrial damage. Overexpression of BNIP3 preserved muscle homeostasis by enhancing mitophagy, maintaining mitochondrial integrity, and suppressing ROS accumulation. Importantly, muscle-specific expression of BNIP3 in indirect flight muscles extended lifespan and alleviated age-associated neurodegenerative phenotypes, including protein aggregation, β-galactosidase accumulation, and pathological vacuolization in the brain. Mechanistically, BNIP3 inhibited ROS-mediated activation of Relish, thereby reducing expression of antimicrobial peptide (AMP) genes. These findings identify BNIP3 as a key regulator of aging that links mitochondrial quality control to systemic aging and neurodegeneration. Moreover, our results provide direct evidence of muscle-to-brain signaling, revealing a non-autonomous mechanism by which muscle mitophagy mitigates age-related neurodegeneration.
    Keywords:  BNIP3; aging; inflammation; mitophagy; neurodegeneration; non‐autonomous regulation
    DOI:  https://doi.org/10.1111/acel.70539
  32. Aging Cell. 2026 05;25(5): e70508
    FAM162A Is a Key Regulator of Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity.
    Andrea Matamoros, Juan Pablo Soffia, Marcelo Muñoz, Michael Maturana, Ma Andreina Rangel-Ramirez, Alvaro Gonzalez-Ibañez, Gabriela Gómez-Lillo, Cesar Astorga, Lina M Ruiz, Ramón A Jorquera, Alejandra San Martín, Alvaro A Elorza.
      FAM162A is an inner mitochondrial protein known for its role in hypoxia-induced apoptosis. However, it is often overexpressed in cancer, where its pro-apoptotic function appears to be overridden, suggesting novel unknown roles in mitochondrial function and cell survival. Furthermore, its precise localization, topology, and orientation remain controversial. In this study, we aimed to assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cellular and organismal stress resistance, while also establishing its localization, topology, and orientation. To this end, localization, topology, and orientation were determined by protease-protection assays in COS7 cells. In vitro loss- and gain-of-function experiments assessed mitochondrial structure and function by confocal microscopy, immunoblotting, and Seahorse analysis, while a transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and heat stress conditions. We found that FAM162A localized to the inner mitochondrial membrane, predominantly within the cristae, and supported cristae ultrastructure, bioenergetics, and mitochondrial turnover, thereby enhancing oxidative metabolism, cell viability, and stress resistance. FAM162A expression was positively associated with the fusion protein OPA1 and interacted with OPA1 to regulate the proportion of long- and short-OPA1 isoforms. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. Overall, FAM162A emerges as a key regulator of mitochondrial integrity and bioenergetics through its association with OPA1, confirming a novel role in cellular health and stress resistance.
    Keywords:  FAM162A; HGTD‐P; OPA1; bioenergetics; mitochondrial dynamics; stress resistance
    DOI:  https://doi.org/10.1111/acel.70508
  33. Sci Rep. 2026 May 13.
    Therapeutic potential of mitochondrial transfer in reversing mutant-to-wild-type mtDNA ratio and improving mitochondrial dysfunction in 1555A>G mtDNA mutation-associated hearing loss.
    Yujin Kim, Chang-Hee Kim, Dong Woo Nam, Bong Jik Kim, Ngoc-Trinh Tran, Jin Hee Han, Minyoung Kim, Shin-Hye Yu, Seo-Eun Lee, Jeong Seon Yeo, Iksun Kwon, Kyuboem Han, Chun-Hyung Kim, Young Cheol Kang, Byung Yoon Choi.
      Mitochondrial DNA (mtDNA) mutations are a major cause of sensorineural hearing loss (SNHL). The m.1555A >G mutation in the mitochondrial 12S rRNA gene is closely linked to nonsyndromic and aminoglycoside-induced hearing loss, leading to impaired oxidative phosphorylation (OXPHOS) and ATP production. Current treatments focus on auditory rehabilitation without addressing mitochondrial pathology. This study investigated mitochondrial transplantation as a therapeutic approach. Fibroblasts from two patients with homoplasmic m.1555A > G mutations identified during cochlear implant surgery received allogeneic mitochondria (PN-101) derived from human umbilical cord mesenchymal stem cells. Transplantation significantly increased intracellular ATP levels, complex I activity, and OXPHOS protein expression, while protecting against kanamycin-induced mitochondrial dysfunction. Importantly, PN-101 induced a heteroplasmy shift toward wild-type mtDNA, with repeated treatments sustaining and enhancing this effect. These findings demonstrate that PN-101-mediated mitochondrial transplantation improves mitochondrial bioenergetics and modulates mtDNA heteroplasmy in m.1555A > G mutant cells, suggesting a promising disease-modifying therapy for mtDNA-related hearing loss and a potential precision medicine approach.
    Keywords:  Hearing loss; Heteroplasmy; Mitochondrial transplantation; PN-101; mtDNA 1555A >G mutation
    DOI:  https://doi.org/10.1038/s41598-026-51402-4
  34. Biophys Rep (N Y). 2026 May 08. pii: S2667-0747(26)00018-2. [Epub ahead of print] 100265
    Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.
    Amrendra Kumar, Olesia Lunko, Erin Smith, Ikram Mezghani, Subhash Eedarapalli, Yangyu Wu, Khondoker Adeba Ferdous, Emma Amjad, Han-A Park, Nelli Mnatsakanyan.
      FOF1-ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane and the primary enzyme responsible for ATP production in eukaryotic cells. Nevertheless, it was recently reported to play a prominent role in cell death by forming a large-conductance leak channel in the mitochondrial permeability transition pore (mPTP), making it a promising therapeutic target. Bedaquiline (BDQ), a member of the diarylquinoline class of drugs, was shown to selectively inhibit the catalytic activity of Mycobacterium tuberculosis ATP synthase with no effect on the mammalian enzyme. Here, we report a new role for BDQ as a potent inhibitor of the ATP synthase c-subunit leak channel in mammals. BDQ inhibited the single-channel activity of porcine heart ATP synthase in planar lipid bilayer recordings, inner membrane channel activity of porcine mitochondria in patch-clamp recordings, and prevented glutamate-induced cell death in primary hippocampal neurons. These findings reveal the potential new application of BDQ for treating mPTP-related diseases by targeting the ATP synthase c-subunit leak channel.
    DOI:  https://doi.org/10.1016/j.bpr.2026.100265
  35. Open Biol. 2026 May 13. pii: 250319. [Epub ahead of print]16(5):
    Investigating how changes in the levels of kinesins impact neuronal health in Drosophila and human iPSC-derived neurons AD model.
    Deepthy Francis, Francesco Paonessa, Victoria L Hewitt, Maria Southall, Isabel Peset, Alexander J Whitworth, Frederick J Livesey, Caroline C G Fabre, Isabel M Palacios.
      Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of AD may help identify new ways to reduce neuronal damage. In the past decades, Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here, we investigate how the expression of the human 42-residue β-amyloid (Aβ) carrying the E22G pathogenic 'Arctic' mutation (Aβ42Arc) affects axonal health and behaviour in Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondria and aberrant terminal boutons at neuromuscular junctions. We demonstrate that the motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and in human induced pluripotent stem cell-derived cortical neurons. We then show that the overexpression of kinesin-1 or kinesin-3 restores the correct number and morphology of boutons in Aβ42Arc-expressing neurons and rescues neuronal function measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence towards understanding the mechanisms of axonal transport defects in AD, and our results support the idea that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.
    Keywords:   Drosophila neurons; Alzheimer’s disease; amyloid beta; axonal transport; human neurons; induced pluripotent stem cell; motor proteins; neurodegeneration
    DOI:  https://doi.org/10.1098/rsob.250319
  36. Am J Physiol Cell Physiol. 2026 May 13.
    Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
    Klaudia Sztolsztener, Thulasi Mahendran, David A Hood.
      Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.
    Keywords:  integrated stress response; mitochondrial biogenesis; mitochondrial proteostasis; mitochondrial unfolded protein response; muscle contractile activity
    DOI:  https://doi.org/10.1152/ajpcell.00167.2026
  37. Neuroophthalmology. 2026 ;50(3): 215-221
    Gene Therapy for Leber Hereditary Optic Neuropathy (LHON): A Systematic Review and Meta-Analysis.
    Lama Nasser Alghamdi, Ali Saleh Alsudais, Salma Hamdan Almarwani, Rose Abdullah Alraddadi, Abdulrahman Hamid Alsamadani, Abdulrahman Ahmed Alnamlah, Saif Kamal Aljehani, Yousof Fahad Allarakia, Amer M Alghamdi, Daniah Alshowaeir.
       Background: LHON is a rare mitochondrial disease causing bilateral vision loss, most commonly due to the m.11778G>A mutation. rAAV2/2-ND4 gene therapy is a potential disease-modifying treatment.
    Methods: Systematic review and meta-analysis of three RCTs (RESCUE, REVERSE, REFLECT) including 175 patients.
    Results: Gene therapy significantly improved best-corrected visual acuity but did not significantly increase responder rates. Adverse events were mostly mild ocular inflammation, with no treatment-related mortality.
    Conclusions: rAAV2/2-ND4 is a moderately effective and safe treatment for LHON, though long-term outcomes and predictors of response remain unclear.
    Keywords:  Leber hereditary optic neuropathy; gene therapy; intravitreal injection; mitochondrial DNA; rAAV2/2-ND4; retinal disease
    DOI:  https://doi.org/10.1080/01658107.2026.2624440
  38. Exp Cell Res. 2026 May 14. pii: S0014-4827(26)00179-5. [Epub ahead of print] 115062
    Glutathione Decline Coordinates Mitochondria to License Histone Acetylation and Zygotic Genome Activation.
    Yingpei Xu, Lingyan Huang, Yuting Wu, Linli Cai, Junwen Zhang.
      The glutathione (GSH) metabolism pathway plays a pivotal role in maintaining redox homeostasis, yet its coordination with mitochondrial function and reactive oxygen species (ROS) dynamics during this process remains poorly defined. Here, we report that a developmentally programmed decline in endogenous GSH occurs from the zygote to the 2-cell stage, while ROS levels and mitochondrial activity remain low. Perturbation of this physiological GSH decrease-either by depletion or excessive supplementation-led to developmental arrest at the 2-cell stage, accompanied by aberrant histone acetylation, premature elevation of mitochondrial activity. Further examination revealed these interferences downregulated key zygotic genome activation (ZGA) transcription factors and mitochondrial genes. Furthermore, we show that antioxidants such as GSH, α-lipoic acid, and vitamin C can partially rescue embryonic defects induced by redox imbalance, albeit with varying efficacy. Our findings uncover GSH-mediated redox balance in regulating histone acetylation and mitochondrial maturation from the zygote to 2-cell stages, providing new insights into the metabolic-epigenetic interplay that guides early embryogenesis.
    Keywords:  GSH metabolism pathway; ROS; early embryonic development; mitochondrial activity; redox balance
    DOI:  https://doi.org/10.1016/j.yexcr.2026.115062
  39. Commun Biol. 2026 May 12.
    Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.
    Maha S Alfaidi, Léa M D Wenger, Kornélia Szebényi, Thomas B Stoker, Xiaoling He, Shaline V Fazal, Jana Sebestikova, Amir Jassim, Richard J Gilbertson, Raquel Garza, Johan Jakobsson, Maria Grazia Spillantini, Roger A Barker, Wei-Li Kuan.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and accumulation of α-synuclein (α-syn) into pathological aggregates known as Lewy bodies. PD remains incurable, partly due to limited physiologically relevant models that recapitulate human pathology to enable therapeutic development. We developed a novel in vitro PD dementia model using fetal human cortical neurons seeded with α-syn preformed fibrils (PFFs). This model successfully replicates key PD features, including α-syn aggregation and mitochondrial gene dysregulation. Importantly, RNA sequencing revealed significant transcriptomic concordance between our model and PD postmortem tissue, particularly in the downregulation of mitochondrial genes linked to oxidative phosphorylation. We then evaluated two peptide inhibitors, β-syn36D (B36D) and S62. Both peptides demonstrated effective disaggregation of α-syn fibrils, with B36D showing particular promise by reversing PFF-induced functional and transcriptional changes to baseline levels. This human-relevant model captures essential pathological and transcriptomic disease hallmarks as well as demonstrating utility for therapeutic screening of drugs that block α-syn aggregation.
    DOI:  https://doi.org/10.1038/s42003-026-10134-x
  40. Nat Commun. 2026 May 15.
    α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
    Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-κB-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-Syn-induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.
    DOI:  https://doi.org/10.1038/s41467-026-73136-7
  41. Eur J Hum Genet. 2026 May 14.
    Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.
    Chiara Folland, Gavin Monahan, James Breen, Mridul Johari, Hardip R Patel, Gianina Ravenscroft.
      Despite considerable efforts investigating the genetic aetiology of rare diseases in the past decades, approximately 50% of cases remain without a genetic diagnosis. Many missing diagnoses can be attributed to the limitations of short-read sequencing (SRS), compounded by (mis)-alignment to incomplete and inaccurate reference genomes such as GRCh37/38. SRS cannot resolve many regions that are challenging to map, including large contiguous tandem repeats, segmental duplications (SDs), sites of complex structural variants (SV), or highly diverged population-specific loci. Long-read sequencing (LRS) technologies have delivered the first complete human genome assembly, T2T-CHM13. Compared to GRCh38, T2T-CHM13 resolves the remaining 8% of the genome, corrects structural errors and improves both SRS- and LRS-based read mapping and variant discovery. LRS has also facilitated the generation of high-quality, haplotype-resolved assemblies from globally diverse cohorts, enabling the construction of pangenome references for multiple ancestral groups. By representing more human genomic variation, a pangenome reference can improve mapping and variant calling accuracy. These new genome resources represent alternative reference paradigms that have the potential to uncover pathogenic variants underlying unsolved rare genetic diseases. Here, we examine the limitations of GRCh38 for rare disease variant discovery and explore how emerging resources like T2T-CHM13 and pangenomes can improve accuracy. We highlight key studies that have leveraged these references to improve diagnostic outcomes and discuss the potential for broader adoption. Finally, we consider the current barriers to research and clinical implementation and outline available resources and tools to expedite the transition to these new reference models.
    DOI:  https://doi.org/10.1038/s41431-026-02125-7
  42. Pharmacol Res. 2026 May 07. pii: S1043-6618(26)00149-0. [Epub ahead of print]229 108234
    Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.
    Emanuela Franchini, Matteo Bulloni, Anna Sorgente, Katarina Paulikova, Laura Cassina, Ilaria Marafelli, Irene Sambri, Linda Pattini, Giorgio Casari.
      The mitochondrial permeability transition pore (mPTP) is a voltage‑ and calcium‑regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from SPG7 patient cells and healthy control confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.
    Keywords:  Berberine; Hereditary spastic paraplegia; High content screening; MPTP; Mitochondrial permeability transition pore; SPG7
    DOI:  https://doi.org/10.1016/j.phrs.2026.108234
  43. Mol Cells. 2026 May 13. pii: S1016-8478(26)00060-9. [Epub ahead of print] 100369
    Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.
    Seyed Majed Modaresi, Leilei Zhang, Amir Ata Saei, Morris Degen, Mohammad Khavani, Hassan Gharibi, Ákos Végvári, Zhiwei Ye, Jie Zhang, Evgeny Pavlov, Elizabeth A Jonas, Kenneth D Tew, Sebastian Hiller, Danyelle M Townsend, Eduardo N Maldonado.
      Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. NADH closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using High-resolution Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and ATP production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains ATP production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work set a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.
    Keywords:  SC18; VDAC1; cancer metabolism; glycolysis; mitochondria
    DOI:  https://doi.org/10.1016/j.mocell.2026.100369
  44. J Neuroinflammation. 2026 May 11.
    IFI204 drives gasdermin D-mediated mitochondrial permeabilization to amplify neuronal pyroptosis in ischemic stroke.
    Pengfei Xu, Nan Shen, Tian Qiu, Mingyue Zhou, Rui Li, Chunrong Tao, Yuyou Zhu, Wei Hu.
      Gasdermin D (GSDMD)-mediated pore formation on mitochondrial membranes is known to exacerbate pyroptosis. The cytosolic DNA sensor interferon activated gene 204 (IFI204) can activate the inflammasome to induce pyroptosis. However, whether and how IFI204 regulates mitochondrial membrane permeabilization to drive pathological outcomes in ischemic stroke remains unclear. Here, using a mouse model of middle cerebral artery occlusion (MCAO), we demonstrate that IFI204 was predominantly expressed in neurons and increased to peak at 24 h after ischemic injury. Neuron-specific deletion of IFI204 alleviated cerebral infarction, reduced neuronal degeneration, and restored long-term sensorimotor coordination and cognitive function. These protective effects correlated with attenuated neuronal pyroptosis and mitochondrial dysfunction, as evidenced by decreased levels of GSDMD N-terminal fragment (GSDMD-N) and reduced mitochondrial colocalization. Conversely, adeno-associated virus-mediated re-expression of IFI204 in knockout mice restores these pathological features. In vitro, IFI204 is both necessary and sufficient to trigger this cascade. Transcriptomic profiling revealed a significant downregulation of the stimulator of interferon genes (STING) within the NOD-like receptor signaling pathway in IFI204-deficient neurons. Mechanistically, glutathione S-transferase (GST) pull-down assays confirmed a direct interaction between the pyrin domain (PYD) of IFI204 and STING. This interaction triggers caspase-1 activation and GSDMD cleavage, generating GSDMD-N, which subsequently forms pores specifically on mitochondrial membranes. These pyroptotic pores disrupted mitochondrial integrity, exacerbating dysfunction, and facilitating the cytosolic release of mitochondrial DNA (mtDNA), cytochrome c, and aconitase 2. Notably, the released mtDNA further activated IFI204, establishing a pathogenic feed-forward cycle that exacerbates mitochondrial damage and inflammatory neuronal death. Genetic ablation of STING partially abrogated the pyroptosis-promoting effect of IFI204. Collectively, these findings demonstrate that IFI204-driven cytosolic mtDNA sensing underlies a neuronal inflammatory mechanism responsible for pyroptosis and mitochondrial damage in ischemic stroke.
    Keywords:  GSDMD; IFI204; Ischemic stroke; Mitochondrial DNA (mtDNA); Neuroinflammation; Pyroptosis
    DOI:  https://doi.org/10.1186/s12974-026-03847-7
  45. Int J Mol Sci. 2026 Apr 30. pii: 4018. [Epub ahead of print]27(9):
    Therapeutic Impact of Mitochondrial Transplants for Cardiovascular Diseases.
    Konstantina Antoniadou, Ioannis Shiammoutis, Christina Piperi.
      Mitochondria are vital organelles for human cells with fundamental roles in major metabolic processes such as calcium homeostasis, ATP production, apoptosis and signal transduction. Defective morphology and activity of these organelles have been tightly associated with the pathological onset of severe human disorders, including cardiovascular diseases. Targeting mitochondrial dysfunction has been an area of extensive research encompassing several approaches ranging from pharmacological agents to mitochondrial replacement techniques. Among them, mitochondrial transplantation has been a rapidly evolving approach, especially in the field of cardiovascular dysfunction for the restoration of injured or damaged myocardial cells. Various methods including tunneling nanotubes, nanoblade and "mitopunch" ensure the effective mitochondrial transfer from the donor to the recipient cell, with the internalization of the organelles, via endocytosis, enabling functional restoration. Results of preclinical and clinical trials involving mitochondrial transfer support the application of this technique in improving the function of the myocardium after damage caused by ischemia reperfusion injury. Herein, we discuss the beneficial role of mitochondrial transplantation in cardiovascular diseases and the current technical challenges of mitochondrial isolation, preservation, and targeted delivery, as well as their role in advancing precision medicine, offering a patient tailored therapeutic approach.
    Keywords:  CVD; ischemia/reperfusion injury; mitochondrial replacement therapy; mitochondrial transplantation; mtDNA
    DOI:  https://doi.org/10.3390/ijms27094018
  46. bioRxiv. 2026 Feb 27. pii: 2026.02.26.708316. [Epub ahead of print]
    Convergent effects of neurodevelopmental disorder-associated variants at mitochondria.
    Maxine I Robinette, Jada B Gundy, Xinyan Leng, Duc Duong, Ananth Shantaraman, Liang Shi, Elizabeth A Candelario, Anson Sing, Shubhangi Vibhor Garg, Weibo Niu, Nicholas T Seyfried, Steven A Sloan, Zhexing Wen, Joseph F Cubells, Erica Duncan, Jennifer G Mulle, Victor Faundez, Gary J Bassell, Ryan H Purcell.
      Investigations into the molecular pathogenesis of clinically defined neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD) and schizophrenia (SCZ) have produced evidence implicating dysfunctional mitochondrial metabolism. However, the functional connection between risk variants and mitochondrial proteins largely remains unclear. We tested the hypothesis that proteins encoded by NDD-associated copy number variants (CNVs) and SCZ risk genes are enriched within the mitochondrial interactome. We found that NDD- and SCZ-associated genes exhibit mitochondrial association comparable to their overlap with synaptic proteins, with interaction networks converging most strongly on mitochondrial translation. Two high-risk CNVs, the 3q29 deletion (3q29Del) and the 22q11.2 deletion (22q11Del), confer similar risks for ASD and SCZ and have independently been linked to mitochondrial phenotypes. To test whether these CNVs produce convergent effects on mitochondrial proteins in developing human neural tissue, we generated an isogenic series of 3q29Del and 22q11Del induced-pluripotent stem cells (iPSCs) and differentiated them into forebrain cortical organoids. Quantitative proteomic analysis showed high similarity in the profiles of dysregulated proteins in 3q29Del and 22q11Del compared to isogenic controls. Enrichment analysis of proteins altered in both variants revealed significant convergence on the mitochondrial ribosome and translation machinery. Furthermore, manipulation of mitochondrial translation elicited similar proteomic and functional responses in organoids and neural progenitor cells across both CNVs. These findings indicate that NDD-associated genes have rich interactions with mitochondrial proteins and that two of the strongest risk factors for NDDs may similarly disrupt neural mitochondrial metabolism through impaired mitochondrial translation.
    DOI:  https://doi.org/10.64898/2026.02.26.708316
  47. Epilepsia. 2026 May 14.
    Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.
    Annika Breuer, Chiara A Hummel, Tobias Baumgartner, Juliane L Berns, Afaf Milad Said, Isabel Bünger, Susanne Schoch, Gábor Zsurka, Harald Prüss, Wolfram S Kunz, Rainer Surges, Albert J Becker, Julika Pitsch.
       OBJECTIVE: We investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures, who were negative for known antineuronal autoantibodies.
    METHODS: We screened serum samples from 387 patients autoantibody-negative for known antineuronal autoantibodies with psychiatric disturbances and/or epileptic seizures, including patients with temporal lobe epilepsy of unknown etiology. Various techniques, including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and in vitro assays assessing neuronal autoantibody uptake, neuronal viability, pyruvate dehydrogenase (PDH) enzyme activity, and mitochondrial DNA levels in biofluids were applied.
    RESULTS: Mass spectrometry detected all three subunits of the intramitochondrial PDHc-pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, and dihydrolipoyl dehydrogenase-as targets of antibodies present in serum samples from three index patients suspicious for AIE with psychiatric symptoms or seizures. The presence of the anti-PDHc autoantibodies was confirmed by immunoblotting in 12 of 387 patients. Exposure of cultured primary neurons to commercial anti-PDH antibodies resulted in neuronal uptake and loss of neuronal viability. Patient-derived autoantibodies also impaired PDH enzyme activity in vitro. Additionally, cell-free mitochondrial DNA fragment levels were elevated in the serum and cerebrospinal fluid of PDH-positive patients compared to controls.
    SIGNIFICANCE: Anti-PDH autoantibodies were detected in patients suspicious for AIE with seizures and/or psychiatric symptoms as core manifestation in the absence of known antineuronal autoantibodies. These autoantibodies bind neuronal structures and reduce PDH enzyme activity under experimental conditions, supporting mechanistic plausibility of a functional role in disease.
    Keywords:  antimitochondrial autoantibodies; enzyme activity; mitochondria; psychiatric symptoms; seizures
    DOI:  https://doi.org/10.1002/epi.70282
  48. Stud Health Technol Inform. 2026 May 07. 335 89-95
    Flexible Data Integration for Genomics-Driven Decision Support in Rare Genetic Epilepsy.
    Ariadna Pérez Garriga, Philipp Honrath, Stefan Wolking, Beatrice Coldewey, Susann A Bozkir, Nils Freyer, Patrick May, Yvonne Weber, Rainer Röhrig, Myriam Lipprandt.
       BACKGROUND: Precision medicine for complex diseases like epilepsy requires integrating heterogeneous clinical and genomic data but interpreting numerous disease-associated genes remains challenging.
    OBJECTIVES: How can data from disparate biomedical sources be organized efficiently and flexibly to support precision medicine in early project stages in genetic epilepsy?
    METHODS: We applied a three-step system design approach tailored for academic medical research, considering project requirements, available resources, and technology selection.
    RESULTS: The EAV-hybrid model accommodated diverse clinical and genetic data while preserving flexibility for future expansion. Integration with cBioPortal enabled intuitive visualization and interpretation. The design supports future migration to standard CDMs such as OMOP or i2b2.
    CONCLUSION: A flexible, metadata-driven EAV-hybrid model supports rapid prototyping and structured data integration in early-stage precision medicine projects, providing an infrastructure for molecular boards and clinical decision-making for genetic epilepsies.
    Keywords:  Common Data Model; Data Management; Data Standardization; Epilepsy; Precision Medicine
    DOI:  https://doi.org/10.3233/SHTI260061
  49. Nucleic Acids Res. 2026 May 05. pii: gkag480. [Epub ahead of print]54(9):
    Universal conditional knockout approach to multiple species, from fish to human induced pluripotent stem cells.
    Jung-Hwa Choi, Jihoon Moon, Youngchul Oh, Thomas M Klompstra, Yujin Kim, Gayoung Baek, Yejin Kwak, Yeongjun Kim, Sangmin Lee, Sujin Park, Jeongmin Ha, Ohbin Kwon, Young Ki Choi, Jeong Hun Kim, Ji-Hyun Lee, Jeongbin Park, Jong Kyoung Kim, Dong Ho Woo, Ki-Jun Yoon, Bon-Kyoung Koo, Heetak Lee.
      Investigating essential gene function in vertebrate development and disease is challenging due to associated lethality, necessitating precise conditional inactivation. While existing conditional knockout methods can be inefficient and demanding, especially in models like zebrafish and human induced pluripotent stem cells (iPSCs), a widely applicable system has remained elusive. Here, we demonstrate the expanded utility and versatility of a Short Conditional intrON (SCON) knockout cassette, now validated for efficient conditional loss-of-function mutation generation in diverse vertebrate models, including zebrafish, human iPSCs, and intestinal organoids. Building on this validated broad applicability, we establish a comprehensive, user-friendly web-based GenPos-SCON database (https://genpos.org/) to streamline conditional knockout design for over 300 vertebrate species. This powerful resource and proven methodology significantly accelerate systematic gene functional studies across the vertebrate tree, providing an unprecedented tool for dissecting fundamental biological processes and disease mechanisms in relevant contexts.
    DOI:  https://doi.org/10.1093/nar/gkag480
  50. Nat Metab. 2026 May 14.
    Whole-blood NAD+ levels do not reflect healthy ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01540-w
  51. Nat Commun. 2026 May 12.
    Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
    Linghui Kong, Jiajian Liang, Dan Liu, Shanshan Jia, Hui Gu, Yiwen He, Wenting Luo, Songying Cao, Yizhang Dong, Chao Yang, Minghui Liao, Guojia Wan, Bo Du, Dongxue Ding, Wei Ma, Xiaowei Wei, Anhua Wu, Zhengwei Yuan.
      Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-13C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-026-72988-3
  52. Acta Physiol (Oxf). 2026 Jun;242(6): e70246
    A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis.
    Riccardo Cavalieri, Margeoux A S Dela Rosa, Camila A Cotrim, Danielle Copeman, Mehmethan Aris, Callum Eke, Hannah Staggs-Sandy, Paul G Crichton.
      Uncoupling Protein 1 (UCP1) is a defining feature of brown fat and facilitates the specialized ability of the tissue to generate heat in the process of non-shivering thermogenesis. The protein is activated by fatty acids, which overcome its inhibition by purine nucleotides, to catalyze proton leak across the mitochondrial inner membrane, uncoupling nutrient oxidation from ATP production to release energy as heat. Thermogenesis through this process contributes to thermoregulation in many mammals and can promote nutrient turnover in humans to support metabolic health. UCP1 is a member of the mitochondrial carrier family of solute exchangers. For many years, its underlying mechanisms of activity and regulation have remained unclear. However, recent cryo-EM structures of UCP1 have clarified details on nucleotide inhibition and, with advances in our understanding of the mitochondrial carrier transport mechanism, provided important molecular constraints to rationalize how the protein may operate. Here, we review the molecular nature of UCP1, re-evaluating past structure-function relations in this structural context. Key carrier features and putative novel bonding that likely support state changes in the protein and proton leak activity are highlighted, as well as new hypotheses to explain subtleties in purine nucleotide binding discrimination.
    Keywords:  UCP1 structure; brown adipose tissue; energy expenditure; fatty acid activation; mitochondrial carrier; molecular modeling; proton transport; purine nucleotide inhibition
    DOI:  https://doi.org/10.1111/apha.70246
  53. Cell. 2026 May 14. pii: S0092-8674(26)00521-0. [Epub ahead of print]
    Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
    Shiwei Du, Qi Long, Yanshuang Zhou, Jiangqin Fu, Hao Wu, Liang Yang, Yaohang Xie, Yingzhe Ding, Maolei Zhang, Jingyi Guo, Mengfei Wang, Jiajun Lin, Mingli Hu, Jian Zhang, Deyang Yao, Wei Li, Feixiang Bao, Ge Xiang, Yi Wu, Yile Huang, Haozhao Liang, Rui Wang, Heying Li, Baodan Chen, Chong Li, Junwei Wang, Jiwei Zhang, Dajiang Qin, Jianwei Sun, Yun Zhu, Fei Sun, Wuming Wang, Gang Lu, Wai-Yee Chan, Hui Zhao, Chenli Liu, Xingguo Liu.
      
    DOI:  https://doi.org/10.1016/j.cell.2026.05.004
  54. Nat Commun. 2026 May 13.
    Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer.
    Andrea Palamidessi, Emanuela Frittoli, Monica Corada, Emanuele Martini, Leonardo Barzaghi, Chiara Milanese, Galina V Beznoussenko, Alessandro Lazzarin, Edoardo N Bellini, Alexander A Mironov, Zeno Lavagnino, Serena Magni, Sara Barozzi, Dario Parazzoli, Laura Tizzoni, Valentina Dall'Olio, Valeria Cancila, Patrizia Romani, Melody Di Bona, Renata Zobalova, Stepana Boukalova, Mattia Rediti, Pier G Mastroberardino, Jiri Neuzil, Marco Foiani, Sirio Dupont, Claudio Tripodo, Giorgio Scita.
      Why some tumors respond to immunotherapy ("hot" tumors) while others remain resistant ("cold" tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK-AKAP1-DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS-STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-71795-0
  55. bioRxiv. 2026 Feb 23. pii: 2026.02.22.707308. [Epub ahead of print]
    Reverse electron transfer at mitochondrial complex I restrains dopaminergic neuron activity to promote early-life sleep in Drosophila.
    Jeffrey B Rosa, Hayle H Kim, Jenny Luong, Jianing Yang, Peyton Yee, Allen Yan, Anyara Rodriguez, Matthew S Kayser.
      Sleep architecture and depth undergo profound changes across early life. In many species, including Drosophila melanogaster , juvenile animals exhibit elevated sleep drive and deeper sleep states relative to adults, a process linked to reduced activity of wake-promoting dopaminergic neurons (DANs). To identify cell-intrinsic mechanisms regulating developmental sleep, we profiled gene expression in juvenile and mature DANs and performed a targeted RNAi screen of genes with higher juvenile expression. From this screen, we found that the magnitude of mitochondrial complex I (MCI) disruption produced distinct behavioral outcomes. Severe MCI loss-of-function caused locomotor deficits due to mitochondrial dysfunction and reduced neuronal activity. Surprisingly, partial MCI inhibition preserved mitochondrial integrity but resulted in sleep loss, with a most pronounced impact on juvenile adult sleep fragmentation and depth. We demonstrate that dopaminergic neuron activity in juvenile flies is sensitive to the Coenzyme Q redox state with a low CoQ/CoQH2 promoting sleep depth by restraining DAN activity. Our results are consistent with a model in which the reverse transfer of electrons from CoQH2 to NAD+ at MCI limits DAN activity. By dissociating changes in CoQ redox state from catastrophic mitochondrial failure, this work indicates that sleep phenotypes may serve as sensitive indicators of emerging mitochondrial dysfunction, with implications for understanding the developmental origins of neurodegenerative vulnerability.
    DOI:  https://doi.org/10.64898/2026.02.22.707308
  56. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70309
    Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
    Rodrigo W Alves de Souza, Hyo In Kim, Paula Ketilly Nascimento Alves, Ailma Oliveira da Paixão, Ashlee Rasmussen, Sidharth Shankar, James Harbison, Vanessa Azevedo Voltarelli, Leo E Otterbein.
       BACKGROUND: Heme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states.
    METHODS: We generated Hmox1/2 double-knockout mice (Hmox1/2-/-) and compared their skeletal muscle phenotype with that of single HO-1 or HO-2 knockouts and wild-type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (n = 8-12 per group), assessed fibre-type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high-resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance.
    RESULTS: HO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2-/- mice restored fibre-type distribution toward oxidative fibres (increased by 25%, p < 0.01), improved mitochondrial respiratory parameters and doubled endurance performance (p < 0.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance.
    CONCLUSIONS: HO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.
    Keywords:  carbon monoxide; exercise adaptation; heme oxygenase; mitochondrial dysfunction; neuromuscular junction; skeletal muscle metabolism
    DOI:  https://doi.org/10.1002/jcsm.70309
  57. Biochim Biophys Acta Bioenerg. 2026 May 09. pii: S0005-2728(26)00015-0. [Epub ahead of print]1867(4): 149595
    Mitochondrial dysfunction redirects proton transport and energy homeostasis in Saccharomyces cerevisiae under variable pH and glucose conditions.
    Liana Anikyan, Anahit Shirvanyan, Nicoletta Guaragnella, Karen Trchounian.
      Mitochondrial function is crucial for the regulation of energy metabolism, proton homeostasis, and stress adaptation in Saccharomyces cerevisiae. This study demonstrates the role of mitochondria in modulating cellular responses to varying extracellular pH (3.0, 5.0, 6.5) and glucose availability (0.5%, 2%). Results indicate that mitochondrial deficiencies in Δhap4 and ρ0 mutants selectively impair growth under acidic pH and 0.5% glucose conditions, whereas wild-type cells maintain pH-independent growth. Mitochondrial impairment redistributes intracellular H+ homeostasis regulation to plasma membrane and cytosolic H+-ATPases in a glucose- and pH-dependent manner, with ρ0 cells exhibiting maximal reliance on non-mitochondrial ATPases. The N, N'- dicyclohexylcarbodiimide (DCCD)-sensitive JH+ scales inversely with glucose availability, reflecting energy demand under nutrient limitation and acid stress. ρ0 cells exhibit the highest alcohol dehydrogenase activity to regulate the redox balance in response to non-functional mitochondria. The highest total H+-ATPase activity measured in ρ0 cells at pH 6.5 and 0.5% glucose conditions, combined with proton flux data, indicates the upregulation of plasma membrane and cytosolic ATPases activity for maintaining proton motive force and intracellular pH due to a complete loss of FoF1-ATPase contribution. These results pave the way for the construction of robust S. cerevisiae yeast strains to varying glucose and extracellular pH conditions.
    Keywords:  ATPase activity; Crabtree effect; Glucose sensing; Mitochondrial dysfunction; Saccharomyces cerevisiae; pH sensing
    DOI:  https://doi.org/10.1016/j.bbabio.2026.149595
  58. Anal Chim Acta. 2026 Jul 15. pii: S0003-2670(26)00465-4. [Epub ahead of print]1407 345515
    Recent advances in the design mechanisms of mitochondrial fluorescent probes: A review.
    Fei Peng, Bo Wang, Yunjia Xu, Ran Chai, Aibing Wu, Mingming Xue, Huijuan Tian, Yan Lv, Xiangyu Guo, Bin Hao, Baoxiang Gao.
      Mitochondria are central regulators of cellular energy metabolism, redox balance, and signal transduction, and fluorescent probes have become indispensable tools for visualizing their structure and function with high spatial and temporal precision. Because mitochondrial physiological parameters, including membrane potential, pH, viscosity, reactive species, and ion fluxes, arise from distinct microenvironmental features, their accurate detection requires probe designs based on different photophysical mechanisms. Although several reviews have summarized probes for specific mitochondrial indicators, systematic discussions focused on the underlying photophysical design mechanisms remain scarce. In this review, we comprehensively summarize the major mechanisms that govern mitochondrial probe performance, including photoinduced electron transfer (PET), intramolecular charge transfer (ICT), Förster resonance energy transfer (FRET), aggregation-induced emission (AIE), and excited-state intramolecular proton transfer (ESIPT). Particular emphasis is placed on their design principles, analytical characteristics, representative applications, and inherent advantages and limitations from a bioanalytical perspective. It is respected that this mechanism-oriented review will provide useful guidance for the rational development of next-generation mitochondrial fluorescent probes for precise imaging and sensing.
    Keywords:  Design strategies; Fluorescent probes; Mitochondria; Physiological parameters
    DOI:  https://doi.org/10.1016/j.aca.2026.345515
  59. Mol Biol Rep. 2026 May 12. pii: 745. [Epub ahead of print]53(1):
    Modeling human neurodegenerative disorders in Drosophila: strategies and translational opportunities.
    Shereen A Mohamed, Omnia A Badr.
      Drosophila melanogaster provides a genetically tractable and evolutionarily conserved platform for interrogating mechanisms of human neurodegeneration. This revised review critically evaluates how transgenic and genome-edited fly models expressing amyloid-beta, tau, alpha-synuclein, mutant huntingtin, and patient-relevant variants reproduce selective aspects of Alzheimer's disease, Parkinson's disease, and polyglutamine disorders, while also highlighting the boundaries of translational inference. We emphasize conserved pathogenic modules, including oxidative stress, mitochondrial dysfunction, impaired proteostasis, and stress signaling through Nrf2, JNK, and PINK1/Parkin, and distinguish robust mechanistic insights from findings that are primarily descriptive or overexpression-driven. We further discuss the specific contribution of Drosophila genetic tools such as GAL4/UAS, RNA interference, CRISPR-Cas9, and FLP/FRT-based mosaic analysis for dissecting cell-autonomous and non-cell-autonomous neurotoxicity. To improve usability, the manuscript now summarizes major disease models and natural compounds in dedicated tables, expands therapeutic discussion to include HDAC inhibitors and mitochondria/redox-directed small molecules, and outlines how fly studies can function within translational pipelines for variant interpretation, target prioritization, and preclinical triage before mammalian validation and human trials. Finally, we address key limitations of Drosophila relative to humans, including differences in metabolism, blood-brain barrier properties, immune complexity, and disease timescale, to provide a more balanced framework for using fly neurodegeneration models in precision medicine.
    Keywords:   Drosophila melanogaster ; Alzheimer’s disease; Antioxidants; Genetic modeling; Neurodegeneration; Oxidative stress; Parkinson’s disease; Precision medicine
    DOI:  https://doi.org/10.1007/s11033-026-11844-5
  60. Nature. 2026 May 15.
    Genetic survey exposes flaws in widely used mouse models.
    Ewen Callaway.
      
    Keywords:  Biological techniques; Genetics
    DOI:  https://doi.org/10.1038/d41586-026-01534-4
  61. Redox Biol. 2026 May 06. pii: S2213-2317(26)00198-9. [Epub ahead of print]94 104200
    PSG6: A mitochondrially-targeted gentisic acid derivative exerts antiplatelet action via mitochondrial complex I inhibition.
    Francisca Tellería, Matías Monroy-Cárdenas, Cristina Pecorilla, Amina Djurabekova, Diego Méndez, Magdalena Sepúlveda, Felipe Lagos, Santiago Mansilla, Laura Castro, Andrés Trostchansky, Adriana Covarrubias-Pinto, Alexis González, Ivan Dikic, Iván Palomo, Volker Zickermann, Vivek Sharma, Lisandra Morales-Malvarez, Héctor Montecino-Garrido, Ramiro Araya-Maturana, Eduardo Fuentes.
      Cardiovascular diseases are the leading cause of death worldwide, and cancer-associated thrombosis remains a major clinical challenge because of the interplay between tumour progression and platelet activation. Platelets contribute to thrombus formation by adhering to damaged endothelium and undergoing aggregation. Since mitochondria-targeted compounds are useful as antitumour and antiplatelet agents, we evaluated a series of triphenylphosphonium salts derived from gentisic acid alkyl esters with varying chain lengths, searching for antiplatelet agents with dual activity. The compound with a six-carbon chain (PSG6) exhibited the highest antiplatelet activity without increasing bleeding risk, whereas the cytotoxicity was found to increase with the chain length. PSG6 also showed selective anticancer effects, reducing tumour cell viability at micromolar concentrations, inducing mitochondrial fission, and lowering the mitochondrial membrane potential (ΔΨm) at 10 μM. Mechanistically, PSG6 decreased ΔΨm, inhibited the mitochondrial electron transport chain (ETC) at complex I, and increased intracellular calcium and reactive oxygen species (ROS) production. Complex I inhibition was confirmed in the yeast model organism Yarrowia lipolytica (IC50 = 2.9 μM), and atomistic molecular dynamics simulations suggest that PSG6 may inhibit complex I by binding at the shallow site of the ∼30 Å long ubiquinone tunnel. These results position PSG6 as a promising mito-inhibitor candidate for antiplatelet therapy.
    Keywords:  Antiplatelet; Gentisic acid; Mitochondria; Triphenylphosphonium; complex I
    DOI:  https://doi.org/10.1016/j.redox.2026.104200
  62. bioRxiv. 2026 Feb 25. pii: 2026.02.24.707575. [Epub ahead of print]
    Liver Disease Reveals KIF12 as a Critical Regulator of Mitochondria, Lysosome and Cilia Localization.
    Anubha Seth, Joseph Brancale, Nina Dashti-Gibson, Rodrigo M Florentino, Lanuza A P Faccioli, Zhenghao Liu, Chigoziri Konkwo, Hyunseok Hong, Alejandro Soto-Gutierrez, Silvia Vilarinho.
      Pathogenic variants in kinesin family member 12 (KIF12) cause pediatric liver disease, yet the cellular mechanisms underlying this phenotype remain unknown. Here we show that KIF12 expression in the healthy human liver is primarily detected in biliary epithelial cells, as revealed by single cell RNA-sequencing data. To investigate its role in biliary pathology, we introduced a homozygous KIF12 p.Arg219* mutation into induced pluripotent stem cells (iPSCs), which were differentiated into 2D cholangiocyte-like cells (iCCs) and 3D biliary organoids. Pioneering single-molecule fluorescence microscopy in live iCCs, we observed wildtype KIF12 co-localizing with microtubules, consistent with its predicted role as a microtubule-associated motor protein. Our data reveals that KIF12 dysfunction causes abnormal perinuclear clustering of mitochondria and lysosomes, and mislocalization of primary cilia in cholangiocytes. Restoration of wildtype KIF12 expression in mutant KIF12 iCCs rescued organelle positioning and normalized GGT activity. This study uncovers a novel link between KIF12 dysfunction and organelle dynamics in human cholangiocytes, extending our understanding of kinesin roles beyond their established functions in neuronal systems. Our findings provide new insights into the pathogenesis of KIF12-related cholestatic liver disease and lay the groundwork for developing targeted genetic therapies.
    DOI:  https://doi.org/10.64898/2026.02.24.707575
  63. Trends Biotechnol. 2026 May 14. pii: S0167-7799(26)00148-4. [Epub ahead of print]
    Automated stem cell-derived organoid platforms for disease modeling.
    Xingrui Mou, Nathan Dale, Kiran Ramnarine, Filippo Cipriani.
      Complex diseases arise from genetic, environmental, and lifestyle factors, the combination of which is difficult to model. Conventional animal and 2D cell culture models have limitations in scalability, reproducibility, or human relevance. Human-induced pluripotent stem cells (iPSCs) can be differentiated into 3D organoids that better mimic human biology. However, organoid protocols can be lengthy, variable, and labor-intensive, limiting high-throughput applications. Suspension bioreactors and multilineage differentiation have improved yield and function, but challenges remain in tissue maturity, vascularization, and consistency. Automated high-throughput liquid handling systems are emerging as a solution, enabling large-scale, reproducible production. Here, we discuss how combining iPSC-derived organoids with automation is poised to transform disease modeling and drug development.
    Keywords:  automation and high-throughput systems; complex disease modeling; iPSC-derived organoids
    DOI:  https://doi.org/10.1016/j.tibtech.2026.04.013
  64. Food Chem Toxicol. 2026 May 13. pii: S0278-6915(26)00228-0. [Epub ahead of print]214 116154
    Environmental stress-induced mitochondrial metabolic reprogramming as a central driver of endocrine dysfunction: A food and chemical toxicology perspective.
    K Jayadevan, Mishel Abdullah, P K V Kavyasree, Amalkrishnan Therayil.
      Dietary and environmental chemical exposures including food contact materials, pesticide residues, heavy metals, mycotoxins, and synthetic food additives are increasingly recognized as contributors to endocrine and metabolic disease via mitochondrial mechanisms not captured by classical receptor-based screening. Mitochondria function as central integrators of metabolism, redox signaling, and stress responses, extending beyond bioenergetics to regulate endocrine function. These chemicals disrupt oxidative phosphorylation, mitochondrial dynamics, and metabolite fluxes, inducing metabolic reprogramming in hormone-sensitive tissues. Consequences include impaired ATP production, altered reactive oxygen species signaling, and epigenetic dysregulation, leading to defects in hormone synthesis, secretion, and tissue responsiveness. Developmental vulnerability and genetic variation in mitochondrial and nuclear-encoded genes further modulate susceptibility. Mechanistically, a cascade progresses from oxidative damage and impaired biogenesis to disrupted dynamics and mitophagy, followed by retrograde metabolite signaling that epigenetically stabilizes endocrine dysfunction. This underlies insulin resistance, steroidogenic impairment, thyroid imbalance, and neuroendocrine dysregulation. Tissue-specific mitochondrial vulnerabilities align with distinct chemical classes across endocrine cell types. While pharmacological and lifestyle interventions show promise, limitations in bioavailability and safety of food-derived bioactives remain. This review integrates causal evidence, chemical classification, and tissue-specific mapping to provide a translational framework for food toxicology and regulatory assessment.
    Keywords:  Endocrine disruption; Epigenetics; Food additives; Food contaminants; Insulin resistance; Metabolic reprogramming; Mitochondria; Mycotoxins
    DOI:  https://doi.org/10.1016/j.fct.2026.116154
  65. Cells. 2026 May 01. pii: 830. [Epub ahead of print]15(9):
    Mitochondrial ROS Production at Complexes I and III in Human Myocardium and Skeletal Muscle: A Distinct Pattern Compared with Rat Tissue.
    Ivan Mihanovic, Jasna Marinovic, Cristijan Bulat, Bruno Luksic, Zlatko Marovic, Marko Ljubkovic.
      Mitochondrial reactive oxygen species (ROS) play a central role in cardiac ischemia/reperfusion injury, heart failure, and arrhythmogenesis, while also serving essential signaling functions under physiological conditions. Among the eleven identified mitochondrial ROS-producing sites, complexes I and III are considered the major contributors, particularly under conditions of impaired electron flow. However, much of the existing knowledge comes from rodent models or cultured cells and is often assumed to apply to humans. Here, ROS production from complexes I and III was measured directly in human myocardial and skeletal muscle biopsies and compared with corresponding rat tissues under identical experimental conditions. Hydrogen peroxide generation was quantified using Amplex UltraRed, with simultaneous monitoring of mitochondrial respiration using a Clark-type oxygen electrode. Across all examined mechanisms-reverse and forward electron transport at complex I and the ubiquinol oxidation site of complex III, rat tissues produced more ROS than human tissues, consistent with their higher respiratory rates. However, the dominant ROS-producing sites differed: in rats, complex III was the primary source, whereas in human tissues the highest ROS production occurred during reverse electron transport at complex I. When normalized to respiration, human tissues showed relatively greater ROS generation at complex I but markedly lower production at complex III. These direct measurements of mitochondrial ROS production in human myocardium provide new insight into cardiac redox physiology and may explain the limited clinical translation of cardioprotective strategies targeting mitochondrial ROS production, such as interventions aimed at modulating reperfusion injury or preconditioning.
    Keywords:  complex I; complex III; human myocardium; mitochondrial ROS hierarchy; mitochondrial reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.3390/cells15090830
  66. J Hum Immun. 2026 Jul 06. 2(4): e20250235
    Adult-onset STING-associated vasculopathy.
    Penn Medicine Biobank
      Genetic contributions to systemic autoimmunity are often considered more significant in children than in adults. As such, genetic evaluation may be more frequently pursued in pediatric rheumatology patients. Motivated by the discovery of a STING-associated vasculopathy with onset in infancy (SAVI) mutation in a patient with adult-onset relapsing polychondritis and systemic lupus erythematosus, we hypothesized that STING gain-of-function mutations might underlie a broader spectrum of autoimmune disease in adults. We systematically screened 43,731 exomes from the Penn Medicine Biobank, revealing five additional unrelated adults with SAVI-associated STING gain-of-function mutations, including several patients with clinical features of SAVI, as well as asymptomatic individuals with type I IFN signatures. We propose the term adult-onset STING-associated vasculopathy (AO-SAVI) to describe these patients. Our findings challenge the conventional symptom-driven diagnostic paradigm, revealing that parallel molecular classification can uncover shared mechanisms and genetic etiologies across seemingly distinct diseases.
    DOI:  https://doi.org/10.70962/jhi.20250235
  67. Nat Commun. 2026 May 15. pii: 4371. [Epub ahead of print]17(1):
    A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA.
    Lianting Fu, Jieyi Chen, Da Lian, Siyuan Du, Dongya Wu, Chentao Yang, Ziyi Wang, Hongyi Ma, Zhengtong Li, Nicole J Lake, Xiangyu Yang, Yongyong Shi, Guojie Zhang, Kaiyue Ma, Yafei Mao.
      Nuclear-embedded mitochondrial DNA segments (NUMT) preserve a record of ongoing mitochondrial-to-nuclear DNA transfer during evolution, with important implications for disease mechanisms and genome organization. Here, we develop a pangenome graph-based NUMT detection approach, achieving a 2.52-fold improvement in sensitivity and generating a high-resolution human NUMT map comprising 774 fixed and 280 polymorphic events, alongside 74 superpopulation-stratified loci. Notably, NUMTs derived from the 3'-end of mtDNA D-loop are less frequently fixed and exhibit cis-regulatory activity, revealing selective pressures shaping their genomic landscape. We also identify seven NUMTs associated with gene expression or splicing, suggesting their potential modulatory functions. Comparative analysis of complete primate genomes reveals lineage-specific NUMT dynamics, with particularly high rates in the Pan lineage. Furthermore, we uncover two NUMT-derived tandem repeats, establishing them as a novel source of complex variants. In summary, the integrated analysis enhances understanding of NUMT genomic architecture, population dynamics, and evolutionary implications, establishing them as dynamic genomic components of biomedical relevance.
    DOI:  https://doi.org/10.1038/s41467-026-71348-5
  68. Nat Rev Mol Cell Biol. 2026 May 11.
    New developments and applications of human organoids.
    Amanda Andersson-Rolf, Hans Clevers.
      Organoid technology offers unique opportunities for studying human biology and disease in vitro. Organoids are self-organizing 3D structures, derived from pluripotent or tissue-resident stem cells that recapitulate key aspects of primary tissues. Compared with classical cell lines, organoids provide distinct advantages. They can be derived from both healthy tissues and diseased tissues, enabling the investigation of disease mechanisms and the development of personalized therapies, and they better recapitulate the cellular heterogeneity of the native tissue, allowing for better modelling of human (patho)physiology. Although current organoids have provided valuable insights, these insights are inherently reductionist and do not fully capture the complexity of human tissues. The research field is, therefore, moving towards next-generation models that more accurately represent the intricate cellular interactions, tissue architecture and microenvironmental cues that underlie human biology and disease. In this Review, we outline the limitations and challenges of current organoid systems, highlight recent advances aimed at increasing their complexity, and discuss innovations that support their translation into clinical applications. The focus is on human tissue stem cell-derived organoids, with comparisons to pluripotent stem cell-derived organoids where relevant. We conclude by identifying key factors and remaining challenges for developing the next generation of organoids.
    DOI:  https://doi.org/10.1038/s41580-026-00974-0
  69. Sci Rep. 2026 May 14.
    Generation of spinal cord organoids from human induced pluripotent stem cells caudalised to a lumbar fate.
    Li Jun Loh, Pratibha Panwar, Shila Ghazanfar, Kwaku Dad Abu-Bonsrah, Forough Habibollahi, Joel Mason, Brett J Kagan, Bradley J Turner, Samantha K Barton.
      Organoids offer a powerful platform to model human development and disease in vitro, while preserving key features of in vivo tissue architecture and complexity. In this study, we developed a protocol to generate human induced pluripotent stem cell (iPSC)-derived spinal cord organoids patterned to the lumbar region. Through immunofluorescent labelling and single-cell RNA sequencing analyses of these lumbar spinal cord organoids, we identified an enriched neuronal population complemented by a diverse array of glial subtypes that successfully recapitulate the ventral spinal cord, demonstrating greater anatomical relevance than conventional 2D motor neuron cultures. Notably, these organoids displayed functional neuronal properties, including spontaneous activity, indicative of integrated neural networks. This spinal cord organoid platform provides a physiologically relevant model for investigating human spinal cord development and presents a promising tool for studying neurodegenerative diseases and spinal cord injury in a controlled, human-specific context.
    Keywords:  Differentiation; Lumbar; Motor neurons; Organoid; Pluripotent stem cell; Spinal cord
    DOI:  https://doi.org/10.1038/s41598-026-45679-8
  70. Nat Commun. 2026 May 09.
    Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
    Takashi Nishimura, Chisei Arakawa, Yuto Yoshinari.
      Metabolic homeostasis regulated by nutrient-responsive endocrine hormones is essential for organismal survival. In insects, lipid and carbohydrate mobilization is controlled by adipokinetic hormone (Akh), a glucagon-like peptide secreted from neuroendocrine cells. However, whether Akh secretion is subject to negative feedback via its downstream catabolic effects remains unclear. Here, we develop a quantitative assay for Akh using tandem mass spectrometry and show that inter-organ metabolic communication regulates Akh secretion during starvation in Drosophila. Metabolic profiling reveals that Akh signaling in the fat body promotes branched-chain amino acid (BCAA) catabolism by inducing BCAA transaminase (Bcat). Loss of Akh signaling impairs clearance of BCAAs derived from fat body autophagy, resulting in Akh hypersecretion. BCAA catabolism is coupled to glutathione biosynthesis and redox homeostasis during nutrient stress. Our findings reveal a feedback mechanism in which Akh signaling regulates its own secretion via amino acid catabolism, linking energy mobilization to redox homeostasis during starvation.
    DOI:  https://doi.org/10.1038/s41467-026-72677-1
  71. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2527963123
    Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.
    Christina Elsner, Anton Hanke, Oscar Vadas, Francesco Luigi Gervasio, Enrica Bordignon.
      Intrinsic apoptosis is a form of cell death which is activated, executed, and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structural model of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing interresidue distances and dynamic solvent accessibilities complemented by integrative modeling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBid's C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis.
    Keywords:  Bcl-2 proteins; DEER; MD simulations; apoptosis; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2527963123
  72. Mitochondrion. 2026 May 14. pii: S1567-7249(26)00056-5. [Epub ahead of print] 102166
    m6A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.
    Abhishek Jauhari.
      Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N6-methyladenosine (m6A), in mitochondrial gene expression regulation and cellular stress responses. m6A modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by readers proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases ("erasers," FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that m6A modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of m6A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m6A regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how m6A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.
    Keywords:  Epitranscriptomics; Mitochondrial dysfunction; Neurodegeneration; m(6)A RNA modification
    DOI:  https://doi.org/10.1016/j.mito.2026.102166
  73. Bio Protoc. 2026 May 05. 16(9): e5667
    Assessing Mitochondrial Respiratory Complex-Associated Function From Previously Frozen Mouse Placental Tissue.
    Tina Podinic, Donald Xhuti, Cristina Monaco, Joshua P Nederveen, Sandeep Raha.
      The placenta is a metabolically active organ whose mitochondrial activity is tightly linked to fetal growth, oxygenation, and nutrient transport, mediating fetal susceptibility to environmental exposures. Accordingly, aberrant mitochondrial function has been implicated in the progression of placental dysfunction. However, existing respirometry platforms require primarily fresh or cryopreserved placental tissue and offer limited throughput, rendering these platforms impractical in the context of large-scale placental dissections. Here, we describe and validate a Seahorse XF approach for measuring mitochondrial respiration in previously frozen placentae, enabling the functional interrogation of placental mitochondria in prenatal studies. Our protocol fundamentally relies on the restoration of matrix substrates that are depleted due to increased mitochondrial membrane permeability following freeze-thaw cycles. We provide a strategy to assess complex I and II-associated respiration adapted for the Seahorse XFe24 Analyzer and further demonstrate comparable oxygen consumption readouts between fresh and frozen placentae. We further demonstrate distinct differences in the magnitude of oxygen consumption between fresh and frozen placentae in the absence of exogenous NADH. Taken together, we present a simplified and convenient protocol for the assessment of respiratory enzyme complex-associated respiration from archived placental tissue. Key features • This protocol is suitable for use with previously frozen mouse placental tissue. • Streamlined protocol for complex-associated respirometry assessments following large-scale placental dissections. • Respirometry data may be acquired in <4 hours.
    Keywords:  Bioenergetics; Electron transport-chain enzyme activity; Fresh tissue; Frozen tissue; Metabolism; Mitochondria; Oxygen consumption; Placenta; Respiration; Respirometry
    DOI:  https://doi.org/10.21769/BioProtoc.5667
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