bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–09–27
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The predicted interactome of the human mitochondrial proteome.
  2. Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.
  3. Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
  4. How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
  5. Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
  6. Proteolytic remodeling by Yme1 enables mitochondrial-derived compartment formation.
  7. ATAD3A structurally links mtDNA replication and mitochondrial fission.
  8. Immunohistochemical Findings of Organ-Specific ECHS1 Depletion in a Neonate With ECHS1 Deficiency.
  9. Diaphragmatic Mitochondrial Myopathy in a Patient-Derived Mouse Model of Barth Syndrome.
  10. Optimized High-Resolution Respirometry Defines the Bioenergetic Signature of Drosophila melanogaster Thoracic Muscle.
  11. Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
  12. Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
  13. Astrocyte Senescence Disrupts the Extracellular Mitochondrial Compartment and Compromises Bioenergetic Support to Human Neurons.
  14. From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).
  15. Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
  16. Phosphodiesterase-5 inhibition as an off-label therapy in mitochondrial disease.
  17. Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
  18. Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
  19. International Guideline on the Diagnosis, Treatment, and Monitoring of Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD).
  20. Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch.
  21. Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
  22. ACAD10 encodes two orphan enzymes in the ether lipid biosynthetic and salvage pathways.
  23. Inhibition of STING Protects the Neuroretina in an Ndufs4 Knockout Mouse Model of Mitochondrial Complex 1 Deficiency.
  24. Identification of a human mitochondrial isoform of TRPV1: a thermostat regulating mitochondrial maximal temperature?
  25. Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
  26. Comparative characterization of mitochondrial components across size-defined extracellular vesicle populations derived from HaCaT keratinocytes.
  27. Mitochondrial transfer and transplantation in tendon, ligament, and enthesis repair: current evidence, mechanistic rationale, and regenerative opportunities.
  28. Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
  29. Mitochondrial Calcium Sensor Tusc2 Protects the Aging Hippocampus from Proteostasis Collapse in a Sex-Specific Manner.
  30. MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.
  31. Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
  32. Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model.
  33. Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
  34. Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.
  35. Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.
  36. Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.
  37. Enhanced axonal mitochondrial motility and neural activity-induced energy deficits destabilize synaptic transmission in models of bipolar disorder.
  38. Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
  39. Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson's disease.
  40. Fungal-Derived Decahydrofluorene Alkaloids Promote Mitochondrial Resilience and Neuroprotection in Cellular and Animal Models of Parkinson's Disease.
  41. OPA1-dependent mitochondrial remodeling coordinates TCR signaling and metabolic adaptation during iNKT cell differentiation.
  42. High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control.
  43. A De Novo Gain-of-Function Variant of DNM1L Causes Developmental Encephalopathy.
  44. Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
  45. Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
  46. Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
  47. PERM1 Gene Therapy Prevents Pressure Overload-induced Heart Failure Through a Sarcomere-Mitochondria Energetic Microdomain.
  48. What is needed for regenerative medicine to flourish?
  49. NanoTS: a deep learning tool for accurate SNP calling in nanopore long-read transcriptome data.
  50. Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
  51. Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism.
  52. Mitochondrial dysfunction drives metabolic reprogramming in Gitelman syndrome: insights from proteomics and isogenic modeling.
  53. Tutorial: interrogating biology using organoid technologies.
  54. Recent advances in mitochondrial fission and fusion in diabetic cardiomyopathy.
  55. Novel Targets and Treatments for Neurodegenerative Diseases Revealed by Drosophila.
  56. Brain energy metabolism in neurodegenerative disease.
  57. Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
  58. TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity.
  59. Mitochondria-ER contact sites in neurological disorders.
  60. Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.
  61. Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.
  62. 2,4-dichlorophenoxyacetic acid (2,4-D) potentiates vanadium-induced Parkinsonian neurodegeneration: Evidence from mitochondrial bioenergetic dysfunction and dopaminergic and GABAergic neurodegeneration.
  63. NAD+-sirtuin-mitochondrial quality control in lens epithelial cells: a candidate modulatory network in crystalline lens aging.
  64. Cuproptosis and ferroptosis: signal pathways, diseases and therapeutic targets.
  65. Inter-Organelle Membrane Contact Sites as Physiological Regulatory Hubs in the Brain: From Neurons to Glial Cells.
  66. NIX-associated mitochondrial remodeling contributes to esophageal epithelial differentiation.
  67. Context-Dependent modulation of astrocytic Ca2+ signals by mitochondria: a computational study.
  68. SIM2s coordinates programmed mitophagy with respiratory chain supercomplex remodeling during mammary epithelial differentiation.
  69. Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.
  70. Base Editing: Mechanisms and Therapeutic Applications.
  71. Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans.
  72. Directing GABAergic neuronal identity from human iPSCs through developmental patterning.
  1. Nat Commun. 2026 Aug 25. pii: 10162. [Epub ahead of print]17(1):
    The predicted interactome of the human mitochondrial proteome.
    Abhinav B Swaminathan, Mohammad Zulkifli, Rachel M Guerra, Sofia M Calabrese, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Despite the fundamental importance of mitochondria in cellular metabolism, the molecular function(s) of many mitochondrial proteins remain unknown. Since protein function can be inferred from their interacting partners, we repurpose the protein structure prediction algorithm AlphaFold Multimer (AFM) as a classification model to predict protein-protein interactions of the entire human mitochondrial proteome. By screening 630,003 protein pairs, we create a compendium of 2,895 previously known and newly observed interactions, which include the interacting partner(s) of 85 uncharacterized mitochondrial proteins, thereby linking them to a known biochemical pathway. Extending the AFM-based analysis to 11 diverse eukaryotes identifies evolutionarily conserved interactions among human hits, including regulators of core bioenergetic pathways. Our experiments, guided by these predictions, nominate protein interactions that form the coenzyme Q metabolon and define the mitochondrial copper delivery pathway to cytochrome c oxidase. Our compendium represents a powerful resource for the systematic, structure-based functionalization of the human mitochondrial proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77112-z
  2. Nucleic Acids Res. 2026 Sep 22. pii: gkag925. [Epub ahead of print]54(18):
    Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.
    Viktoriia Sokolova, Gina Buchel, Sarah Strock, Ashok R Nayak, Dmitry Temiakov.
      Defects in human mitochondrial DNA (mtDNA) replication can lead to somatic mutations associated with a range of devastating mitochondrial diseases. However, the molecular mechanisms governing the earliest steps of mtDNA replication and their fidelity remain poorly understood. Here, we found that DNA polymerase gamma (Polγ) forms stable complexes with RNA-DNA primer-template substrates, exhibiting greater stability and lower misincorporation than on DNA-primed substrates. Structural analysis revealed that Polγ interacts with the 2'-OH groups of ribose within the first four nucleotides of the primer, explaining the stability of complexes that utilize RNA primers. Although Polγ requires TWINKLE to extend RNA primers, its intrinsic strand-displacement activity allows it to extend DNA primers independently. Structural data further show that the strand-separation mechanism in human Polγ is distinct from that of its yeast paralog, Mip1, and involves previously unresolved elements-the catcher and a GP loop in the exonuclease domain-that support intrinsic strand-displacement synthesis by Polγ. Structure-guided mutagenesis of elements involved in strand separation supports these structural observations. Together, our study provides mechanistic insight into mtDNA replication initiation and strand separation and has implications for understanding the molecular basis of mitochondrial disease.
    DOI:  https://doi.org/10.1093/nar/gkag925
  3. Int J Mol Sci. 2026 Sep 17. pii: 8270. [Epub ahead of print]27(18):
    Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
    Chung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Huang-Ying Huang, Hsiang-Yu Lin, Shuan-Pei Lin.
      Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
    Keywords:  Barth syndrome; Friedreich ataxia; cardiolipin; elamipretide; gene therapy; mitochondrial cardiomyopathy; mitochondrial quality control; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms27188270
  4. Commun Biol. 2026 Sep 24. pii: 1248. [Epub ahead of print]9(1):
    How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
    Pierre-Jean Desmaison, Giulia Bertolin.
      Mitochondria are traditionally viewed as a homogeneous network supporting cellular energy production. However, increasing evidence reveals substantial heterogeneity across biological scales, from intramitochondrial microdomains to specialised mitochondrial populations within cells and tissues. These subpopulations differ in morphology, metabolism, bioenergetics, and spatial organisation, reflecting adaptation to local functional demands. In this Review, we discuss the mechanisms underlying mitochondrial heterogeneity, the emerging concept of mitochondrial subclasses, their functional integration within cellular metabolism, and the challenge of distinguishing stable subclasses from transient states. We propose a shift from a network-based view toward a dynamic mitochondrial ecosystem with important implications for physiology and disease.
    DOI:  https://doi.org/10.1038/s42003-026-11029-7
  5. Mol Neurobiol. 2026 Sep 21. pii: 912. [Epub ahead of print]63(1):
    Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
    Xing Wei, Fuxian Liu, Jingxi Yao, Peng Feng, Fuchun Xue, Zhenggang Shi.
      Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.
    Keywords:  Bioenergetics; Intercellular mitochondrial transfer; Mitochondrial extracellular vesicles; Neuroimmune interactions; Neuroinflammation; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/s12035-026-06224-w
  6. bioRxiv. 2026 Apr 05. pii: 2026.04.03.716366. [Epub ahead of print]
    Proteolytic remodeling by Yme1 enables mitochondrial-derived compartment formation.
    Sai Sangeetha Balasubramaniam, Amy E Curtis, Jonathan R Friedman, Adam L Hughes.
      Mitochondrial-derived compartments (MDCs) are remodeling domains that form from the outer mitochondrial membrane during metabolic and proteotoxic stress and selectively sequester hydrophobic membrane proteins. Although MDC formation depends on mitochondrial lipid composition and occurs at organelle contact sites, the molecular mechanisms that permit their biogenesis remain poorly defined. Here we identify the conserved inner mitochondrial membrane i-AAA protease Yme1 as a critical regulator of MDC formation. Loss of Yme1 blocks MDC biogenesis in response to multiple stressors, and this requirement depends on its proteolytic activity rather than secondary defects in mitochondrial morphology. Quantitative mitochondrial proteomics under MDC-inducing conditions revealed Yme1-dependent remodeling of lipid transfer proteins of the Ups family and components of the MICOS complex. Disruption of either pathway partially restores MDC formation in yme1Δ cells, while combined perturbation substantially bypasses the requirement for Yme1. Finally, Yme1 overexpression drives MDC formation in the absence of stress, although this activity remains constrained by metabolic conditions. Together, these findings support a model in which Yme1-dependent proteolysis relieves lipid- and MICOS-dependent constraints to permit MDC formation.
    DOI:  https://doi.org/10.64898/2026.04.03.716366
  7. bioRxiv. 2026 Jun 25. pii: 2026.06.23.733767. [Epub ahead of print]
    ATAD3A structurally links mtDNA replication and mitochondrial fission.
    Nitish Dua, Boyuan Ma, Samantha Oviedo, Hamidreza Rahmani, Tumara Boyd, Donghyun Park, R Luke Wiseman, Danielle A Grotjahn.
      Mitochondrial function depends on the maintenance of its genome, and disruptions in copy number and distribution are hallmarks of mitochondrial disorders. Mitochondrial DNA (mtDNA) replication is spatially and temporally linked to mitochondrial division (i.e., fission). However, the signal that coordinates these two events, which are physically separated by the barrier of two mitochondrial membranes, remains unknown. To gain insight into this coordination, we employed correlative cryo-electron tomography (cryo-ET) to analyze the microenvironment surrounding replicating nucleoids. Mitochondrial regions containing replicating mtDNA exhibit a unique membrane architecture defined by the presence of clustered, membrane-spanning tethers that traverse the inner membrane space. Using a combination of superresolution microscopy and genetically encoded cryo-ET tagging technology, we identify these tethers as the AAA+ ATPase ATAD3A. We further show that ATAD3A knockdown reduces recruitment of the mitochondrial fission machinery, whereas overexpression promotes its recruitment and subsequent fission. Our work suggests that ATAD3A forms nanoscale linkages that coordinate these two distinct processes, revealing a new structural paradigm for organellar communication across distinct membrane-defined environments.
    Highlights: Replicating mitochondrial DNA (mtDNA) nucleoids are surrounded by a distinct membrane microenvironment.ATAD3A forms membrane-spanning tethers enriched at replicating mtDNA sites.ATAD3A enrichment is necessary and sufficient to recruit mitochondrial fission machinery and induce fission at mtDNA replication sites.ATAD3A structurally couples mtDNA replication state to mitochondrial fission across distinct organellar subcompartments.
    DOI:  https://doi.org/10.64898/2026.06.23.733767
  8. Pediatr Int. 2026 Jan-Dec;68(1):68(1): e70552
    Immunohistochemical Findings of Organ-Specific ECHS1 Depletion in a Neonate With ECHS1 Deficiency.
    Ai Nakagawa, Chika Kanno, Noriko Watanabe, Hirofumi Ohashi, Sayaka Ajihara, Kei Murayama, Masaki Shimizu.
      
    Keywords:  ECHS1; immunohistochemical test; mitochondrial cardiomyopathy; mitochondrial disease; neonatal onset
    DOI:  https://doi.org/10.1111/ped.70552
  9. J Dev Biol. 2026 Sep 03. pii: 40. [Epub ahead of print]14(3):
    Diaphragmatic Mitochondrial Myopathy in a Patient-Derived Mouse Model of Barth Syndrome.
    Kristen Tentler, Paige L Snider, Catalina Matias, Jeffrey J Brault, Simon J Conway.
      Barth syndrome (BTHS) is a rare, X-linked genetic disorder caused by mutations in the enzyme TAFAZZIN (TAZ), resulting in insufficient cardiolipin (CL) remodeling and mitochondrial dysfunction. While BTHS respiratory distress and breathing difficulties are commonly reported, the precise role of intrinsic respiratory tissue vulnerabilities has only recently begun to be appreciated. Historically, BTHS respiratory distress is frequently attributed to secondary consequences like cardiomyopathy or generalized skeletal myopathy, leaving the intrinsic vulnerability of vital respiratory muscles poorly understood. Using a patient-tailored point mutant knock-in mouse model (TazPM) harboring a stable but enzymatically deficient TazD75H protein, we investigated the autonomous physiological and metabolic responses in the diaphragm and lungs. Contrary to the paradigm that respiratory muscles are unaffected, TazPM diaphragms exhibit structurally abnormal mitochondria and undergo a survival-critical, bifurcated compensatory remodeling response to prevent fatal respiratory failure under severe bioenergetic stress. The TazPM adaptive mechanism is orchestrated by chronic activation of the mitochondrial Integrated Stress Response (ISR) via the Gcn2/eIF2α signaling pathway. This stress pathway halts global translation to conserve cellular ATP at the expense of reduced NAD+ levels, while selectively upregulating defensive mitokines and metabolic sirtuins and structural muscle remodeling. Furthermore, the TazPM diaphragm transitions into a highly specialized, slow-twitch motor system that is expected to reduce the energy cost per contraction. Concurrently, despite TazPM lungs exhibiting structurally abnormal mitochondria, they resist generalized mitochondrial collapse despite ADP reduction, executing tissue-specific metabolic reprogramming and localized biochemical adaptations to sustain respiratory homeostasis.
    Keywords:  Barth syndrome; CRISPR/Cas mouse model; bioenergetics; diaphragmatic mitochondrial myopathy; tafazzin
    DOI:  https://doi.org/10.3390/jdb14030040
  10. Biochimie. 2026 Sep 22. pii: S0300-9084(26)00226-9. [Epub ahead of print]
    Optimized High-Resolution Respirometry Defines the Bioenergetic Signature of Drosophila melanogaster Thoracic Muscle.
    Felipe Berti Valer, Giulia Covolo Spegiorim, Jonathas Rodrigo Dos Santos, Ana Elisa Caleiro Seixas Azzolini, Marcus F Oliveira, Luciane Carla Alberici.
      Drosophila melanogaster provides a robust model system for investigating mitochondrial metabolism in muscle tissue, particularly due to availability of fly strains that recapitulate genetic mitochondrial disorders, muscle atrophy, and related pathological conditions. However, most experimental approaches are adaptations of protocols originally developed for mammalian muscles, primarily rodents. Here, we systematically applied and refined variations of these mammalian-based protocols to female adult thoracic muscles of D. melanogaster, with particular emphasis on tissue permeabilization, respiratory substrates, respiratory chain inhibitors, and oxidative phosphorylation uncouplers. Our findings appointed pyruvate as the principal respiratory substrate and suggested succinate as a major anaplerotic contributor to the tricarboxylic acid cycle during NADH dehydrogenase-supported respiration. In addition, Drosophila thoracic muscle exhibits a maximal respiratory flux strongly dependent on ADP levels, with oxidative phosphorylation operating near the maximal capacity of the electron transfer system. We compared Drosophila thoracic muscle with Drosophila larvae fillet muscle, as well as murine and human skeletal muscle, revealing species- and tissue-specific differences in mitochondrial metabolism. Finally, we validated our refined protocol in a PINK1 RNAi Drosophila model, extending previous evidence of mitochondrial dysfunction associated with PINK1 deficiency in flies.
    Keywords:  Drosophila melanogaster; High-resolution respirometry; Indirect flight muscles; Mitochondria
    DOI:  https://doi.org/10.1016/j.biochi.2026.09.007
  11. bioRxiv. 2026 Sep 15. pii: 2026.09.09.750228. [Epub ahead of print]
    Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
    Wenyu Tang, Haoyu Xu, Steven Beck, Marcus T Cicerone, Sung Min Han, Wei-Wen Chen.
      Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo .
    DOI:  https://doi.org/10.64898/2026.09.09.750228
  12. bioRxiv. 2026 Sep 20. pii: 2026.09.17.752159. [Epub ahead of print]
    Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
    Madison T Jones, Natalie Noble, Robert B Darnell, Ezgi Hacisuleyman.
      Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.
    DOI:  https://doi.org/10.64898/2026.09.17.752159
  13. Antioxidants (Basel). 2026 Sep 06. pii: 1127. [Epub ahead of print]15(9):
    Astrocyte Senescence Disrupts the Extracellular Mitochondrial Compartment and Compromises Bioenergetic Support to Human Neurons.
    Pedro Amorim, Lívia de Sá Hayashide, Vitor Emanuel Leocadio, Mariana Marques, Isabelle Navarra, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Rafael Serafim Pinto, Luan Pereira Diniz.
      Astrocyte senescence is a recognized feature of brain aging, but its impact on neuronal mitochondrial homeostasis remains poorly defined, particularly in human cells. Here we show that doxorubicin-induced senescence disrupts mitochondrial function in primary human astrocytes and compromises their capacity to sustain neuronal bioenergetics. Senescent astrocytes accumulated a denser population of smaller, ultrastructurally damaged mitochondria together with increased levels of fission, fusion and biogenesis-associated proteins. Despite this apparent expansion of the mitochondrial compartment, these cells displayed reduced mitochondrial membrane potential, intracellular ATP and cellular metabolic activity, indicating accumulation of a functionally impaired mitochondrial population. Senescence also remodeled the extracellular mitochondrial compartment: conditioned medium from senescent astrocytes contained fewer mitochondrial particles with lower membrane potential and reduced ATP. Functionally, conditioned medium from control astrocytes increased TOMM20 and PGC-1α levels in human postmitotic neurons, whereas medium from senescent astrocytes failed to elicit this response and instead promoted hydrogen peroxide accumulation, ATP depletion and reduced cellular metabolic activity in the absence of overt cytotoxicity. Neurons acquired an astrocyte-derived MitoTracker signal from both conditions. Our data indicate that factors released by senescent human astrocytes are sufficient to induce neuronal mitochondrial and redox dysfunction.
    Keywords:  astrocyte senescence; astrocyte–neuron communication; brain aging; doxorubicin; extracellular mitochondria; human astrocytes; mitochondrial dysfunction; neuronal bioenergetics; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15091127
  14. Exp Ther Med. 2026 Oct;32(4): 291
    From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).
    Hui Liu, Yao Zhang, Ziliang Zhuo, Wei Zhong, Manyun Yan, Zhongbo Zhao.
      Neurodegenerative diseases (NDDs) are commonly accompanied by persistent low-grade neuroinflammation, yet current therapies rarely achieve durable disease modification. This review aims to systematically delineate the role of mitochondrial DNA (mtDNA) leakage in linking mitochondrial injury to innate immune activation and to explore its pathological significance in NDDs. A comprehensive review of recent literature on mitochondrial stress, mtDNA release and innate immune signaling was conducted. Evidence was integrated regarding the sources of mtDNA immunogenicity, routes of mtDNA escape, mitophagy-lysosome gating mechanisms and the modulation of leakage baseline by aging and metabolic stress. Accumulating evidence indicates that cytosolic mtDNA is sensed by cyclic GMP-AMP synthase (cGAS) and activates the stimulator of interferon (IFN) genes (STING) pathway signaling through the TANK-binding kinase 1 and IFN regulatory factor 3 axis to induce type I IFN responses and promoting NF-κB-driven inflammatory transcription, thereby enhancing NLRP3 inflammasome priming. Oxidized mtDNA, pore-forming membrane events and ionic imbalance further facilitate NLRP3 assembly and pyroptotic execution, exacerbating mitochondrial damage and mtDNA release in a self-amplifying loop. Based on these findings, a modular assessment framework was proposed across the 'input-chronicity-amplification' layers and the potential of mtDNA-cGAS/STING-NLRP3 axis-informed stratified diagnosis and treatment was discussed Central nervous system-targeted delivery, cellular heterogeneity and immune safety windows remain critical for translational research. This review provides a testable mechanistic framework and a clinical evaluation pathway for understanding mtDNA-driven persistent inflammation in NDDs.
    Keywords:  NLRP3 inflammasome; cGAS/STING; mtDNA; neuroinflammation; stratified assessment
    DOI:  https://doi.org/10.3892/etm.2026.13286
  15. Aging Cell. 2026 Oct;25(10): e70720
    Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
    Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.
      Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.
    Keywords:  HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux
    DOI:  https://doi.org/10.1111/acel.70720
  16. Mol Genet Metab. 2026 Sep 16. pii: S1096-7192(26)00544-5. [Epub ahead of print]149(3): 110261
    Phosphodiesterase-5 inhibition as an off-label therapy in mitochondrial disease.
    Ibrahim Elsharkawi, Graeme Preston, Tamas Kozicz, Eva Morava.
      
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110261
  17. Front Cell Dev Biol. 2026 ;14 1963467
    Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
    Xiaoqian Fu, Qianyi Huang, Huimei Wu, Lidan Liu.
      Mitochondrial Ca2+ homeostasis is a critical interface connecting ovarian cell signaling, energy metabolism, redox balance, and reproductive competence. Transient Ca2+ uptake into the mitochondrial matrix activates Ca2+-sensitive dehydrogenases, enhances reducing-equivalent generation, and supports oxidative phosphorylation. By contrast, sustained Ca2+ accumulation promotes reactive oxygen species production, membrane-potential collapse, mitochondrial permeability transition, and cell death. The identification of the mitochondrial calcium uniporter together with its regulators MICU1, MICU2, and EMRE, has established a molecular framework for mitochondrial Ca2+ influx. NCLX and its interacting protein TMEM65 contribute to Ca2+ efflux and determine recovery after individual Ca2+ transients. In ovarian cells and oocytes, endoplasmic reticulum (endoplasmic reticulum)-mitochondria contact sites, including the IP3R1-GRP75-VDAC1 axis, couple cytosolic Ca2+ signals to mitochondrial metabolism. Evidence from mouse, porcine, avian, zebrafish, Xenopus, and sea-urchin models implicates mitochondrial Ca2+ in follicular-cell survival, oocyte meiotic maturation, fertilization-associated Ca2+ oscillations, the oocyte-to-embryo transition, and early embryonic development. Obesity, aging, cryopreservation, heavy metals, environmental chemicals, and oxidative stress can disturb this system. However, mitochondrial Ca2+ dysregulation is not always readily separable from broader mitochondrial or ER dysfunction. Major limitations of the current literature include reliance on non-selective pharmacological agents, incomplete calibration of organelle-targeted indicators, insufficient temporal resolution, interspecies differences, and limited direct evidence from human oocytes. Future studies should integrate cell-type-specific genetic perturbation, quantitative multi-organelle Ca2+ imaging, mitochondrial bioenergetics, and long-term developmental assessment. Mitochondrial Ca2+ is a promising mechanistic node and candidate biomarker, but it is not yet a validated clinical target in reproductive medicine.
    Keywords:  ER-mitochondria contact; MCU; MICU1; NCLX; embryo development; fertilization; mitochondrial Ca2+; oocyte competence
    DOI:  https://doi.org/10.3389/fcell.2026.1963467
  18. J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02464-6. [Epub ahead of print] 113592
    Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
    Michael D Guile, Kyle A Anderson, Akash Jain, Alexandre Toulmay, William A Prinz, Catherine F Clarke.
      Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.
    Keywords:  Saccharomyces cerevisiae; Vps1; autophagy; dynamin; lipid raft; lipid trafficking; mitochondria; ubiquinone; vacuole; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113592
  19. J Inherit Metab Dis. 2026 Sep;49(5): e70251
    International Guideline on the Diagnosis, Treatment, and Monitoring of Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD).
    International LC‐FAOD Guideline Workgroup
      Long-chain fatty acid oxidation disorders (LC-FAOD) are rare inherited defects of mitochondrial β-oxidation that impair energy generation during fasting or metabolic stress. Clinical manifestations range from neonatal hypoketotic hypoglycemia and cardiomyopathy to hepatopathy, recurrent rhabdomyolysis, and chronic myopathy. Although newborn screening (NBS) enables early detection, management remains inconsistent due to limited evidence, broadening phenotypic spectrum, and regional practice variation. An international multidisciplinary workgroup of 34 members, including clinicians, nurses, dietitians, and patient representatives, systematically reviewed the literature (1990-2022) using PubMed, Embase, and Web of Science. Evidence was graded using an adapted Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and consensus was achieved through a modified Delphi-Nominal Group-Delphi methodology, with agreement defined as ≥ 75%. Especially when evidence was low, expert consensus was the basis for this guideline. Recommendations address diagnosis, dietary management, fasting tolerance, use of medium-chain fat sources, exercise and illness protocols, pregnancy care, and long-term monitoring. Evidence quality ranged from very low to moderate. Strong consensus was reached for critical clinical interventions. Standardized approaches for diagnostic work-up, management during metabolic stress, and follow-up monitoring were developed to promote uniform care across age groups, disease groups, and phenotypic severity. This international guideline integrates available evidence and expert consensus to provide standardized recommendations for diagnosis, treatment and lifelong management of LC-FAOD. They aim to harmonize clinical practice, improve patient outcomes, and support global implementation of evidence-based metabolic care.
    Keywords:  consensus; diagnosis; dietary management; guideline; long‐chain fatty acid oxidation disorders; newborn screening; outcome
    DOI:  https://doi.org/10.1002/jimd.70251
  20. bioRxiv. 2026 Sep 18. pii: 2026.09.16.752001. [Epub ahead of print]
    Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch.
    Sharon Kaisari, Ethan Lane, Raymond Wang, Jeffrey Estrada, Marta Collu, Daniele Simoneschi, Yeon-Tae Jeong, Mengxi Liu, Qingyue Zhang, Yuki Kito, Ifat Abramovich, Jason Yin, Tori Rodrick, Gyles Ward, Tyler Cropley, Adriana Heguy, Sang Yong Kim, Ran Brosh, Herman Wolosker, Namrat D Udeshi, Steven A Carr, Cynthia A Loomis, Feng-Xia Liang, Beatrix Ueberheide, Drew Jones, Ning Zheng, Michele Pagano.
      Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.
    DOI:  https://doi.org/10.64898/2026.09.16.752001
  21. Antioxidants (Basel). 2026 Aug 22. pii: 1051. [Epub ahead of print]15(9):
    Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
    Giuseppe Petito, Maria Ventriglia, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Francesco Manfrevola, Flora Guerra, Lucia Bertuccini, Giulia Ricci, Gilda Cobellis, Antonia Lanni, Cecilia Bucci, Roberta Romano, Rosalba Senese.
      Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPRmt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPRER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); Endoplasmic Reticulum stress; Mitochondrial Quality Control (MQC); TDP-43; mitochondrial Unfolded Protein Response (UPRmt); mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15091051
  22. bioRxiv. 2026 Sep 15. pii: 2025.09.10.675409. [Epub ahead of print]
    ACAD10 encodes two orphan enzymes in the ether lipid biosynthetic and salvage pathways.
    James S Ye, Elena Purlyte, Victor A Lopez, Jericha Mill, Lexus Tatge, Thomas Kizzar, Dominique Baldwin, Edrees Rashan, Juhee Kim, David J Pagliarini, Diana R Tomchick, Krzysztof Pawłowski, Peter M Douglas, Judith Simcox, Vincent S Tagliabracci.
      Ether lipids play critical roles in membrane dynamics, antioxidant defense, and signaling. They comprise ~20% of mammalian phospholipids, and disruptions in their metabolism cause severe genetic disorders and are associated with neurodegenerative and metabolic diseases. Ether lipids are synthesized de novo from glycolytic intermediates or salvaged from the diet. While the products of these pathways are known, several key enzymes remain unidentified, including the 1-O-alkylglycerol kinase and the 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate phosphatase. Here, we show that acyl-CoA dehydrogenase member 10 (ACAD10) catalyzes the phosphorylation of 1-O-alkylglycerols and the dephosphorylation of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate. Worms and mice lacking ACAD10 have reduced ether lipid levels and cannot salvage dietary alkylglycerols. Furthermore, individuals from the Akimel O'odham (Pima) tribe carrying ACAD10 polymorphisms also show decreased plasma ether lipid levels. Collectively, our findings resolve two long-standing gaps in ether lipid biochemistry and reveal a mechanistic link between ether lipid metabolism and a population-associated risk factor for type 2 diabetes.
    DOI:  https://doi.org/10.1101/2025.09.10.675409
  23. Exp Eye Res. 2026 Sep 23. pii: S0014-4835(26)00394-5. [Epub ahead of print] 111238
    Inhibition of STING Protects the Neuroretina in an Ndufs4 Knockout Mouse Model of Mitochondrial Complex 1 Deficiency.
    Jong-Jer Lee, Yu-Ting Hsiao, Hsiu-Mei Huang, Mu-Chan Ke, Shih-Ting Tsao, Yao-Sheng Huang, Tsu-Kung Lin.
       PURPOSE: Ndufs4 encodes a key subunit of mitochondrial complex I, and its mutation causes NADH dehydrogenase deficiency associated with Leigh syndrome and Leber hereditary optic neuropathy. In Ndufs4 knockout (KO) mice, vision loss occurs alongside an "inflammatory wave" that disrupts neuroretinal function. In this study, we explore a novel inflammation-driven pathogenic mechanism and whether treatments targeting inflammatory pathways can mitigate neuroretina degeneration.
    METHODS: Transcriptomic analysis of neuroretinal tissue from Ndufs4-KO mice identified immune-response activation as the most enriched pathway, with a twofold upregulation of stimulator of interferon genes (STING). Based on these findings, Ndufs4-KO mice received intraperitoneal injections of the STING inhibitors C-176 or SN-011 three times weekly from postnatal day 29 to 42; controls received vehicle only. Inflammatory cytokines were measured using ELISA, while retinal structure and function were evaluated through immunofluorescence and electroretinography (ERG).
    RESULTS: Immunofluorescence showed infiltration of Iba1-positive microglia into inner retinal layers of Ndufs4-KO mice, which was reduced by nearly 50% following C-176 and SN-011 treatment. ELISA confirmed decreased levels of the inflammatory markers CCL5 and ICAM-1. Untreated Ndufs4 retinas exhibited thinning of the inner retinal layers to about 70% of normal, whereas treated mice retained ∼85-90% of control thickness. ERG recordings demonstrated significantly improved retinal responses after STING inhibition.
    CONCLUSIONS: STING inhibition preserves neuroretina structure and function, highlighting its role in Ndufs4 pathology. This is the first study to show improved ERG responses following treatment in Ndufs4-KO mice, supporting STING as a promising therapeutic target for mitochondrial NADH dehydrogenase deficiency disorders.
    Keywords:  NADH dehydrogenase; Ndufs4; STING; complex 1 deficiency; mitochondria; neurodegeneration; retina
    DOI:  https://doi.org/10.1016/j.exer.2026.111238
  24. Cell Mol Life Sci. 2026 Jul 23. pii: 339. [Epub ahead of print]83(1):
    Identification of a human mitochondrial isoform of TRPV1: a thermostat regulating mitochondrial maximal temperature?
    Florian Beignon, Sylvie Ducreux, Artur Wardaszka, Joanna K Bujak, Léa Tuifua, Camille Blaecke, Caroline Bosson, Lucie Maujean, Florentin Moulin, Yannick Le Dantec, Morgane LeMao, Adélie Mellinger, Méline Wery, David Goudenège, Arnaud Chevrollier, Salim Khiati, Hélène Tricoire-Leignel, Naig Gueguen, Nathalie Roux-Buisson, Julien Fauré, Piotr Bednarczyk, Guy Lenaers, César Mattei.
      Mitochondria are well known to produce ATP for cell energy requirements and thermogenesis simultaneously by the respiratory chain, with a potential optimum temperature of 50 °C, while deleterious overheating should be prevented by a yet unknown system. Here, we report the identification of a human Transient Receptor Potential Vanilloid 1 (mitoTRPV1) alternative isoform located in the mitochondrial inner membrane, which acts as a thermostat regulating mitochondrial maximal temperature. The ubiquitously expressed mitoTRPV1 open reading frame overlaps TRPV1 exons 1 and 2 and intron 2 in a + 1 frame, encoding for an effective 150 amino-acid N-terminal mitochondrial targeting sequence (MTS) conserved amongst mammalian species, followed by the 687 amino acids of the TRPV1 C-terminal sequence. Pharmacological activation of mitoTRPV1 induces a low cytoplasmic Ca2+ increase and mitochondrial cooling without modification of mitochondrial respiration and ATP production. We conclude that, in our experimental conditions, mitoTRPV1 acts as a thermostat to promote mitochondrial thermolysis without impairing respiration and ATP production. They point to the potential implication of mitoTRPV1 in human diseases related to temperature dysregulation, and should be further studied in physiological conditions in cellular and animal models expressing mitoTRPV1 endogenously.
    Keywords:  Calcium; Ion channel; Mitochondria; Mitochondrial targeting sequence; TRPV1; Thermoregulation
    DOI:  https://doi.org/10.1007/s00018-026-06360-5
  25. Int J Mol Sci. 2026 Sep 11. pii: 8086. [Epub ahead of print]27(18):
    Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
    Yongxu Chen, Chunsheng Wang.
      Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder in which variable symptom profiles, progression rates, and treatment responses likely reflect distinct but partially convergent pathogenic mechanisms. Among these, mitochondrial dysfunction recurs across both familial and sporadic PD; however, this broad concept alone cannot explain disease heterogeneity. To preserve mitochondrial homeostasis, cells rely on a complex mitochondrial quality control (MQC) system that encompasses protein import and proteostasis, redox surveillance, organellar dynamics and positioning, biogenesis, and selective elimination of damaged mitochondria. MQC also depends on coordination with other organelles, particularly the endoplasmic reticulum and lysosomes. In this review, we discuss how different layers of MQC maintain mitochondrial integrity and how these pathways are functionally coupled. We further consider how an MQC-based framework may help explain the clinical heterogeneity of PD, including selective neuronal vulnerability, subtype formation, and divergent disease progression, and how it can frame recent therapeutic advances aimed at biologically stratified intervention.
    Keywords:  Parkinson’s disease; heterogeneity; mitochondrial quality control; selective vulnerability; stratified transformation
    DOI:  https://doi.org/10.3390/ijms27188086
  26. Int J Pharm. 2026 Sep 23. pii: S0378-5173(26)00910-5. [Epub ahead of print] 127462
    Comparative characterization of mitochondrial components across size-defined extracellular vesicle populations derived from HaCaT keratinocytes.
    Finn Brigger, Ana Kitanovic, Sébastien Meurant, David Scherer, Mattia Pagotto, Davide Borghesi, Daniel Gao, Sabine Werner, Tatjana Kleele, Jean-Christophe Leroux.
      The transfer of mitochondrial cargo through extracellular vesicles (EVs) has been reported in several model systems and cell types, yet a detailed characterization of mitochondrial components across different EV populations remains limited. Here, we characterized the mitochondrial cargo of small EVs (sEVs) and large EVs (lEVs) released by human HaCaT keratinocytes and examined the impact of oxidative stress on their content composition. EVs were isolated from keratinocyte-conditioned medium and characterized using complementary analytical approaches. Their mitochondrial cargo was assessed using super-resolution microscopy, RT-qPCR, nano-flow cytometry, and mass spectrometry. We found that mitochondrial proteins and transcripts were predominantly associated with lEVs, whereas sEVs contained low levels of selected mitochondrial proteins and RNA. Comparative proteomic analysis revealed distinct mitochondrial-associated signatures between EV populations. lEVs were enriched in proteins with predominantly mitochondrial localization and proteins associated with antioxidant-related functions, whereas sEVs were enriched in proteins associated with RNA- and tRNA-related processes. The preferential association of mitochondrial cargo with lEVs was increased upon oxidative stress. Together, these findings highlight EV heterogeneity as an important determinant of mitochondrial cargo transfer and reveal that mitochondrial cargo is preferentially associated with larger EV populations.
    Keywords:  Extracellular vesicles; Keratinocyte; Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial proteins; Oxidative stress; Skin
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127462
  27. Front Cell Dev Biol. 2026 ;14 1927682
    Mitochondrial transfer and transplantation in tendon, ligament, and enthesis repair: current evidence, mechanistic rationale, and regenerative opportunities.
    Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Zechen Zhang, Chengjie Wang, Binbin Tang, Xiaolin Shi, Kang Liu.
      Tendon, ligament, and enthesis injuries often heal through fibrovascular scar rather than restoration of native matrix organization, mechanical function, and graded interface architecture. Mitochondrial dysfunction has emerged as a recurrent feature of these repair failures, linking impaired bioenergetics, oxidative stress, persistent inflammation, cell death, and defective matrix remodeling. In parallel, mitochondria are increasingly recognized as transferable organelles that can move between cells or be delivered therapeutically as isolated mitochondria, mitochondria-rich extracellular vesicles, or engineered mitochondria-based products. This review examines mitochondrial transfer and transplantation as organelle-level mechanisms and therapeutic strategies in tendon, ligament, rotator cuff muscle, and enthesis-related repair. We define key terminology and characterization requirements for verifying mitochondrial identity, integrity, uptake, and function, and synthesize evidence across disease-relevant repair contexts. Direct preclinical support is most developed in tendinopathy/tendon repair and rotator cuff tear-associated muscle degeneration, whereas evidence in anterior cruciate ligament-related repair remains early, and application to enthesis regeneration or tendon-to-bone healing is still largely hypothesis-driven. Further therapeutic development will depend on defined donor sources, product identity, indication-specific potency, tissue retention, dosing strategies, safety assessment, disease-relevant models, and functional endpoints.
    Keywords:  enthesis; ligament repair; mitochondrial transfer; mitochondrial transplantation; tendon repair; tendon-to-bone healing
    DOI:  https://doi.org/10.3389/fcell.2026.1927682
  28. Cells. 2026 Sep 17. pii: 1683. [Epub ahead of print]15(18):
    Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
    Mateusz Mamala, Izabela Skowron, Karolina Marczuk, Arkadiusz Bujas, Jolanta Harasiuk, Julita Kulbacka.
      Mitochondrial dysfunction is a recurrent but context-dependent feature of neurodegenerative disease, and its position in the pathogenic cascade differs fundamentally between disorders. This narrative review argues that this heterogeneity, rather than mitochondrial biology itself, determines therapeutic tractability. We synthesize evidence on mitochondrial regulation of neuronal development, organelle quality control, redox signaling and neuroinflammation; on oxidative biomarkers, whose clinical use remains constrained by limited disease specificity, methodological heterogeneity and insufficient longitudinal validation; and on therapeutic strategies ranging from antioxidants and NAD+ augmentation to mitochondrial genome engineering, targeted delivery and organelle transfer. A consistent pattern emerges across these domains: broadly acting interventions have repeatedly failed in sporadic disease, whereas the strongest translational signals arise where mitochondrial dysfunction is genetically anchored and pathway-proximal. Mitochondrial modulation is therefore unlikely to provide a universal disease-modifying strategy, but remains a useful, carefully targeted addition for patient groups identified by genetic or specific biological markers.
    Keywords:  mitochondrial DNA; mitochondrial dysfunction; mitochondrial therapeutics; mitophagy; neurodegeneration; oxidative stress; redox biomarkers
    DOI:  https://doi.org/10.3390/cells15181683
  29. Mech Ageing Dev. 2026 Sep 19. pii: S0047-6374(26)00105-3. [Epub ahead of print] 112253
    Mitochondrial Calcium Sensor Tusc2 Protects the Aging Hippocampus from Proteostasis Collapse in a Sex-Specific Manner.
    Sergey V Ivanov, Victor Paromov, Metin Aksu, Harshana Rajakaruna, Jane Tonello, Salvador González-Ochoa, Muna Mohammed, Tonie Farris, George Babineaux, Sanika S Chirwa, Anil Shanker, Alla V Ivanova.
      Progressive mitochondrial dysfunction coupled with calcium dyshomeostasis is a hallmark of aging and neurodegenerative conditions, yet the molecular links to cognitive decline remain unclear. Moreover, although sex differences in susceptibility to neurodegeneration are well recognized, their molecular basis remains poorly defined. In our previously engineered mouse model, systemic depletion of Tusc2 (Fus1), a mitochondrial calcium-regulatory protein, accelerates aging and recapitulates key features of human aging, including sex-specific cognitive decline. Here, we identify Tusc2 as a key modulator of hippocampal (HP) resilience to aging. To define the impact of Tusc2 loss on molecular determinants of cognition, we profiled HP transcriptomes in both sexes and proteomes in males at 4 months of age, when sex-specific differences in cognitive behavior first emerge. Male knockout HP exhibited broad mitochondrial dysfunction, including suppression of oxidative phosphorylation (OxPhos) proteins, activation of the ATF4 branch of the integrated stress response (ISR), and coordinated downregulation of translational, proteasomal, and synaptic pathways. These molecular alterations were accompanied by increased protein aggregate size, consistent with impaired proteostatic capacity, and reduced PSD-95 neuropil intensity, indicative of compromised synaptic integrity in the HP. In contrast, female knockout HP exhibited comparatively modest transcriptional alterations and preferential activation of adaptive ATF6-associated unfolded protein response (UPR) pathways, consistent with a protective response that may be influenced by estrogen signaling, sex chromosome complement, epigenetic regulation, and other sex-dependent mechanisms. Comparative analysis with aging human HP datasets revealed significant and broad overlaps, suggesting that Tusc2 deficiency recapitulates key molecular features of human brain aging. Together, these findings identify TUSC2 as a principal regulator of mitochondrial calcium homeostasis that contributes to maintenance of proteostatic and synaptic integrity of the HP during aging, and reveal marked sex differences in mitochondrial stress resilience. These results establish Tusc2 deficiency as a mechanistically defined model for investigating early, potentially reversible stages of mitochondrial and proteostatic decline in brain aging.
    Keywords:  Aging; Dementia; Mitochondrial calcium signaling; Proteostasis; TUSC2 (FUS1)
    DOI:  https://doi.org/10.1016/j.mad.2026.112253
  30. Res Sq. 2026 Sep 14. pii: rs.3.rs-10994808. [Epub ahead of print]
    MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.
    Yoshiyasu Tongu, Tomoko Kasahara, Kohta Nakamura, Alexander Tyshkovskiy, Yoshitsugu Oikawa, Tetsuro Matsuhashi, Chikahiko Numakura, Risako Fujita, Yoshiteru Kagawa, Zhiqian Yu, Tomoyuki Furuyashiki, Rina Inoue, Daisuke Saigusa, Ryota Kujirai, Yotaro Matsumoto, Eiji Kakazu, Masaru Shimura, Yohei Sugiyama, Shun Watanabe, Yohei Honkura, Kuniyasu Niizuma, Hidenori Endo, Ko Hashimoto, Chiharu Kawabe, Hidetaka Tokuno, Koichi Kikuchi, Chitose Suzuki, Naoyuki Matsumoto, Junken Aoki, Kei Murayama, Hiroaki Tomita, Yuji Owada, Yukio Katori, Tomoyoshi Soga, Yoshihisa Tomioka, Takeya Sato, Takehiro Suzuki, Takafumi Toyohara, Yasushi Okazaki, Paul Anderson, Vadim N Gladyshev, Takaaki Abe.
      Chronic inflammation and mitochondrial dysfunction are hallmarks of neurodegeneration and aging, yet how mitochondrial damage contributes to inflammatory and aging-like cellular programs remains poorly understood. Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, which also represent a major genetic risk factor for Parkinson's disease. In a GD mouse model, we identified marked mitochondrial cristae disorganization accompanied by mitochondrial DNA release, activation of the cGAS-STING and NLRP3 inflammasome pathways, and subsequent inflammatory microglial activation. Circulating galectin-3 was also elevated in both model mice and patients with GD, supporting its potential relevance as a systemic marker of disease-associated inflammation. Mitochonic acid-5 (MA-5) is a mitochondria-targeting compound that interacts with mitofilin/MIC60 in the mitochondrial inner membrane and enhances ATP production. In a GD mouse model and patient-derived iPSC microglia, MA-5 increased ATP levels, preserved mitochondrial cristae integrity, limited mtDNA release, and suppressed cGAS-STING and NLRP3 inflammasome signaling, thereby attenuating microglial innate immune activation and galectin-3 expression. MA-5 also prolonged survival and reversed accelerated transcriptomic aging across multiple brain cell types, with particularly prominent effects in microglia. In the liver, GD was similarly associated with inflammatory, stress-related, and aging-associated transcriptional changes, whereas MA-5 improved liver function, restored mitochondrial morphology, suppressed inflammatory and stress responses, restored metabolic programs, and reduced transcriptomic age. Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.
    Keywords:  Aging clock (tAge); Gaucher disease; NLRP3 inflammasome; cGAS-STING pathway; galectin-3; inflammation; microglia; mitochondria
    DOI:  https://doi.org/10.21203/rs.3.rs-10994808/v1
  31. J Physiol. 2026 Sep 24.
    Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Sung Gi Noh, Martin Picard, Abbey-Gale Mannings, Michael S Cohen, Dennis W Wolan, Terence E Ryan, Russell T Hepple.
      Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.
    Keywords:  mitochondrial permeability transition; mitophagy; muscle atrophy; muscle wasting; neuromuscular junction
    DOI:  https://doi.org/10.1113/JP291213
  32. Antioxidants (Basel). 2026 Sep 20. pii: 1212. [Epub ahead of print]15(9):
    Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model.
    Lavanya Vadupu, Vijay Aditya Mavuduru, Writoban Basu Ball.
      Mitochondrial dysfunctions are often associated with cellular aging as well as metabolic disorders. Therapeutic strategies for rewiring mitochondrial stress signaling in a disease context could be beneficial. New evidence indicates that mitochondrial membrane lipids actively regulate mitochondrial signaling pathways that influence cellular health, stress responses, and longevity. Phosphatidylethanolamine (PE), the non-bilayer-forming phospholipid, plays major roles in mitochondrial morphology and ETC function. The biosynthesis of PE takes place within the inner mitochondrial membrane and is catalyzed by the enzyme phosphatidylserine decarboxylase-1 (PSD-1), which converts phosphatidylserine (PS) to PE. While the biochemical role of PSD-1 in PE biosynthesis is well established, how its dysfunction translates into mitochondrial pathology remains poorly understood. In this work, we describe the physiological implications of PSD-1 function and validate a novel disease model for human PISD (the ortholog of C. elegans psd-1) by undertaking targeted gene knockdown using RNA interference (RNAi) in Caenorhabditis elegans. We show that psd-1 deficiency causes several physiological defects in C. elegans, demonstrating that PE biosynthesis via PSD-1 is critical for mitochondrial activity and organismal development (mitochondrial PE levels were reduced by 69.51% in psd-1 knockdown worms compared to controls). These findings establish psd-1 knockdown worms as a reliable model for studying human PISD-related disease. Surprisingly, co-knockdown of psd-1 along with the ETC component clk-1 rescued physiological defects such as restoring the lifespan of from 13.48 ± 0.51 days psd-1 RNAi worms to 17.36 ± 0.44 days in psd-1; clk-1 double-knockdown worms and normalizing oxygen consumption rate, suggesting that ETC-mediated retrograde signaling, rather than phospholipid depletion alone, is the primary driver of the observed pathology.
    Keywords:  Caenorhabditis elegans; DAF-16/FOXO; RNA interference; clk-1; mitochondrial rescue; phosphatidylethanolamine; psd-1; reactive oxygen species; retrograde signaling
    DOI:  https://doi.org/10.3390/antiox15091212
  33. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2607452123
    Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
    Qing Li, Tong Shu, Chen Liu, Min Zheng, Yuanpei Li, Lei Zhang, Gao Fan, Wenbin Lu, Huiwen Zhang, Pingping Liu, Xiaoniu He, Hong Zheng, Wen Liu, Jing Ye, Zhenyu Yin, Xianming Deng, Chensong Zhang, Canhua Huang, Han You.
      PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD+ pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.
    Keywords:  PARPi resistance; de novo mitochondrial dTMP biosynthesis; mitochondrial NAD+ metabolism
    DOI:  https://doi.org/10.1073/pnas.2607452123
  34. JCI Insight. 2026 Sep 22. pii: e200761. [Epub ahead of print]11(18):
    Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.
    Yoshitsugu Oikawa, Yuhan Luo, Naoki Suzuki, Tomoko Kasahara, Yoshiyasu Tongu, Yuki Yoshida, Tsukasa Tominari, Shogo Tanabe, Yoshiko Suto, Hitomi Kashiwagi, Saki Saito, Kensuke Ikeda, Chitose Suzuki, Arata Kuranaga, Tetsuya Akiyama, Satoru Morimoto, Yoshitsugu Aoki, Rieko Muramatsu, Tomoyoshi Soga, Masashi Aoki, Hideyuki Okano, Tetsuhiro Tanaka, Takaaki Abe, Erina Kuranaga, Takafumi Toyohara.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.
    Keywords:  ALS; Biomarkers; Drug therapy; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.200761
  35. bioRxiv. 2026 Sep 17. pii: 2026.09.14.751483. [Epub ahead of print]
    Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.
    Ankit Sabharwal, Md Roushan Ali, Kyler S Mitra, Jun Morisue, Jace Klein, Rishav Sarkar, Kaila Savage, Lucy Rai Thulung, Amanda Zumbrock, Cassidy Petree, Santiago Restrepo Castillo, Mireya Mota, Gaurav K Varshney, Karl J Clark, Eiko Nakamuru-Ogiso, Stephen C Ekker.
      Pathogenic variants in the 13 protein-coding genes of the mitochondrial genome underlie clinically and biochemically heterogeneous disorders. Most mtDNA-encoded genes lack defined loss-of-function (LOF) models in vivo . To address this gap, we have generated Z-Terminator, a systematic in vivo atlas of loss-of-function alleles covering all the mtDNA-encoded OXPHOS subunits in zebrafish ( Danio rerio ). We used mitochondrial TALE base editors to introduce premature termination codon (PTC) alleles via C-to-T transitions across Complexes I, III, IV, and V. Larvae harboring PTC alleles displayed bioenergetic defects and elevated lactate. While mtDNA mutations are associated with sensorineural hearing loss, the cellular basis has remained unclear. We show that engineered mtDNA LOF alleles directly impair hair cell function in proportion to heteroplasmy in a living vertebrate. We investigated the germline transmission and tissue-specific heteroplasmy of these LOF alleles and observed that a subset of variants was transmitted to the F1 generation and displayed distinct mutant loads across organs. These findings establish Z-Terminator as a vertebrate platform for interrogating the role of mtDNA protein-coding genes in cellular dysfunction and for elucidating the pathophysiology of mitochondrial disorders.
    DOI:  https://doi.org/10.64898/2026.09.14.751483
  36. Children (Basel). 2026 Sep 04. pii: 1194. [Epub ahead of print]13(9):
    Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.
    Natàlia Caelles-Gramunt, Jordi Pijuan.
       BACKGROUND: Rare diseases collectively affect millions of children worldwide and are a major cause of pediatric morbidity, mortality, and lifelong disability. Although most have a genetic basis, obtaining a timely molecular diagnosis remains challenging because of substantial clinical and genetic heterogeneity. Advances in genomic medicine are transforming rare disease diagnosis and establishing genomics as the center of precision medicine.
    METHODS: This review summarizes current evidence on genomic approaches for pediatric rare diseases, including established and emerging sequencing technologies, their clinical applications, implementation challenges, and future directions.
    RESULTS: Whole-genome sequencing is increasingly being adopted as a first-line genomic test for suspected rare genetic disorders, particularly when the phenotype is heterogeneous or does not point to a specific diagnosis. Conventional cytogenetic and targeted molecular techniques remain important complementary approaches for selected phenotypes, variant classes, and orthogonal confirmation. Gene panels are effective for well-defined phenotypes, whereas whole-exome sequencing remains a high-yield approach for genetically heterogeneous disorders, particularly when whole-genome sequencing is not available or is not clinically indicated. Long-read whole-genome sequencing expands diagnostic capacity by detecting structural variants, repeat expansions, complex rearrangements, and non-coding pathogenic variants that frequently escape short-read technologies. Emerging multi-omics approaches further improve variant interpretation and help resolve previously unsolved cases. Beyond diagnosis, molecular findings guide personalized clinical management, genetic counselling, reproductive planning, and access to targeted therapies and genotype-driven clinical trials. However, broad implementation is constrained by challenges in variant interpretation, ethical and legal considerations, data governance, workforce capacity, cost, and inequitable access to genomic services. Artificial intelligence, international data-sharing initiatives, and coordinated healthcare networks are helping overcome these barriers and improve diagnostic equity.
    CONCLUSIONS: Whole-genome sequencing is increasingly emerging as a first-line genomic strategy for pediatric rare diseases, while complementary technologies, expert phenotyping, and iterative data interpretation remain essential for comprehensive and accurate diagnosis and equitable access to genomic medicine.
    Keywords:  genome sequencing; genomic medicine; molecular diagnosis; precision medicine; rare diseases
    DOI:  https://doi.org/10.3390/children13091194
  37. Nat Commun. 2026 Aug 22. pii: 10159. [Epub ahead of print]17(1):
    Enhanced axonal mitochondrial motility and neural activity-induced energy deficits destabilize synaptic transmission in models of bipolar disorder.
    Sunan Li, Gui-Jing Xiong, Zezhi Li, Zu-Hang Sheng.
      Synaptic communication requires mitochondria to supply ATP and buffer calcium at presynaptic terminals. In bipolar disorder, manic episodes are associated with elevated mood and neural activity, but the underlying cellular mechanisms remain unclear. Here we show that hiPSC-derived cortical neurons from donors with bipolar disorder exhibit increased axonal mitochondrial motility and frequent mitochondrial entry-exit transitions, reducing stable mitochondrial retention at presynaptic terminals. This destabilizes local ATP maintenance and calcium buffering, increasing synaptic variability without altering mean synaptic strength. Knockdown of the bipolar disorder risk gene AKAP11 in mouse neurons reproduced these synaptoenergetic deficits. HiPSC-derived neurons from donors with bipolar disorder exhibited reduced expression of the mitochondrial anchor protein syntaphilin(SNPH), and  snph knockout mice displayed manic-like behavioral phenotypes. Lithium restored presynaptic mitochondrial retention, improved ATP maintenance, rescued synaptic variability, and reversed behavioral phenotypes. These findings support impaired presynaptic mitochondrial retention and activity-induced synaptoenergetic deficits as cellular mechanisms contributing to bipolar disorder.
    DOI:  https://doi.org/10.1038/s41467-026-76722-x
  38. Mol Vis. 2026 ;32 196-208
    Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
    Jacob Dohl, Nyan Lin Zaw, Jett Nguyen, Gordon Burns, Brandon Park, Shari Atilano, Kevin Schneider, Marilyn Chwa, Maria Cristina Kenney.
       Purpose: Dry age-related macular degeneration (DAMD) is the leading cause of vision loss in developed countries, yet there are no FDA-approved treatments currently available. Mitochondria play a significant role in the pathology of DAMD; the retinal pigment epithelium cells of patients with DAMD exhibit mitochondrial dysfunction, elevated levels of mitochondrial DNA lesions, and increased mitochondrial reactive oxygen species. Investigations into the mitochondrial contributions to DAMD are complex as human tissue is challenging to acquire, and animal models do not fully recapitulate disease phenotypes. Cytoplasmic hybrid (cybrid) cells, formed by depleting the mitochondria of an immortalized cell line and fusing with patient platelets, are a possible model for mitochondrial studies on DAMD. This study evaluates if cybrid models of DAMD recapitulate the mitochondrial hallmarks of the disease, including mitochondrial dysfunction, decreased mitochondrial protein levels, lipid accumulation, and mitochondrial DNA lesions.
    Methods: The mitochondrial functions of five healthy and five DAMD cybrid cell lines were compared based on mitochondrial oxygen consumption rates, membrane potential, and protein expression. Secondary factors of mitochondrial dysfunction, including lipid accumulation and mitochondrial DNA stress response, were also examined.
    Results: Compared to healthy control cybrid lines, we found no alterations in bioenergetics, protein levels, and lipid accumulation in DAMD cybrid lines. Mitochondrial DNA stress responses were aberrant in DAMD cybrids compared to healthy controls, suggesting some conserved mitochondrial dysfunction.
    Conclusions: Taken together, this study suggests that these DAMD cybrids do not fully recapitulate DAMD mitochondrial pathology, though this is limited to the study population of males with the H mtDNA haplogroup. However, there may be a niche for cybrid cell lines in investigating mitochondrial DNA phenotypes in patients with DAMD. This is likely because DAMD is a multifactorial disease, dependent upon an individual's genetics and the retinal microenvironment.
    DOI:  https://doi.org/10.63500/mv_v32_196
  39. Cell Death Dis. 2026 Aug 04. pii: 834. [Epub ahead of print]17(1):
    Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson's disease.
    Rafael Medina-Guzmán, Bazhena Bahatyrevich-Kharitonik, Marie-Kim St-Pierre, Sara Márquez-Pérez, Elena Gavilán, Cristóbal Coronel-Guisado, Alicia Flores-Cortes, Rodrigo García-Valiente, Sandro Argüelles, Edel Kavanagh, Yiyi Yang, Tomas Deierborg, José Luis Venero, Cristina González-Aguilera, Bertrand Joseph, Miguel Ángel Burguillos.
      Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to splicing dysregulation. Loss of basal caspase-3 activity also increases double-stranded RNA (dsRNA) accumulation, inducing a type I interferon response. Additionally, caspase-3 deficiency impairs mitochondrial respiration, reduces ATP production, and causes sex-specific mitochondrial abnormalities, predominantly in female microglia. Together, our findings uncover a non-apoptotic, homeostatic role for basal caspase-3 activity in microglia. Its disruption, such as in PD, may drive key molecular features of neuroinflammation and neurodegeneration, positioning caspase-3 as a critical regulator of microglial function in health and disease.
    DOI:  https://doi.org/10.1038/s41419-026-09141-x
  40. Antioxidants (Basel). 2026 Sep 10. pii: 1151. [Epub ahead of print]15(9):
    Fungal-Derived Decahydrofluorene Alkaloids Promote Mitochondrial Resilience and Neuroprotection in Cellular and Animal Models of Parkinson's Disease.
    Alberto Vázquez-Jiménez, Margarita M Marques, José M Sánchez, Jesús Agulla, Rebeca Lapresa, Mónica Trigal-Martínez, Rosalía Fernández-Alonso, Gracia Merino, Antonio Fernández, Antonella Consiglio, Juan P Bolaños, Ángeles Almeida, María C Marín, Lorena López-Ferreras.
      Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP+)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP+. CL0179 also enhanced SIRT1 activity under MPP+ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood-brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders.
    Keywords:  6-OHDA; MPP+; Parkinson’s disease; antioxidant; mitochondrial network; mitochondrial resilience; neurodegenerative disease; neuroprotection
    DOI:  https://doi.org/10.3390/antiox15091151
  41. bioRxiv. 2026 Sep 18. pii: 2026.09.12.751163. [Epub ahead of print]
    OPA1-dependent mitochondrial remodeling coordinates TCR signaling and metabolic adaptation during iNKT cell differentiation.
    Sophia Sok, Jianan Cheng, Rufei Lu, Tommy L Lewis, Hiromi Sesaki, Renata O Pereira, Kai Sun, Victoria Sun, Meng Zhao.
      Invariant natural killer T (iNKT) cells require mitochondrial metabolism for terminal effector development. We found iNKT cells express elevated levels of proteins regulating mitochondrial membrane dynamics, and identified Opa1, but not Drp1, as selectively required for iNKT cell differentiation. OPA1 deficiency disrupted mitochondrial cristae organization, reduced mitochondrial membrane potential, increased mitochondrial mass, and altered calcium homeostasis in iNKT cells. Bulk and single-cell transcriptomic analyses revealed impaired TCR-responsive gene expression, activation of mitochondrial stress adaptation and integrated stress response, enhanced glycolysis, and retention of immature differentiation features. SCENITH analysis demonstrated increased glycolytic dependence; LDHA became required in Opa1-deficient iNKT cells while dispensable for normal iNKT development, indicating compensatory glycolytic adaptation. EGTA in thymic organ culture partially restored NKT1 marker expression in Opa1-deficient cells. Co-deletion of Drp1 improved mitochondrial morphology, TCR signaling, stress and metabolic adaptation, and partially rescued iNKT cell differentiation, demonstrating that balanced mitochondrial dynamics coordinate mitochondrial function and terminal effector development.
    DOI:  https://doi.org/10.64898/2026.09.12.751163
  42. Cell Metab. 2026 08 04. pii: S1550-4131(26)00282-2. [Epub ahead of print]38(8): 1722
    High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control.
    Daolin Tang, Rui Kang, Kristen M Livesey, Guido Kroemer, Timothy R Billiar, Bennett Van Houten, Herbert J Zeh, Michael T Lotze.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.009
  43. Eur J Med Genet. 2026 Sep 23. pii: S1769-7212(26)00040-6. [Epub ahead of print] 105106
    A De Novo Gain-of-Function Variant of DNM1L Causes Developmental Encephalopathy.
    Shangsheng Dong, Yanjuan Chen, Mengfang Yan, Xiaoli Huang, Qiannan Deng, Jianxiang Liao, Ke Zhang.
       BACKGROUND: Variants in the dynamin 1-like (DNM1L) gene, which encodes dynamin-related protein 1 (Drp1), can cause encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1) and optic atrophy 5 (OPA5), two neurodevelopmental disorders with distinct symptoms. Given the critical role of Drp1 in mitochondrial fission, it is believed that disrupted mitochondrial fission is key to EMPF1 and OPA5 pathogenesis. However, it is unclear whether other cellular defects also contribute to pathogenesis.
    RESULTS: Here, we report a novel DNM1L variant (c.1994+3T>G) in an EMPF1 patient with delayed psychomotor development, microcephaly, and hypotonia but without epilepsy. This de novo, heterozygous, and intronic variant causes the retention of a DNM1L intron, leading to an aberrant Drp1 protein with a gain of toxicity. Mechanistic studies suggested that the mutant Drp1 forms aggregates and disrupts mitochondrial morphology in cultured cells. Compared to expressing the mutant protein alone, co-expressing both wild-type and mutant Drp1 causes defects at a similar level, suggesting that the mutant Drp1 can confer toxicity to wild-type proteins.
    CONCLUSIONS: Combined, our findings broadened the spectrum of pathogenic DNM1L variants and suggested protein aggregation as a potentially novel pathogenic contributor.
    Keywords:  DNM1L; mitochondria; neurodevelopmental disorders; protein aggregate
    DOI:  https://doi.org/10.1016/j.ejmg.2026.105106
  44. Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):
    Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
    Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.
      Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77023-z
  45. Nat Rev Nephrol. 2026 Sep 24.
    Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
    Shen Li, E Dale Abel, Zoltan Arany, Joseph A Baur, Liming Pei, Katalin Susztak.
      Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41581-026-01127-4
  46. Blood. 2026 Sep 21. pii: blood.2026034660. [Epub ahead of print]
    Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
    Priyasmita Chakrabarti, Abhishek K Singh, Nicola K Wilson, Iwo Kucinski, Orit Kollet, Lizeth-Alejandra Ordonez Moreno, Arturo Simoni-Nieves, M S Vijayabaskar, Sarah J Kinston, Tzu-Hsuan Chang, Yi-Hao Wang, Montaser Haddad, Angelica Varesi, Ekaterina Petrovich-Kopitman, Ziv Porat, Tatiana Smirnova, Jiffin Paulose, Avik Choudhuri, John Hogenesch, You-Yang Zhao, Ping-Chih Ho, Amnon Buxboim, Leonard I Zon, Marie-Dominique Filippi, Regina P Markus, John E Dick, Stephanie Z Xie, Berthold Gottgens, Jose A Cancelas, Tsvee Lapidot.
      Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.
    DOI:  https://doi.org/10.1182/blood.2026034660
  47. Res Sq. 2026 Sep 14. pii: rs.3.rs-10832916. [Epub ahead of print]
    PERM1 Gene Therapy Prevents Pressure Overload-induced Heart Failure Through a Sarcomere-Mitochondria Energetic Microdomain.
    Junco Warren, Karthi Sreedevi, Abigail Doku, Alexey Zaitsev, Ryan Montalvo, Clare Dennison, Audrey Korte, Sarah Salama, Mysha Alabbi, Samia Tasneem, Rebekah Thomas, Mark Renton, Seby Edassery, Stephanie Deditz, Steven Burrows, Garima Patel, Scott Johnstone, Zhen Yan, James Smyth, Jonathan Kirk.
      Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, characterized by impaired contractile function and mitochondrial dysfunction, yet therapies that simultaneously restore cardiac energetics and mechanical performance remain limited. Here, we show that adeno-associated virus-mediated overexpression of PERM1 (AAV-PERM1), a striated muscle-specific mitochondrial regulator, prevents pressure overload-induced HFrEF through a non-transcriptional mechanism that preserves both mitochondrial function and contractility. AAV-PERM1 mitigated declines in mitochondrial respiration and mitochondrial DNA content, maintained mitochondrial morphology under pressure overload, and attenuated pathological hypertrophy and fibrosis. Unexpectedly, these cardioprotective effects occurred despite persistent suppression of oxidative phosphorylation and fatty acid oxidation transcripts. Instead, PERM1 localized to a mitochondria-sarcomere microdomain, where it associated with ribosomal proteins and a creatine kinase-troponin C complex, suppressed pathological O-GlcNAcylation, and post-transcriptionally preserved electron transport chain protein abundance. Functionally, PERM1 enhanced myofibrillar force generation. These findings identify a previously unrecognized mechanism by which PERM1 preserves mitochondrial protein homeostasis and couples energy production to force generation, establishing a new paradigm for post-transcriptional metabolic control and positioning PERM1 as a therapeutic target for heart failure.
    DOI:  https://doi.org/10.21203/rs.3.rs-10832916/v1
  48. Nature. 2026 Sep;657(8133): S51
    What is needed for regenerative medicine to flourish?
    Alexia Austin.
      
    Keywords:  Cell biology; Ethics; Medical research; Regeneration
    DOI:  https://doi.org/10.1038/d41586-026-02854-1
  49. Nat Methods. 2026 Sep 22.
    NanoTS: a deep learning tool for accurate SNP calling in nanopore long-read transcriptome data.
    Zelin Liu, Feng Wang, Robert Wang, David W Wu, Nicole DeBruyne, Kelsey Keith, Elizabeth M McCormick, Joseph Jee-Hwan Park, Matthew T Sullenberger, Andrew C Edmondson, Marni J Falk, Lan Lin, Yi Xing.
      Accurate variant detection using nanopore long-read transcriptome data remains challenging. Here we present NanoTS-a deep learning-based tool for single nucleotide polymorphism detection from diverse types of nanopore transcriptome sequencing data. NanoTS outperforms existing methods, achieving F1 scores above 0.980 and 0.966 on nanopore direct RNA and cDNA sequencing data, respectively, for single nucleotide polymorphisms with at least five supporting reads. Notably, NanoTS shows strong improvements over existing methods for allelically imbalanced variants. We also demonstrate that NanoTS enables accurate detection and genotype calling of pathogenic variants underlying Mendelian disorders, highlighting its potential clinical utility.
    DOI:  https://doi.org/10.1038/s41592-026-03225-4
  50. Elife. 2026 Sep 24. pii: RP108681. [Epub ahead of print]14
    Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
    Farheen Akhtar, Dania M Malik, Arjun Sengupta, Paula Haynes, Andrew D Nguyen, C Jaco Klok, Amita Sehgal, Aalim Weljie.
      Sleep and circadian rhythms shape organismal energy patterns, but how this timing connects to oxygen use and carbon dioxide production remains incompletely understood. We combined high-resolution respirometry with liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster, resolving genotype-specific impacts of sleep disruption and circadian regulation. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. Short-sleep mutants (fmn, sss) exhibited elevated metabolic rates, with reactive shifts of fuel preferences toward lipid and amino acid catabolism, and altered mitochondrial respiration. The clock mutant (per01) and flies under constant darkness (WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems contribute to aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.
    Keywords:  D. melanogaster; biochemistry; chemical biology; circadian rhythms; metabolic flexibility; metabolism; metabolomics; respirometry; sleep
    DOI:  https://doi.org/10.7554/eLife.108681
  51. bioRxiv. 2026 Sep 17. pii: 2026.09.15.751849. [Epub ahead of print]
    Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism.
    Woo Sung Kim, Rebecca Danner, Juyeong Cho, Jonathan Williams, Luiz Lopez, Yutong Bao, Julia K Hansen, Elizabeth M Poad, Haania Khan, Daehan Kim, Brian W Parks, Jonathan G Van Vranken, David A Harris, Andrea Galmozzi, Mary Elizabeth Patti, Snehal N Chaudhari.
      Adipocyte signaling adaptively responds to macronutrients, but how essential micronutrients impact lipid homeostasis remains poorly understood. Here, we demonstrate that folate polyglutamylation, the sequential conjugation of glutamate residues to folate, serves as a dynamic biochemical process regulating metabolic signaling. Using our folate metabolomics platform, we show that polyglutamylated folic acid accumulates in healthy adipose tissue, but is depleted in obesity across mice and humans, independent of circulating folate levels. Genetic ablation of the polyglutamylation enzyme folylpolyglutamate synthase (Fpgs) in adipocytes suppresses lipid catabolism to induce cell-autonomous lipid accumulation, operating independently of canonical adipogenesis or downstream one-carbon flux. Target-engagement proteomics identifies monoglutamylated folic acid as a Map2k5-interacting molecule that inhibits Map2k5 activity, whereas Fpgs-mediated folic acid polyglutamylation acts as a chemical switch that disrupts this interaction to promote lipolysis. In vivo , whole-body inhibition of Map2k5 or adipose-targeted genetic depletion of Fpgs increases body fat mass in the absence of dietary obesogenic triggers. Furthermore, single-cell and single-nuclear transcriptomic analyses establish the Fpgs-Map2k5 pathway as a core transcriptional signature of mouse and human adipose tissues. These findings uncover a non-canonical signaling role for folate that regulates adipocyte lipid homeostasis.
    DOI:  https://doi.org/10.64898/2026.09.15.751849
  52. Hum Genet. 2026 Sep 21. pii: 79. [Epub ahead of print]145(1):
    Mitochondrial dysfunction drives metabolic reprogramming in Gitelman syndrome: insights from proteomics and isogenic modeling.
    Honghan Zhang, Wenqian Zhao, Lanxin Ma, Xueli Yang, Jinghua Gao, Xiaoling Liu, Y-G Xie, Ying Hu, Heng Luo, Jian Han.
      Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by SLC12A3gene mutations. While electrolyte disturbances are well-defined, the systemic metabolic consequences and underlying mechanisms remain unclear. This study investigated whether SLC12A3mutation drives mitochondrial dysfunction and consequent metabolic reprogramming in GS, utilizing a genetically homogeneous founder population with a homozygous SLC12A3p.C421F mutation. We conducted quantitative plasma proteomic analysis (directDIA) in wild-type (WT) and homozygous (HOM) individuals (n = 6/group) and established an isogenic SLC12A3p.C421F homozygous 293T cell model via CRISPR-Cas9. A series of functional assays were performed, including assessment of mitochondrial DNA copy number, membrane potential (JC-1), oxidative stress markers (SOD, MDA, ROS), lipid metabolism (lipid droplets, triglycerides, glycerol, cholesterol), NAD(H)/NADP(H) pools, intracellular ATP levels, enzymatic activities of all five mitochondrial respiratory chain complexes, extracellular acidification rate (ECAR), and expression of key oxidative phosphorylation proteins. Plasma proteomics revealed a significant downregulation of mitochondrial oxidative phosphorylation, TCA cycle, and fatty acid oxidation proteins in HOM individuals. In the cellular model, the mutation recapitulated this signature, showing reduced expression of core respiratory chain subunits (SDHA, UQCRC1, ATP5D). Functionally, HOM cells exhibited impaired activities of respiratory chain complexes I-V, reduced ATP content, and a compensatory increase in glycolytic flux (ECAR). This bioenergetic deficit was accompanied by diminished mtDNA copy number, dissipated mitochondrial membrane potential, elevated oxidative stress, and aberrant lipid metabolism (decreased lipid droplets and triglycerides). Notably, redox cofactor profiling showed a contracted NADP(H) pool alongside an expanded NAD(H) pool. Our integrated multi-omics and functional approach establishes a strong association between the SLC12A3 p.C421F mutation and a state of mitochondrial bioenergetic failure-characterized by impaired oxidative phosphorylation, an ATP deficit, and a compensatory metabolic shift towards glycolysis-in GS. The distinct NAD(H)/NADP(H) imbalance further indicates profound metabolic reprogramming. These findings extend the pathophysiological understanding of GS beyond a pure tubulopathy to a systemic disorder involving mitochondrial dysfunction, offering new mechanistic insights and potential therapeutic targets.
    DOI:  https://doi.org/10.1007/s00439-026-02880-z
  53. Nat Protoc. 2026 Sep 24.
    Tutorial: interrogating biology using organoid technologies.
    Jeroen M Bugter, Simon T Schafer, Roland Rad.
      Organoids provide a versatile platform for studying fundamental biology, complementing traditional cell culture and in vivo models. Their unique features, such as self-organization and the possibility for their precise manipulation, have enabled key discoveries in tissue homeostasis, development and disease. This tutorial presents an overview of organoid technologies and protocols across a broad spectrum of applications, from investigating cell fate decisions and cell-cell or cell-microbe interactions to the study of genetic diseases, species evolution and translational/clinical questions. By focusing on adult stem cell-derived intestinal and human pluripotent stem cell-derived brain organoids, we highlight models with distinct characteristics that together reflect the broader spectrum of organoid systems, tissue types and research contexts. For applications not supported by these models, we discuss organoids derived from other tissues. We also outline current challenges in the field and highlight emerging innovations that are promising to shape future directions.
    DOI:  https://doi.org/10.1038/s41596-026-01447-6
  54. Front Cardiovasc Med. 2026 ;13 1897303
    Recent advances in mitochondrial fission and fusion in diabetic cardiomyopathy.
    Jinjin Hao, Xiaochen Zhang, Xueying Tian, Jingying Su.
      Diabetic cardiomyopathy (dCM) is characterized by myocardial dysfunction in diabetes and reflects interacting metabolic, redox, calcium, inflammatory, fibrotic, and microvascular disturbances. Mitochondrial fission and fusion are not merely morphological endpoints; when uncoupled from mitophagic clearance and cristae maintenance, they contribute to energetic failure and cell-specific cardiac injury. This review synthesizes evidence from human diabetic myocardium and dCM-specific experimental models, while distinguishing direct fission-fusion evidence from broader mitochondrial quality-control findings. We summarize how glucolipotoxicity, impaired energy sensing, calcium entry, mechanosensing, innate immunity, epitranscriptomic regulation, and ubiquitin editing converge on dynamin-related protein 1 (DRP1)/ fission 1 (FIS1)/ mitochondrial fission factor (MFF) and mitofusin 1 (MFN1)/ mitofusin 2 (MFN2)/ optic atrophy 1 (OPA1) pathways. We further compare consequences in cardiomyocytes, cardiac fibroblasts, and coronary microvascular endothelial cells, including ATP depletion, oxidative stress, regulated cell death, fibrosis, and perfusion injury. Candidate interventions are organized according to whether they restrain pathological fission, restore MFN/OPA1-dependent fusion, or normalize mitophagic flux. Despite strong cellular and rodent evidence, direct clinical validation and pharmacodynamic biomarkers remain limited. Future progress will require human myocardial phenotyping, single-cell and spatial analyses, in vivo measurement of mitochondrial dynamics, cell-selective delivery, and standardized flux-based endpoints. The therapeutic goal should be restoration of adaptive mitochondrial dynamics rather than indiscriminate inhibition of fission or promotion of fusion.
    Keywords:  diabetic cardiomyopathy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.3389/fcvm.2026.1897303
  55. Annu Rev Pharmacol Toxicol. 2026 Sep 25.
    Novel Targets and Treatments for Neurodegenerative Diseases Revealed by Drosophila.
    Pablo Reina-Gonzalez, Aiesha Anchan, Jennifer Bekos, Abdulla Abu-Salah, Souvarish Sarkar.
      Neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, and others lack any disease-modifying therapy due to the lack of mechanistic understanding of the disease etiology. The genetic tractability, short lifespan, and conserved cellular biology of Drosophila melanogaster have positioned the fly as a powerful model organism for a pathway-driven therapeutic discovery across NDDs. Fly models expressing human pathogenic proteins, including Aβ, tau, α-synuclein, and others, recapitulate core features of these NDDs such as proteostasis defects, RNA dysregulation, mitochondrial dysfunction, lipid signaling abnormalities, and innate immune activation. Unbiased genetic and pharmacologic screens in these systems have identified conserved therapeutic nodes such as PARP signaling and insulin/IGF pathways. In this review, we discuss these advances to define conserved therapeutic axes identified in Drosophila and evaluate their translational potential for neurodegenerative disorders.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-060325-064705
  56. Neurobiol Dis. 2026 Sep 23. pii: S0969-9961(26)00360-8. [Epub ahead of print] 107615
    Brain energy metabolism in neurodegenerative disease.
    Carmen Lahr, Elle Wilson, Melanie Sengupta, Michela Bernini, Alexander Skupin.
      The brain is a highly complex organ composed of diverse, specialized cell types whose coordinated functions underpin cognition and behavior. While extensive research has elucidated neuronal signaling mechanisms, the metabolic interactions between distinct brain cells that sustain energy homeostasis are not yet comprehensively understood. Recently, brain energy metabolism has gained significant attention as a unifying factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's, potentially opening new avenues for therapeutic development. In this review, we provide an overview of brain energy metabolism, examine its role in neurodegeneration, and highlight current challenges and future perspectives in the field.
    Keywords:  Alzheimer's disease; Brain energy metabolism; Mitochondrial dysfunction; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2026.107615
  57. bioRxiv. 2026 Sep 14. pii: 2026.09.07.749965. [Epub ahead of print]
    Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
    Jessica Alvarez, Sofia Rivera, Sarahbeth Roberts, Natalia Herrera, Tyron Chang, Krishna Kanth Chitta, Jeon Lee, Andrew Lemoff, Dustin C Hancks.
      Dysregulated immunity, a hallmark of many human diseases, co-occurs with mitochondrial dysfunction and is commonly associated with misprimed primary immune signaling. While transcriptionally well-characterized, the impact of mitochondria on the host response at the protein level is less clear. Using in vitro and in vivo approaches including proteotranscriptomics, our data suggest that OXPHOS promotes expression of early, cell autonomous immune proteins whereas mitochondrial perturbation favors mediators of cell extrinsic responses like inflammation. This response is independent of immune cues, time-dependent, conserved, and occurs across tissues in mouse models of mitochondrial dysfunction. These data illustrate unappreciated roles for mitochondrial state in adapting host responses at the protein level, which have implications for complex disease etiology and the ancestral origins for eukaryotic immune sensing.
    DOI:  https://doi.org/10.64898/2026.09.07.749965
  58. Nat Commun. 2026 Aug 21. pii: 9984. [Epub ahead of print]17(1):
    TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity.
    Rafał Tomecki, Małgorzata Drabko, Małgorzata Siek, Maria Matykiewicz, Miłosz Ludwinek, Łukasz S Borowski, Aneta Jurkiewicz, Kamil Kobyłecki, Agnieszka Jabłońska, Dominik Cysewski, Agata Malinowska, Magdalena Bakun, Rafał Płoski, Roman J Szczęsny, Agnieszka Tudek.
      The functions of many human proteins remain unknown, highlighting major gaps in our understanding of cellular biology. TTC33 is an evolutionarily conserved tetratricopeptide repeat (TPR) protein expressed across human tissues, whose molecular role is not defined. Here we identify the TTC33 partners using comparative label-free mass spectrometry. The TTC33-associated network (TAN) comprises WDR61, CCDC97, UNG1/2, PP2A-B55α, PHF5A, and components of the SF3B U2 spliceosomal complex. Using a combination of biochemical assays, structural modeling and molecular dynamics we show that TTC33 directly recruits WDR61 and PHF5A to assemble into a trimeric core complex (TANC), which then forms distinct interactions with either UNG1/2 or SF3B-CCDC97. Somatic TTC33 mutations at key TANC interface residues reduce complex stability and weaken the interaction network. We further show that WDR61 stabilizes TTC33 by protecting it from proteolytic degradation. Loss of network components induces genomic instability and activates DNA damage markers, including γH2AX and p53 phosphorylation.
    DOI:  https://doi.org/10.1038/s41467-026-76928-z
  59. Anim Cells Syst (Seoul). 2026 ;30(1): 16-38
    Mitochondria-ER contact sites in neurological disorders.
    Eun Jin Jang, Jisoo Lee, Seungha Shin, Tran Diem Nghi, Sang Ki Park.
      Mitochondria-associated ER membranes (MAMs) are inter-organelle contact sites that mediate signaling between the ER and mitochondria. MAMs play crucial roles in Ca2+ transfer, lipid metabolism, mitochondrial respiration, protein homeostasis, autophagy, and ER stress. In the central nervous system (CNS), these functions are particularly important because neurons and glial cells require precise communication between ER and mitochondria to sustain various neuronal functions. Previous studies often interpreted the MAM dysfunction associated with disease as an alteration in ER-mitochondria coupling. More recently, however, MAMs are regarded as functionally specialized signaling platforms whose molecular composition is dynamic, cell type- and disease stage-dependent. Here, we discuss how MAM remodeling underlies a range of neurological diseases, including neurodegenerative and neurodevelopmental conditions, neuropsychiatric disorders, neuroinflammation, neuronal aging, and brain tumors.
    Keywords:  MAM remodeling; MAMs; Mitochondria-associated ER membranes; neurological disorders; organelle homeostasis
    DOI:  https://doi.org/10.1080/19768354.2026.2725542
  60. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00079-6. [Epub ahead of print]191 27-59
    Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.
    Deepak Kumar, Snehasish Shee, Ashok Kumar Datusalia, Shyam Sunder Sharma.
      Parkinson's disease (PD) and Alzheimer's disease (AD) are the most prevalent neurodegenerative disorders and represent a major global health burden. Despite distinct clinical features, both diseases share key pathogenic mechanisms, particularly oxidative stress and mitochondrial dysfunction, which contribute to neuronal injury and progression. Current diagnostic approaches based on clinical evaluation, neuroimaging, and cerebrospinal fluid (CSF) biomarkers are invasive, costly, and often detect disease only after significant neuronal loss, underscoring the need for minimally invasive, pathway-relevant assays. This chapter reviews blood- and CSF-based biomarker assays reflecting oxidative stress and mitochondrial dysfunction in PD and AD, including lipid peroxidation products, antioxidant capacity, oxidative DNA damage markers, mitochondrial bioenergetic indices, and quality-control proteins. Emerging assay platforms targeting circulating cell-free mitochondrial DNA, mitochondrial-derived vesicles, extracellular vesicle cargo, and regulatory non-coding RNAs are also discussed. The mechanistic relevance of these biomarkers is examined in relation to impaired mitochondrial quality control, disrupted redox homeostasis, defective oxidative phosphorylation, and interactions with disease-defining proteins such as α-synuclein, amyloid-β, and phosphorylated tau. Collectively, these assay-based biomarkers hold promise for early detection, disease monitoring, and therapeutic stratification, although challenges related to standardization, sensitivity, and longitudinal validation remain.
    Keywords:  Alzheimer’s disease; Blood biomarkers; Cerebrospinal fluid; Extracellular vesicles; Mitochondrial DNA; Mitochondrial dysfunction; Neurodegeneration; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.1016/bs.irn.2026.07.003
  61. Eur J Cell Biol. 2026 Sep 21. pii: S0171-9335(26)00046-4. [Epub ahead of print]105(4): 151575
    Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.
    Shaojie Liu, Jiaqi Zhang, Zihan Zhang, Shilong Yan, Wenyu Di, Jie Yang, Wei Su, Na Song, Haijun Wang.
      Mitochondria integrate bioenergetics, redox homeostasis, calcium signaling, metabolite synthesis, organelle quality control, innate immune sensing, and regulated cell death. In colorectal cancer (CRC), mitochondrial function is not simply suppressed by aerobic glycolysis; rather, tumor cells dynamically redistribute flux between glycolysis, oxidative phosphorylation, glutaminolysis, fatty-acid metabolism, and the mevalonate pathway to meet stage- and treatment-specific demands. This metabolic plasticity determines whether mitochondrial stress is buffered or converted into a lethal signal. Here, we critically synthesize recent evidence linking mitochondrial bioenergetics, reactive oxygen species (ROS), mitophagy, fusion-fission dynamics, mitochondrial DNA (mtDNA) damage and release, mitochondrial biogenesis, and oncogenic signaling to apoptosis and non-apoptotic forms of programmed cell death, including ferroptosis, pyroptosis, necroptosis, PANoptosis, and cuproptosis. We further discuss mtDNA sensors-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Toll-like receptor 9 (TLR9), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and Z-DNA-binding protein 1 (ZBP1)-as links between mitochondrial injury, tumor-cell death, and antitumor immunity. Particular attention is given to B-cell lymphoma 2 (BCL-2) homology 3 (BH3) mimetics, metabolic inhibitors, patient-derived organoids (PDO), patient-derived organoid xenografts (PDOX), and immunocompetent models. Current evidence supports mitochondria as a therapeutically actionable network, but also reveals major context dependencies related to tumor genotype, cell state, treatment schedule, immune competence, and normal-tissue mitochondrial requirements. Biomarker-guided combinations and model systems that preserve patient heterogeneity will therefore be essential for clinical translation.
    Keywords:  Apoptosis; Colorectal cancer; Ferroptosis; Metabolic plasticity; Mitochondria; PANoptosis
    DOI:  https://doi.org/10.1016/j.ejcb.2026.151575
  62. Neurotoxicology. 2026 Sep 19. pii: S0161-813X(26)00197-X. [Epub ahead of print]117 103576
    2,4-dichlorophenoxyacetic acid (2,4-D) potentiates vanadium-induced Parkinsonian neurodegeneration: Evidence from mitochondrial bioenergetic dysfunction and dopaminergic and GABAergic neurodegeneration.
    Adesina A Babalola, Aline Franzen da Silva, Sâmili Wagner da Silva, Marcell Vallandro Soares, Michael Aschner, Felix Alexandre Antunes Soares.
      Vanadium is a critical earth element with broad application in modern technologies, particularly in energy storage systems and in steel production. 2,4-dichlorophenoxyacetic acid (2,4-D) is a synthetic auxin herbicide and one of the most widely applied agrochemicals globally. The extensive industrial and agricultural utilization of these chemicals has increased their environmental co-exposure, given that humans are rarely exposed to single chemical stressors. Parkinson's disease (PD) is a neurodegenerative disorder, pathologically characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. PD is the second most prevalent neurodegenerative disease globally, and understanding its pathogenic environmental contributors and mechanisms is a major priority. We investigated the effects of V and 2,4-D individually, and in combination at relevant environmental doses, on Parkinsonian-related symptoms and mitochondrial endpoints in the Caenorhabditis elegans model. Our data showed that developmental co-exposure of C. elegans to 2,4-D and V for 72 h resulted in sublethal survival but led to more severe dopaminergic and GABAergic neurodegeneration and α-synuclein aggregation than individual exposures. High-resolution respirometry analysis of the mitochondria further revealed that V and 2,4-D mixtures induced mitochondrial dysfunction by jointly impairing complex I and II-linked oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities. Collectively, our novel findings demonstrate that 2,4-D potentiates V-induced neurotoxicity via amplifying oxidative stress and mitochondrial respiratory dysfunction, exacerbating Parkinsonian phenotypes in C. elegans.
    Keywords:  Complex I and Complex II; Dopaminergic and GABAergic neurodegeneration; Mitochondrial dysfunction; Parkinson disease
    DOI:  https://doi.org/10.1016/j.neuro.2026.103576
  63. Exp Eye Res. 2026 Sep 20. pii: S0014-4835(26)00398-2. [Epub ahead of print]272 111242
    NAD+-sirtuin-mitochondrial quality control in lens epithelial cells: a candidate modulatory network in crystalline lens aging.
    Ruili Huo, Nana Chang, Linda Hildegard Bergersen.
      Crystalline lens aging reflects parallel processes: intrinsic chemical modification of exceptionally long-lived fiber-cell proteins, deterioration of lens-wide redox and transport homeostasis, and declining maintenance in metabolically active cellular compartments. Lens epithelial cells (LECs) support antioxidant defense, ion and water balance, stress responses, and the quality of newly formed fibers. Current lens and LEC evidence shows age-associated reductions in mitochondrial oxygen consumption in primary human LECs obtained during cataract surgery; SIRT1-related signaling is linked to epithelial stress tolerance; PINK1/Parkin-dependent mitophagy and autophagy-lysosomal function protect LECs in lens-relevant stress models; and transport systems shape the mature fiber-cell environment. Together, these findings identify NAD+ homeostasis as a testable link among established maintenance components, although age-dependent NAD+ change in normal human LECs and a causal epithelial-to-tissue pathway remain unproven. Direct lens evidence strongly supports crystallin modification, aggregation, insolubilization, redox disruption, and age-related material change. We therefore propose three falsifiable levels of validation: age-stratified measurement of NAD+ homeostasis in ethically sourced human LECs; pathway-dependent testing of whether NAD+ restoration improves sirtuin-dependent mitochondrial quality control (MQC); and determination of whether verified LEC MQC rescue alters intact-lens homeostasis, crystallin damage, material properties, transparency, or optical quality. Presbyopia and age-related cataract are considered distinct outcomes with partially overlapping determinants. This evidence-stratified synthesis positions the LEC NAD+-sirtuin-MQC network as a candidate modulator of crystalline lens aging whose contribution can be supported, restricted, or rejected experimentally.
    Keywords:  Crystallin proteostasis; Crystalline lens aging; Lens epithelial cells; Mitochondrial quality control; NAD(+) homeostasis; Sirtuins
    DOI:  https://doi.org/10.1016/j.exer.2026.111242
  64. Signal Transduct Target Ther. 2026 Sep 23. pii: 406. [Epub ahead of print]11(1):
    Cuproptosis and ferroptosis: signal pathways, diseases and therapeutic targets.
    Yuan-Yuan Li, Franklin R Tay.
      Regulated cell death is essential for tissue homeostasis, and its dysregulation contributes to numerous human diseases. Cuproptosis and ferroptosis are metal-dependent forms of regulated cell death distinguished by different biochemical triggers and pathological consequences. Cuproptosis arises from copper-mediated disruption and aggregation of lipoylated mitochondrial proteins, whereas ferroptosis is driven by iron-dependent phospholipid peroxidation. Despite these mechanistic differences, the two pathways intersect through mitochondrial metabolism, redox imbalance, iron-sulfur cluster biology, and organelle crosstalk. Lysosomes, mitochondria, and the endoplasmic reticulum act as critical regulatory hubs that influence cellular susceptibility to both death modalities. This review summarizes current understanding of the molecular mechanisms governing cuproptosis and ferroptosis. It examines the genetic, epigenetic, transcriptional, post-transcriptional, and protein-level networks that regulate these processes. Evidence linking cuproptosis and ferroptosis to cardiovascular, neurodegenerative, autoimmune, metabolic, oral, infectious, and neoplastic diseases is critically evaluated. Therapeutic approaches are discussed, including metal ionophores, chelators, small-molecule modulators, nanomedicine-based delivery systems, and rational combination strategies. Particular attention is given to the context-dependent consequences of activating or suppressing these pathways, and to the challenge of selectively targeting diseased tissues without disrupting systemic metal homeostasis. Successful clinical translation will require reliable biomarkers, mechanistically informed patient stratification, tissue-selective delivery, and a clearer understanding of interactions between metal metabolism, immune responses, and treatment resistance. The review further identifies unresolved questions concerning pathway specificity, temporal regulation, biomarker validation, and the clinical safety of systemic or prolonged therapeutic modulation. Integrating these concepts may enable more precise exploitation of cuproptosis and ferroptosis as therapeutic targets across diverse diseases.
    DOI:  https://doi.org/10.1038/s41392-026-03043-2
  65. Biomolecules. 2026 Aug 31. pii: 1257. [Epub ahead of print]16(9):
    Inter-Organelle Membrane Contact Sites as Physiological Regulatory Hubs in the Brain: From Neurons to Glial Cells.
    Yuchen Wu, Ginam Cho, Youngshin Lim.
      Inter-organelle membrane contact sites (MCSs) enable direct communication between organelles, and this communication is fundamental to cellular homeostasis, coordinated calcium (Ca2+) signaling, lipid metabolism, energy production, and stress responses. While MCSs are evolutionarily conserved, emerging evidence indicates that their organization and function are highly context dependent. In the brain, neurons and glial cells differ markedly in their physiological roles, morphologies, and metabolic demands, suggesting that inter-organelle contact networks might be specialized in a cell-type-dependent manner. Although much of the existing literature focuses on neurons, growing evidence indicates that these contact sites also play important roles in glial cells. Here, we review recent advances in our understanding of MCSs in the nervous system, focusing on cell-type-specific differences between neurons and glial cells. We highlight the spatial specialization of MCSs within neurons, emphasizing how subcellular localization shapes their functional output. Our analysis of the current literature suggests that neuronal MCSs are primarily optimized for rapid Ca2+ signaling and metabolic adaptation, whereas glial MCSs preferentially coordinate lipid metabolism, inflammatory signaling, and tissue homeostasis. We also review the context-dependent and disease-driven remodeling of MCSs in the brain, reflecting alterations in contact-site composition and function rather than simply increased or decreased organelle proximity. Furthermore, we discuss emerging therapeutic perspectives aimed at modulating inter-organelle communication in multiple neurological diseases and outline key unresolved questions and future directions necessary to elucidate how inter-organelle contact sites shape brain physiology and disease. Collectively, the evidence reviewed here indicates that MCSs serve as dynamic signaling platforms, with their specific physiological and pathological functions varying according to cell type, subcellular localization, and molecular composition.
    Keywords:  brain homeostasis; glial cells; membrane contact sites; neurological diseases; neurons; organelle interactions; potential therapies
    DOI:  https://doi.org/10.3390/biom16091257
  66. bioRxiv. 2026 Sep 18. pii: 2026.09.17.752311. [Epub ahead of print]
    NIX-associated mitochondrial remodeling contributes to esophageal epithelial differentiation.
    No'ad Shanas, Aissata Balde, Annie D Fuller, Jazmyne L Jackson, Abigail J Staub, John M Crespo, William Nazario-Lugo, Alexander Tufano, Nicholas M McDonald, Andres J Klein-Szanto, Kathy Q Cai, Melanie Ruffner, Amanda B Muir, Zachary Wilmer Reichenbach, Kelly A Whelan.
      Mitochondria are increasingly recognized as regulators of cellular differentiation, but their role in esophageal epithelial homeostasis remains poorly understood. Here, we investigated mitochondrial remodeling during esophageal epithelial differentiation and whether mitochondrial depletion contributes to the acquisition of the differentiated phenotype. Mitochondrial abundance was assessed across normal human esophageal epithelium and in non-transformed immortalized human esophageal epithelial cells (EPC2-hTERT) using two differentiation models. Mitochondrial architecture was quantified, and the functional role of mitochondrial abundance was examined using doxycycline-inducible depletion of transcription factor A, mitochondrial (TFAM). Mitochondrial abundance progressively decreased from basal to superficial compartments of normal human esophageal epithelium and during in vitro differentiation, accompanied by fragmentation and remodeling of the mitochondrial network. TFAM depletion reduced mitochondrial abundance and increased squamous differentiation markers, indicating that mitochondrial depletion was sufficient to promote differentiation. Analysis of candidate mitochondrial clearance pathways identified Bcl2-interacting protein 3-like ( BNIP3L )/NIX (NIP3-like protein X) as preferentially associated with differentiated epithelial cells and induced during differentiation. NIX was associated with mitochondria and increased as mitochondrial abundance declined. NIX depletion prevented differentiation-associated mitochondrial depletion and attenuated differentiation marker induction. In human esophageal epithelium, NIX expression increased across the basal-to-suprabasal compartment before declining superficially. BNIP3L expression was reduced in active eosinophilic esophagitis (EoE) and increased following corticosteroid-associated remission. Interleukin-13 similarly reduced BNIP3L expression and suppressed epithelial differentiation in EPC2-hTERT cells. These findings identify NIX-associated mitochondrial remodeling as an important component of esophageal epithelial differentiation and suggest that disruption of mitochondrial quality control may contribute to impaired epithelial differentiation in EoE.
    New and Noteworthy: Although impaired esophageal epithelial differentiation is associated with various esophageal diseases, mechanisms regulating differentiation under homeostasis remain incompletely understood. We show that mitochondria are progressively cleared during esophageal epithelial differentiation and that mitochondrial depletion is sufficient to promote differentiation. BNIP3L/NIX regulates mitochondrial clearance during this process. Moreover, BNIP3L expression is reduced in active eosinophilic esophagitis (EoE) and restored with remission, linking disrupted mitochondrial quality control to epithelial dysfunction in EoE.
    DOI:  https://doi.org/10.64898/2026.09.17.752311
  67. J Comput Neurosci. 2026 Sep 25.
    Context-Dependent modulation of astrocytic Ca2+ signals by mitochondria: a computational study.
    Thiago Ohno Bezerra, Antonio C Roque.
      Mitochondria regulate intracellular Ca2+ by uptake through the mitochondrial Ca2+ uniporter (MCU) and release via the mitochondrial permeability transition pore (mPTP). In astrocytes, neurotransmitter stimulation evokes Ca2+ signaling, yet the role of mitochondria in shaping these responses remains unclear. We extended a compartmental astrocyte model developed by our group to include MCU- and mPTP-mediated dynamics, and simulated glutamatergic and dopaminergic inputs modeled as Poisson processes driving IP3 synthesis through the phospholipase-C (PLC) pathway. Both unipolar and bifurcated-terminal morphologies were considered, with mitochondria positioned in alternating compartments starting from the soma; distal compartments contained mitochondria only when sufficiently large. Simulations show that mitochondria modulate Ca2+ signaling in a context-dependent manner: under weak glutamatergic input, they reduce oscillation frequency and limit signal propagation, whereas under strong glutamatergic input or dopaminergic modulation, they enhance Ca2+ responses by reducing Ca2+-dependent IP3 degradation. These results suggest that mitochondria can play an important role in shaping the spatial organization of Ca2+ signaling in astrocytes.
    Keywords:  Astrocytes; Calcium signaling; Glia; Mitochondria
    DOI:  https://doi.org/10.1007/s10827-026-00956-3
  68. bioRxiv. 2026 Sep 20. pii: 2026.09.14.750442. [Epub ahead of print]
    SIM2s coordinates programmed mitophagy with respiratory chain supercomplex remodeling during mammary epithelial differentiation.
    Ramsey M Jenschke, Madelyn Spooner-Harris, Steven W Wall, Lilia Sanchez, Jessica Epps, Sophia Schutmaat, Kaitlin P Kelly, Tyler Frey, Monique Rijnkels, Weston W Porter.
      Lactation requires mammary epithelial cells (MECs) to rapidly expand mitochondrial function while remodeling the mitochondrial population that supports milk synthesis and secretion. Programmed mitophagy is required for MEC differentiation, yet why mitochondrial turnover is necessary during this developmental transition remains poorly understood. Using Mito-QC reporter mice, we identified developmentally regulated changes in mitolysosome burden across the transition from late pregnancy to lactation that were altered by mammary-specific gain or loss of the bhlh/PAS protein, SIM2s (single-minded 2 s). In differentiating HC11 cells, mitochondrial turnover was accompanied by increased assembly and activity of respiratory supercomplexes containing complexes I, III, and IV. Depletion of PRKN prevented acquisition of this differentiation-associated respiratory profile and impaired lactogenic differentiation. SIM2s co-migrated with higher-order respiratory assemblies, and loss of SIM2s reduced supercomplex assembly and activity in HC11 cells and mammary tissue. SIM2s also localized in close proximity to complex III in differentiated mammary epithelium, whereas loss of SIM2s reduced proximity between complexes III and IV. Together, these findings support a model in which SIM2s coordinates PRKN-dependent mitochondrial turnover with respiratory-chain remodeling during MEC differentiation. Our results suggest that programmed mitophagy does more than remove mitochondria during development; it contributes to establishment of a mitochondrial population with a respiratory-chain architecture suited to the emerging differentiated state.
    DOI:  https://doi.org/10.64898/2026.09.14.750442
  69. Science. 2026 Sep 24. 393(6818): eaec5473
    Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.
    Uladzimir Barayeu, Seiryo Ogata, Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Masanobu Morita, Tomoaki Ida, Mike Lange, Yuka Unno, Saber Boushehri, Paulius Greicius, Akira Nishimura, Lorenzo Catti, Yuexuan Pan, Tianli Zhang, Takayuki Shimizu, Ryo Ushioda, Takakazu Nakabayashi, Seji Asamitsu, Kazuki Fusegawa, Takashi Suzuki, Takanori Ishida, Naoko Tanda, Yasuo Watanabe, Yukihiro Tsuchiya, Ryo Yamaguchi, Shintaro Noguchi, Eikan Mishima, Fumiko Yano, Mieko Arisawa, Dennis J Stuehr, Ning Xia, Huige Li, Bernd Moosmann, Frauke Gräter, Camilo Aponte-Santamaría, James A Olzmann, Marcus Conrad, Albert van der Vliet, Tobias P Dick, Hozumi Motohashi, Michito Yoshizawa, Takaaki Akaike.
      Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo-octasulfur (S8). We found that S8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet-associated nitric oxide synthase as a source of S8 biosynthesis and found that S8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.
    DOI:  https://doi.org/10.1126/science.aec5473
  70. Methods Mol Biol. 2027 ;3075 59-74
    Base Editing: Mechanisms and Therapeutic Applications.
    Fabio Catalano.
      Base editing enables the direct, programmable conversion of one nucleotide into another at a defined genomic site without introducing a double-strand break. First reported in 2016, a decade later, it has expanded into a broad family of molecular tools that has now entered clinical trials. This chapter reviews the development of base editing from its origins, including the early transition of cytosine and adenine base editors, to the more recent emergence of transversion editors. For each class, this section describes the mechanism, the optimization of on-target efficiency, product purity, and specificity, as well as the key strengths and limitations. The following discussion focuses on delivery, which remains one of the central bottlenecks for clinical translation, with particular attention to lipid nanoparticles, engineered virus-like particles, and other emerging strategies. Finally, a review of the current clinical landscape is presented. This already includes the first ex vivo multiplex base-edited cell therapy in T-cell leukemia, ex vivo hematopoietic stem cell transplantation targeting hemoglobin disorders, the first systemic in vivo base editing in humans, and, importantly, the first personalized N-of-1 in vivo base-editing therapy, which was developed within a remarkably short time.  These developments show that base editing has moved from a proof-of-concept to a clinically-ready platform with incredible speed, and that the central questions for the field, perhaps, concern the pace at which the surrounding technology, for example delivery, can keep up with base editors themselves.
    Keywords:  Adenine base editing; Base editing; Cytosine base editing; Gene therapy; Lipid nanoparticles; Mitochondrial DNA editing; Virus-like particles
    DOI:  https://doi.org/10.1007/978-1-0716-5547-4_4
  71. bioRxiv. 2026 Sep 17. pii: 2026.09.15.751667. [Epub ahead of print]
    Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans.
    Chutipong Chiamkunakorn, Juthakorn Poothong, Kongtana Trakarnsanga, Bart P Braeckman, Wichit Suthammarak.
      Mild reductions in mitochondrial electron transport chain (ETC) capacity paradoxically extend organismal lifespan, a conserved phenomenon termed mitohormesis. While the mitochondrial unfolded protein response (UPR mt ) and AMP-activated protein kinase (AMPK) are both established regulators of this process, whether distinct mitochondrial lesions converge on a single, unified survival mechanism remains unclear. By systematically dissecting the genetic architectures governing longevity in Caenorhabditis elegans , we demonstrate that targeted RNAi knockdown of Complex I ( nuo-6 ) and Complex IV ( cco-1 ) subunits activates fundamentally divergent downstream pathways. Both structural defects robustly induce the UPR mt , yet lifespan extension from Complex I impairment highly dependent on the UPR mt master regulator ATFS-1 while bypassing the AMPK ortholog AAK-2. Conversely, Complex IV-mediated longevity operates independent of ATFS-1 but requires AAK-2-driven metabolic reprogramming. Pharmacological intervention with metformin-a Complex I inhibitor and AMPK activator-further exposed complex-specific vulnerabilities: metformin markedly suppressed the longevity phenotype of nuo-6;aak-2 mutants, whereas in cco-1;aak-2 animals it produced a trend toward lifespan extension that appeared independent of AAK-2. Together, these findings challenge the view of mitohormesis as a uniform response, revealing instead that cells engage specialized, molecularly tailored retrograde signaling networks to govern lifespan and respond to pharmacological interventions.
    DOI:  https://doi.org/10.64898/2026.09.15.751667
  72. Stem Cell Reports. 2026 Sep 24. pii: S2213-6711(26)00297-3. [Epub ahead of print] 103086
    Directing GABAergic neuronal identity from human iPSCs through developmental patterning.
    Ruiqi Hu, Linda L Boshans, Yiran Tao, Bohan Zhu, Junlong Li, Xindi Li, Rui Dang, Marianna Liang, Peiwen Cai, Mark Youssef, Gizem Inak, Yingnan Song, Xuran Wang, Alexander M Tsankov, Joseph D Buxbaum, Peng Jiang, Zhiping P Pang, Sai Ma, Nan Yang.
      GABAergic interneurons are implicated in numerous neurodevelopmental and neuropsychiatric disorders. Transcription factor (TF)-mediated induction of human pluripotent stem cells (PSCs) rapidly generates GABAergic neurons, yet their regional identity remains poorly defined. Here, we show that the chromatin state of the starting population constrains the neuronal identities specified by ASCL1 and DLX2. Brief neural patterning via dual-SMAD and WNT inhibition prior to TF induction biases PSCs toward GABAergic neurons with forebrain-associated identities, whereas TF induction of PSCs yields neurons with broader regional signatures, including hypothalamic and thalamic programs. Benchmarking multiple approaches against a human fetal brain atlas reveals distinct regional identity biases and disease gene enrichment profiles across methods, providing a framework for selecting differentiation strategies for disease modeling. Applying this approach to ADNP syndrome, we demonstrate that the recurrent p.Tyr719∗ mutation disrupts interneuron maturation and subtype-associated transcriptional programs and impairs inhibitory synaptic transmission in human GABAergic neurons.
    Keywords:  GABAergic neurons; differentiation; disease modeling; human stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103086
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