bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–09–20
sixty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
  2. Cysteine excess triggers a mitochondrial iron-dependent cell death.
  3. The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
  4. mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture.
  5. MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
  6. Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
  7. Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
  8. Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.
  9. L-Cysteine and N-Acetylcysteine Supplementation Improves Clinical Outcome in a Patient With COXPD10.
  10. Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
  11. [Acute anterior ischemic optic neuropathy in the context of mitochondrial disease].
  12. Beyond Steatosis: Hepatic ERα Couples Estrogen Signaling to Mitochondrial Fuel Adaptation.
  13. Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
  14. Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in RBM20-Related Dilated Cardiomyopathy.
  15. ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.
  16. Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
  17. Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
  18. MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
  19. Advances in mitochondrial compartmentalization for terpenoid synthesis in Saccharomyces cerevisiae.
  20. Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
  21. First for RNA therapy: man with rare motor-neuron disease improves after treatment.
  22. ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
  23. Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
  24. Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.
  25. CRISPR/Cpf1-mediated editing of DNM1L in induced pluripotent stem cells.
  26. Normal neuroimaging in an infant with SUCLA2-related mitochondrial DNA depletion syndrome type 5: a case report of likely pathogenic variant.
  27. Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
  28. Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
  29. Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle.
  30. Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.
  31. CryoBN-PAGE: A Rapid and Cost-Effective Method for the Analysis of Yeast Respiratory Complexes and Their Dynamic Organization.
  32. A new role of iridium(III) complexes in regulating pluripotency acquisition via mitochondrial remodulation.
  33. Mitochondrial defects in the cAMP-PKA-DRP1 pathway in a Crppa deletion model of dystroglycanopathy.
  34. Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.
  35. "NanoDel": Identification of large-scale mitochondrial DNA deletions using long-read sequencing.
  36. Functional evidence of Hv1-mediated proton flux in cardiac mitochondria.
  37. A novel mitochondrial microprotein reprograms cellular bioenergetics and protects against hepatic steatosis.
  38. Targeting prostaglandin catabolism via topical nanotherapy rescues vision in ischemic optic neuropathy.
  39. Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.
  40. PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.
  41. Patient-Derived Fibroblasts as a Clinically Relevant Model of Kearns-Sayre Syndrome.
  42. m6A mRNA methylation regulates pancreatic α-cell plasticity.
  43. Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
  44. Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
  45. Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
  46. Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
  47. Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia.
  48. LRRK2: Molecular Mechanisms in Parkinson's Disease.
  49. Stimulus-Responsive Nanozymes for Mitochondria-Targeted Therapy: Design, Mechanisms, and Biomedical Applications.
  50. Beyond copy number: circulating cell-free mitochondrial DNA Fragmentomics and structural states in liquid biopsy.
  51. Drug firms' secret data supercharge AI protein models.
  52. Mitochondrial abnormalities in Charcot-Marie-Tooth disease: insights from a family harbouring a novel GDAP1 variant.
  53. Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies.
  54. Skeletal Muscle Tissue Engineering: Methods and Analysis for the Bio-Fabrication and Validation of a 3D Scaffold-Free Muscle Construct.
  55. Human cardiovascular organoids: Biomedical applications and ethical challenges.
  56. Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
  57. Friedreich Ataxia: From Genetics to Mechanism to Clinical Features.
  58. Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury.
  59. A Biomimetic 3D Human Skeletal Muscle Microtissue for Modeling Biological and Functional Hallmarks of Aging.
  60. The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.
  61. Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.
  62. Transplanted human brain-tissue takes root in mice without a cortex.
  1. Nat Commun. 2026 Aug 15. pii: 9829. [Epub ahead of print]17(1):
    Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
    Hyunmin Cho, Ruhi Sayana, Abhishek Koladiya, Pasqualina Colella, Sangkyun Cho, James W S Jahng, Juan Jose Vasquez, Jessica Arozqueta Basurto, Joseph C Wu, Natalia Gomez-Ospina.
      Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-026-76775-y
  2. Nat Metab. 2026 Sep 15.
    Cysteine excess triggers a mitochondrial iron-dependent cell death.
    Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.
      Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.
    DOI:  https://doi.org/10.1038/s42255-026-01616-7
  3. Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):
    The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
    Danielle Brister, Mariana Zarate-Mendez, Denisa Hathazi, Rita Horvath.
      Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.
    DOI:  https://doi.org/10.1007/s00335-026-10278-5
  4. Cell Rep. 2026 Sep 11. pii: S2211-1247(26)01057-0. [Epub ahead of print]45(9): 117979
    mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture.
    Ayesha Sen, Olivier R Baris, Yulia Schaumkessel, Sebastian Kallabis, Claudie Gabillard-Lefort, Valerie Desquiret, Rudolf J Wiesner, David Pla-Martín.
      Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.
    Keywords:  CP: developmental biology; mitochondria; mtDNA; muscle differentiation; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117979
  5. Cell Death Dis. 2026 Sep 15. pii: 801. [Epub ahead of print]17(1):
    MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
    Alexander Becker, Thomas O Eichmann, Viacheslav Vasiliev, Kira An Mey, Patrick Petzsch, Andrea Rossi, Felix Distelmaier, Ruchika Anand.
      Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2 A > G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete β-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodeling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype, linking metabolic rewiring to ECM homeostasis. Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09283-y
  6. Mater Today Bio. 2026 Oct;40 103636
    Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
    Xianquan An, Li Zhang, Xin Zhang, Meidan Fang, Cong Wang, Yu Han, Zheng Wang, Jinfeng Wang, Shuting Zuo.
      Neuropathic pain remains a major clinical challenge due to limited efficacy and tolerability of current treatments. Mitochondrial dysfunction in dorsal root ganglion (DRG) cells is recognized as a key pathogenic mechanism, but effective strategies to restore mitochondrial homeostasis are lacking. Here, we first identified profound deficits in mitochondrial quantity and quality in DRG neurons and satellite glial cells (SGCs) from a chemotherapy-induced peripheral neuropathy (CIPN) model. To address this, we developed an extracellular vesicle-based nanoplatform (EVs@Mi/UR) loaded with a mitophagy inducer, which integrates exogenous mitochondrial transplantation with mitophagy induction. EVs@Mi/UR not only increased mitochondrial mass in DRG neurons and SGCs through efficient mitochondrial transplantation, but also improved mitochondrial quality by eliminating damaged organelles, thereby enhancing mitochondrial respiration and metabolic function. In both CIPN and spared nerve injury (SNI) mouse models, EVs@Mi/UR significantly alleviated mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity with superior efficacy. Notably, even in SNI models that did not exhibit baseline mitochondrial deficits, EVs@Mi/UR still produced analgesic effects by improving mitochondrial quality. This work establishes mitochondrial remodeling as a promising strategy for neuropathic pain and provides a translatable EV-based nanoplatform for dual-modality mitochondrial intervention.
    Keywords:  Dorsal root ganglion; Extracellular vesicles; Mitochondrial transplantation; Mitophagy; Neuropathic pain
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103636
  7. J Bioenerg Biomembr. 2026 Sep 14. pii: 52. [Epub ahead of print]58(1):
    Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
    Gino A Kurian.
      Cardiovascular disease is strongly influenced by mitochondrial dysfunction, yet how mitochondrial stress is communicated beyond the affected cell to coordinate systemic responses remains incompletely understood. Mitokines are stress-responsive signaling factors that link mitochondrial perturbation to cellular and interorgan adaptation. These include nuclear-encoded proteins such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), as well as mitochondrial-derived peptides including Humanin and MOTS-c. This review critically examines mitokine regulation and signaling in the context of cardiovascular stress, with emphasis on mitochondrial unfolded protein response and integrated stress response pathways, receptor and downstream signaling mechanisms, and the functional divergence among major mitokines. Transient mitokine responses during physiological or metabolic challenge may support metabolic flexibility, cytoprotection, and stress adaptation, whereas persistent elevations of FGF21 and GDF15 in cardiovascular and cardiometabolic disease frequently accompany unresolved mitochondrial stress and adverse clinical phenotypes. Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides. We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation. We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets. This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.
    Keywords:  Cardiovascular disease; Integrated stress response; Mitochondrial stress signaling; Mitochondrial unfolded protein response; Mitochondrial-derived peptides; Mitokines
    DOI:  https://doi.org/10.1007/s10863-026-10136-8
  8. Int J Mol Sci. 2026 Aug 27. pii: 7678. [Epub ahead of print]27(17):
    Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.
    Haya Sahibzada, Rizwan Malik, Khaled K Abu-Amero.
      Myelination, mitochondrial bioenergetics, and oxidative stress are usually discussed as separate problems in optic nerve disease. This review draws them together and reads the published evidence through a single variable, the balance between the energy a retinal ganglion cell (RGC) axon spends and the energy its mitochondria can supply. We review the role of myelin in conduction and axonal support, the mitochondrial cost of building and maintaining it, the vulnerability of oligodendrocytes and myelin to oxidative injury, and the nuclear control of mitochondrial output. We summarize the inherited optic atrophies linked to OPA1, OPA3, AFG3L2, SPG7, and TMEM126A, and set these primary mitochondrial disorders against the immune-mediated demyelinating optic neuropathies. Published studies already support several parts of this picture, including the energetic cost of demyelination, the mitochondrial dependence of RGC axons, and oxidative injury in inflammatory lesions. Drawing on that evidence, we propose, as a testable hypothesis rather than a settled mechanism, that optic nerve degeneration is favored when axonal ATP demand outruns mitochondrial supply, most sharply where the axon crosses from its unmyelinated to its myelinated segment near the lamina cribrosa. We use this framework to separate initiating lesions from disease modifiers and downstream consequences, and to set out therapeutic predictions open to experimental and clinical tests.
    Keywords:  OPA1; bioenergetics; demyelination; mitochondria; myelination; optic neuropathy; oxidative stress; retinal ganglion cell
    DOI:  https://doi.org/10.3390/ijms27177678
  9. Am J Med Genet A. 2026 Sep 17.
    L-Cysteine and N-Acetylcysteine Supplementation Improves Clinical Outcome in a Patient With COXPD10.
    Nishitha R Pillai, Sara A Elsbecker, Grace Bronken McCarthy, Kaitlin Weisshappel, Peter Karachunski, Fernando Scaglia.
      MTO1 is a nuclear gene that encodes a mitochondrial protein essential for modifying mitochondrial transfer RNAs (tRNAs) and stabilizing codon-anticodon interactions to ensure accurate and efficient mitochondrial protein synthesis and oxidative phosphorylation. Mitochondrial tRNA translation optimization 1 (MTO1) plays an important role in the mitochondrial tRNA taurinomethylation modification by using the amino acid taurine, obtained from cysteine metabolism, at the wobble position U34 of the anticodon loop. Biallelic pathogenic variants in MTO1 cause combined oxidative phosphorylation deficiency 10 (COXPD10) (OMIM#614702). In the severe end of the spectrum, COXPD10 is characterized by infantile-onset hypertrophic cardiomyopathy and lactic acidosis with perinatal mortality when associated with nonsense and frameshift variants. The extra cardiac phenotypes include muscle hypotonia, feeding difficulties, psychomotor delay, optic atrophy, encephalopathy, and seizures. Currently, there is no targeted treatment for this condition aside from supportive care. Herein, we report a 22-month-old child, diagnosed early with a genotype predictive of severe COXPD10, who was initiated on treatment with L-cysteine and N-acetylcysteine (NAC) early in life and did not develop cardiac manifestations. This outcome suggests a potential benefit and improved clinical outcome with early disease-specific treatment initiation.
    Keywords:   MTO1 ; COXPD10; L‐cysteine; NAC; N‐acetylcysteine; cardiomyopathy; combined oxidative phosphorylation deficiency 10; cysteine
    DOI:  https://doi.org/10.1002/ajmg.a.70299
  10. Cells. 2026 Aug 27. pii: 1548. [Epub ahead of print]15(17):
    Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
    Lingling Cheng, Gaojie Song.
      Aging mesenchymal stem/stromal cells (MSCs) lose regenerative capacity as redox imbalance, mitochondrial damage, defective organelle quality control and chronic inflammation converge. Yet these processes are commonly considered in isolation, obscuring whether damaged mitochondrial cargo reaches lysosomes and is ultimately degraded. Here, we define mitochondria-lysosome quality flux (MLQF) as an author-proposed, evidence-graded framework that tracks mitochondrial damage from recognition and sorting through lysosomal delivery to terminal lysosomal degradation in aging MSCs. The framework explicitly separates delivery to an acidic compartment from completed degradation and distinguishes direct MSC evidence from cross-model mechanisms and candidate pathways. MSC studies most strongly support macroautophagy-dependent mitophagy, particularly when assessed using dynamic flux reporters. By contrast, mitochondria-derived vesicles and microautophagy-like or piecemeal routes remain incompletely validated in MSCs. Studies in non-MSC systems further show that mitochondria-lysosome contact sites can support lysosomal acidification, although their contribution to natural MSC aging remains unresolved. By locating rate-limiting defects across this continuum, MLQF provides a testable basis for linking incomplete mitochondrial clearance to inflammatory signaling, lineage drift and regenerative decline, and for selecting bottleneck-matched interventions.
    Keywords:  cellular senescence; mesenchymal stem/stromal cells; mitochondrial quality control; mitochondria–lysosome quality flux; mitophagy
    DOI:  https://doi.org/10.3390/cells15171548
  11. Rev Med Liege. 2026 Sep;81(9): 536-543
    [Acute anterior ischemic optic neuropathy in the context of mitochondrial disease].
    Adrien Mathot, Florence Maraite.
      Mitochondrial diseases can lead to highly heterogeneous clinical manifestations, including optic neuropathies, the prototypical form of which is Leber's hereditary optic neuropathy. We report the case of a 47-year-old man carrying a mitochondrial DNA mutation (m.13513G>A in the MT-ND5 gene), who, after exclusion of differential diagnoses, including Leber's hereditary optic neuropathy, presented with unilateral non-arteritic anterior ischemic optic neuropathy in the absence of cardiovascular risk factors. In this context, the hypothesis of a pathophysiological link between mitochondrial cytopathy and ischemia of the optic nerve head is discussed. Indeed, mitochondrial angiopathy, known to be associated with certain mitochondrial diseases, could represent a contributory mechanism through the microcirculatory disturbances it induces. This case suggests that certain mitochondrial mutations may represent an independent vascular risk factor and highlights the importance of considering a mitochondrial etiology in cases of atypical ischemic optic neuropathy, particularly in young patients without cardiovascular risk factors.
    Keywords:  Acute anterior ischemic optic neuropathy; MELAS Syndrome; Mitochondrial disease
  12. Endocrinology. 2026 Sep 18. pii: bqag107. [Epub ahead of print]
    Beyond Steatosis: Hepatic ERα Couples Estrogen Signaling to Mitochondrial Fuel Adaptation.
    Sara Della Torre.
      
    Keywords:  branched-chain amino acids; estrogen receptor alpha; fatty liver; liver mitochondria; ovariectomy
    DOI:  https://doi.org/10.1210/endocr/bqag107
  13. Aging Cell. 2026 Sep;25(9): e70718
    Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
    Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li.
      The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.
    Keywords:  aging; clonal expansion; heteroplasmy; mitochondrial DNA; molecular clock; respiratory chain deficiency; somatic mutation
    DOI:  https://doi.org/10.1111/acel.70718
  14. Circulation. 2026 Sep 15.
    Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in RBM20-Related Dilated Cardiomyopathy.
    Julia Kornienko, Linda H Müller, Alexander Nickel, Michael Kohlhaas, Mandy Börmel, Carlos Alfonso-Gonzalez, Viola M J Oorschot, Michel Fungate, Susanne Lewey, Jacob Kees, Johanna Müller, Dominik Lindenhofer, Kai Fenzl, Laura Schraft, Sandra Clauder-Münster, Laura Konrad, Per Haberkant, Frank D M Montoya, Vita Dauksaite, Michael Gotthardt, Maarten M G van den Hoogenhof, Christoph Maack, Lars M Steinmetz.
       BACKGROUND: Pathogenic variants in RBM20 cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown.
    METHODS: We investigated the effects of Rbm20 GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell-derived cardioids were used to validate variant-specific phenotypes.
    RESULTS: Rbm20 GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in Rbm20 GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction.
    CONCLUSIONS: Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes RBM20 GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with RBM20 GoF variants. These insights advance the mechanistic understanding of RBM20-related cardiomyopathy and identify mitochondrial mRNA/protein regulation as a key node in cardiac energetics.
    Keywords:  cardiomyopathy, dilated; metabolism; mitochondria, heart; mitochondrial diseases; precision medicine; ribonucleoproteins
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077061
  15. Cell Death Differ. 2026 Sep 15.
    ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.
    Elena Frigo, Manuela Santalla, Michele Brischigliaro, Federica Boscolo Nata, Ludovica Tommasin, Michela Rossini, Denis Komarov, Stefania Ferro, Diana Pendin, Oriano Marin, Rodolfo Costa, Michela Carraro, Paolo Bernardi.
      Beyond its roles in ATP production and shaping cristae architecture, mitochondrial ATP synthase has been implicated in generating the permeability transition pore (PTP), a Ca2+-activated, high-conductance channel that leads to matrix swelling and cell death in mammalian cells. In Drosophila melanogaster, the PTP homolog rather forms a selective Ca2+-induced Ca2+-release (CICR) channel whose physiological relevance at the organism level remains poorly understood. Here, we down-regulated Drosophila subunits e and g, which are essential for PTP formation in yeast and mammalian cells. Ubiquitous down-regulation of either subunit caused larval developmental arrest, whereas tissue-specific suppression in muscle or neurons led to severe locomotor impairment. Dimerization was markedly reduced, altering mitochondrial ultrastructure while leaving respiratory capacity largely preserved. Strikingly, mitochondria from both knockdown animals accumulated larger Ca2+ loads, consistent with an impaired CICR. This was accompanied by near-complete loss of ecdysone, the Ca2+-dependent master hormone of metamorphosis. Neuron-specific knockdown flies displayed defective mitochondrial Ca2+ efflux and altered synaptic organization at the neuromuscular junction. Altogether, our findings establish that ATP synthase functions as a CICR channel controlling Ca2+ homeostasis, endocrine signaling and development in Drosophila.
    DOI:  https://doi.org/10.1038/s41418-026-01869-5
  16. Front Cardiovasc Med. 2026 ;13 1925684
    Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
    Shujun Ding, Yuna Hu, Qin Zhang, Xinyi Liu, Xuan Zhao, Yajing Zhao, Wen Zhang.
      Cardiac function depends on tightly regulated energy metabolism, with mitochondria serving as key sites of cellular energy production. Mitophagy, a selective form of autophagy that maintains mitochondrial quality, has received growing attention for its role in cardiomyocyte metabolism. Under specific physiological and pathological conditions, the myocardium increases its use of ketone bodies as energy substrates, and ketone body metabolism is closely linked to mitochondrial function. However, the relationship between mitophagy and ketone body metabolism is incompletely understood, particularly in cardiovascular disease. This review summarizes their roles and regulatory mechanisms in the myocardium and evaluates evidence for a potential bidirectional relationship. Mitophagy may preserve the mitochondrial capacity required for ketone body oxidation, whereas ketone body metabolism and β-hydroxybutyrate-mediated signaling may regulate mitophagy and mitochondrial stress resilience. By integrating these interactions across cardiovascular disease phenotypes, this review highlights their potential therapeutic relevance and identifies priorities for mechanism-based intervention and clinical translation.
    Keywords:  ketone body; metabolic flexibility; mitochondria; mitophagy; myocardial metabolism
    DOI:  https://doi.org/10.3389/fcvm.2026.1925684
  17. Nucleic Acids Res. 2026 Sep 07. pii: gkag876. [Epub ahead of print]54(17):
    Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
    Lisa Hubers, Alexander Myhr Skjetne, Luisa Luna, Yohan Lefol, Solveig Osnes Lund, Ane Marit Wågbø, Xavier Renaudin, Annikka Polster, Zoe J da Silva, Anders Knoph Berg-Eriksen, Francisco Jose Naranjo-Galindo, Anna Campalans, Torkild Visnes, Hilde Loge Nilsen, Nicola Pietro Montaldo.
      Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.
    DOI:  https://doi.org/10.1093/nar/gkag876
  18. J Neuropathol Exp Neurol. 2026 Sep 16. pii: nlag102. [Epub ahead of print]
    MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
    Allison R Hanaford, Elizaveta A Olkhova, Ryan Liao, Ashley Ching, Alvin Huang, Erin Shien Hsieh, Kino Watanabe, Yihan Chen, Megan Wichman, Noelle Hwang, Katerina James, Michael Mulholland, Vivian Truong, Holly Coulson, Kerry Gibbins, Owen Cairns, Anastasia Dimitriou, Ernst-Bernhard Kayser, Brittany M Johnson, Sarkar Surojit, Vandana Kalia, Simon C Johnson.
      Primary genetic mitochondrial diseases (GMDs) are clinically and genetically diverse diseases. Leigh syndrome (LS), the most common pediatric presentation of GMD is a severe progressive multi-system disorder with diverse manifestations. No effective treatments currently exist. Recent data from the Ndufs4(-/-) LS mouse model show that peripheral macrophages contribute to brain lesions, that disease is driven by innate immune populations and that depletion of innate immune cells prevents disease. However, the mechanisms underlying the immune activation in LS remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and DNA are detected by toll-like receptors (TLRs) at the endosome and may mediate innate immune activation in LS. To assess TLR signaling in an LS mouse model, we generated TLR signaling-deficient Ndufs4(-/-)/MyD88(-/-) animals. Prophylactic antibiotic treatment with enrofloxacin enabled production of MyD88(-/-) animals from Ndufs4(+/-)/MyD88(+/-) breeder pairs. Loss of MyD88 in Ndufs4(-/-) animals increased survival and delayed the onset but disease courses were not altered. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of MyD88(-/-) animals modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in mitochondrial diseases warrants further investigation.
    Keywords:  Leigh syndrome; electron transport chain complex I; innate immune system; mitochondrial disease
    DOI:  https://doi.org/10.1093/jnen/nlag102
  19. Front Bioeng Biotechnol. 2026 ;14 1910253
    Advances in mitochondrial compartmentalization for terpenoid synthesis in Saccharomyces cerevisiae.
    Chuyi Zheng, Tian Ma.
      Mitochondria provide a unique enriched acetyl coenzyme A reservoir and an ideal redox environment, offering an efficient supply for the biosynthesis of terpene precursors and terpene products. This comprehensive review focuses on the engineering of mitochondrial compartmentalization in Saccharomyces cerevisiae to enhance terpene production. We systematically outline the applications from hemiterpenes to tetraterpenes and elaborate on how advanced strategies, such as key enzyme mitochondrial targeting strategy, whole-pathway mitochondrial targeting strategy, dual cytoplasmic-mitochondrial compartmentalization strategy, and multi-organelle synergistic compartmentalization strategy, can effectively improve precursor availability while mitigating metabolic interference and cytotoxic effects. In addition, we critically examine the discussions and long-term challenges associated with these methods. Finally, we highlight the transformative potential of mitochondrial compartmentalization to pioneer future innovations in complex terpene synthesis engineering.
    Keywords:  Saccharomyces cerevisiae; acetyl coenzyme A; compartmentalization; mitochondria; terpenoids
    DOI:  https://doi.org/10.3389/fbioe.2026.1910253
  20. bioRxiv. 2026 Sep 02. pii: 2026.09.02.748825. [Epub ahead of print]
    Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
    Rabina Saud, Kimberly Foster-Lemieur, Brett Duguay, Russell Swerdlow, Maria Kalamvoki.
      Herpes simplex virus 1 (HSV-1) infects approximately 67% of the population worldwide. It establishes lifelong reservoirs in sensory neurons and has been linked to several diseases including neuronal dysfunction. Disruption of mitochondrial homeostasis is a hallmark of HSV-1 infection, however a molecular understanding of these changes and their significance is not yet well defined. HSV-1 infection causes a UL12.5-dependent inhibition of mitochondrial biogenesis through the loss of mitochondrial DNA and mitochondrial transcription factors, PGC-1α (peroxisome proliferator-activated receptor-gamma co-activator) and TFAM (mitochondrial transcription factor). Conversely, UL12.5-independent mechanisms inhibit mitochondrial fusion by activating the OMA1 metallopeptidase that cleaves the inner mitochondrial membrane fusion protein OPA1 (optic atrophy protein 1) and by down-modulating the outer mitochondrial membrane fusion protein MFN2 (mitofusin 2). This inhibition of fusion results in a smaller mitochondrial network that clusters to perinuclear regions, likely supplying energy for viral replication and envelopment. The inner mitochondrial membrane protein TIM23 is also down-modulated during infection in a UL12.5-independent mechanism. Failure of the virus to promote these changes negatively impacts the infection. Despite these changes, mitochondria are protected from mitophagy due to the viral-induced degradation of several mitophagy adaptor proteins, whereby damaged mitochondrial components, including mitochondrial DNA, are extruded via extracellular vesicles. These mitochondrial changes still support functions necessary for HSV-1 infection. Basal cell respiration is preserved, while spare respiratory capacity and extracellular acidification rates increase, indicating glycolytic activity. Mitochondrial membrane potential is also preserved. Overall, our studies provide mechanistic insight into how HSV-1 impacts mitochondria, which could contribute to viral pathogenesis.
    Importance: Mitochondria are often referred to as the "powerhouse" of the cell because they are the main energy producers. Disruption of mitochondrial homeostasis is associated with multiple diseases and occurs after infection with pathogens such as HSV-1. By investigating the mechanism(s) by which HSV-1 disrupts mitochondrial homeostasis, we can better understand how HSV-1 causes pathogenesis. HSV-1 infection impacts mitochondrial homeostasis through disruption of four key processes, including: 1) inhibition of mitochondrial biogenesis and the generation of new mitochondria; 2) inhibition of mitochondrial fusion, which rescues reversibly damaged mitochondria; 3) sustaining mitochondrial fission, which removes damaged content; and 4) preventing mitophagy, which clears damaged mitochondria. UL12.5-dependent and UL12.5- independent events during HSV-1 infection disrupt mitochondrial homeostasis, redirecting mitochondrial resources towards progeny virus production. These changes cause irreversible damage to host cells, ultimately driving pathogenesis.
    DOI:  https://doi.org/10.64898/2026.09.02.748825
  21. Nature. 2026 Sep 18.
    First for RNA therapy: man with rare motor-neuron disease improves after treatment.
    Rachel Fieldhouse.
      
    Keywords:  Brain; Diseases; Gene therapy; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-02945-z
  22. Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01087-9. [Epub ahead of print]45(10): 118009
    ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
    Songnan Wang, Yingjie Guo, Weidong An, J Michelle Lee, Yu Li, Valentino Sudaryo, Jacqueline A Carozza, Gabriel Grenot, Gemini Skariah, Saranya C Reghupaty, Sonny Young, Xiaochen Bai, Katrin J Svensson, Lingyin Li.
      The mechanism underlying the role of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in metabolic disease remains unsolved. Using a 2'3'-cyclic GMP-AMP (cGAMP)-hydrolysis-deficient mouse (Enpp1H362A), we show that selective loss of this activity exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An in vivo glucose-uptake screen identifies brown adipose tissue (BAT) as a key site of metabolic impairment, marked by extracellular cGAMP accumulation and defective insulin-stimulated glucose uptake. Mechanistically, nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP synthesis and export. Excess extracellular cGAMP directly suppresses glucose uptake in brown adipocytes via stimulator of interferon genes (STING) pathway. Furthermore, impaired cGAMP clearance acts as a paracrine signal that recruits and polarizes BAT macrophages toward a pro-inflammatory M1-like phenotype. Finally, the human ENPP1 K173Q variant associated with obesity and diabetes displays reduced cGAMP hydrolysis activity. Together, these findings establish ENPP1 as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis.
    Keywords:  CP: immunology; CP: metabolism; ENPP1; STING; brown adipose tissue; diabetes; extracellular cGAMP; immune checkpoint; immunometabolism; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2026.118009
  23. Autophagy. 2026 Sep 16.
    Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
    Jiamin Yi, Xin Yong, Da Jia.
      Mitochondrial ubiquitination is a central component of mitochondrial quality control. The PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway established how loss of mitochondrial membrane potential can trigger a phospho-ubiquitin feed-forward cascade on the outer mitochondrial membrane (OMM). It remains less clear how mitochondrial ubiquitination is achieved when PRKN is absent or inactivated. In our recent work, we identify a recruitment platform organized by AMBRA1 (autophagy and beclin 1 regulator 1), in which RMC1 (regulator of MON1-CCZ1) positions HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) at mitochondria. This spatial arrangement promotes HUWE1-dependent ubiquitination and turnover of OMM proteins, including MFN2 (mitofusin 2), VDAC1 (voltage-dependent anion channel 1), and VDAC2 (voltage-dependent anion channel 2). Our findings raise the question of how cells select among distinct mitochondrial ubiquitination pathways and whether these pathways function independently, sequentially, or cooperatively.
    Keywords:  AMBRA1; HUWE1; PINK1-PRKN; RMC1; mitochondrial quality control; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2026.2735210
  24. Science. 2026 Sep 17. 393(6817): eady6372
    Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.
    Raghabendra Adhikari, Alexander Hillsley, Alana Dowdell Johnson, Shihong Max Gao, Isabel Espinosa-Medina, Jan Funke, Daniel Feliciano.
      Cell-state diversity drives tissue adaptability, repair, and disease resilience, but capturing this complexity is a challenge. Current approaches rely on transcriptional profiling and overlook organelle structure, a key indicator of metabolism and stress. We developed spatial Organellomics (sOrganellomics), an imaging workflow that integrates automated segmentation with machine learning to classify and spatially map cell states from multi-organelle signatures. In liver and pancreas, these signatures distinguished broad cellular classes. In liver, sOrganellomics revealed that zonal position did not fully explain organelle-defined hepatocyte categories. Instead, hepatocytes formed intermixed communities within canonical zones, supporting a refined subzonal diversity model. Nutritional stress reshaped this organization. Intravital imaging linked fasting-induced organelle remodeling with altered mitochondrial membrane potential in vivo, supporting multi-organelle architecture as a structural readout of tissue adaptation.
    DOI:  https://doi.org/10.1126/science.ady6372
  25. Stem Cell Res. 2026 Sep 10. pii: S1873-5061(26)00198-4. [Epub ahead of print]96 104102
    CRISPR/Cpf1-mediated editing of DNM1L in induced pluripotent stem cells.
    Roohallah Ghodrat, Haribaskar Ramachandran, Barbara Hildebrandt, Stephanie Binder, Andrea Rossi, Andreas S Reichert.
      The dynamin-1-like protein (DNM1L), also termed DRP1, is essential for mitochondrial fission. Mutations in DNM1L are associated with neurological disorders and cardiac dysfunction. To decipher the role of DNM1L in human induced pluripotent stem cells (hiPSCs) and in their differentiated counterparts, we used CRISPR/Cpf1 and generated a human iPSC line with a mutation by targeting exon 18 of the DNM1L gene. The generated compound heterozygous (biallelic) DNM1L mutant cell line showed normal cell morphology, genomic stability, and expression of classical stem cell markers. Furthermore, the cells can be differentiated efficiently into the three germ layers meso-, endo-, and ectoderm.
    DOI:  https://doi.org/10.1016/j.scr.2026.104102
  26. Oxf Med Case Reports. 2026 Sep;2026(9): omag172
    Normal neuroimaging in an infant with SUCLA2-related mitochondrial DNA depletion syndrome type 5: a case report of likely pathogenic variant.
    Mohammad Obada Alsadi, Youssef Heikal, Farah Al-Hasani, Dana Al Khasawneh, Aia Nasab, Heba Hrizat, Fatema Almoustafa, Barah Hussain.
      Mitochondrial DNA depletion syndrome type 5 (MTDPS5), caused by SUCLA2 mutations, is a rare autosomal recessive disorder manifesting as early-onset encephalomyopathy. Clinical diagnosis is challenging due to phenotypic overlap and potentially unremarkable early investigations. We report a male infant of consanguineous parents who presented with progressive hypotonia, global developmental delay, and involuntary nocturnal movements at 3 months. Despite an unremarkable newborn metabolic screen and normal initial brain MRI, the patient demonstrated a significant failure to achieve age-appropriate gross motor milestones, including independent sitting and crawling, by 12 months. Whole-exome sequencing (WES) definitively identified a homozygous likely pathogenic SUCLA2 variant (p.Met329Val). Following the initiation of a mitochondrial cocktail, the patient showed substantial clinical improvement. This case emphasizes that MTDPS5 should be considered in infants with unexplained encephalomyopathy, even when initial findings are normal, underscoring the necessity of early WES to guide clinical management.
    Keywords:  Encephalomyopathy; SUCLA2; WES; mitochondrial
    DOI:  https://doi.org/10.1093/omcr/omag172
  27. Mol Med Rep. 2026 Nov;pii: 309. [Epub ahead of print]34(5):
    Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
    Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Xu Zhang, Yanguang Cao, Binbin Tang, Xiaolin Shi, Kang Liu.
      Mitochondria‑associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER‑mitochondrial contact sites that coordinate Ca²+ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER‑mitochondrial communication has been linked to recurrent disturbances in Ca²+ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM‑associated regulators and functional pathways, whereas sarcopenia‑specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain‑ or loss‑of‑contact model. Interventions targeting contact‑site regulators or MAM‑related Ca²+ and mitochondrial pathways have shown preclinical benefit, but MAM‑specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient‑derived systems.
    Keywords:  ER‑mitochondrial contacts; endoplasmic reticulum stress; ferroptosis; mitochondrial dysfunction; mitochondria‑associated endoplasmic reticulum membranes; musculoskeletal degeneration; organelle communication
    DOI:  https://doi.org/10.3892/mmr.2026.14020
  28. Amino Acids. 2026 Aug 30. pii: 48. [Epub ahead of print]58(1):
    Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
    Zoya R Bangash, Hiroyoshi Matsui, Bedri Ranxhi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou.
      Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression partially restored α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30, Uch-L5R, RNF185, and the mitochondrial ornithine carrier SLC25A15. At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions, and reduced mitochondrial accumulation of α-Syn. Functional analyses further showed that SAT1 increased steady-state ATP levels and attenuated the ATP depletion induced by α-Syn expression. These findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and preservation of mitochondrial homeostasis during α-Syn-associated stress.
    Keywords:  Autophagy; Mitochondrial quality control; Neurodegeneration; Parkinson’s disease; Polyamine interconversion; RNA sequencing
    DOI:  https://doi.org/10.1007/s00726-026-03544-y
  29. J Physiol. 2026 Sep 14.
    Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle.
    Anusha Liaqat, Salman Ahmad.
      
    Keywords:  Duchenne muscular dystrophy; glucocorticoid; high‐fat; high‐sucrose diet; mdx mice; mitochondria
    DOI:  https://doi.org/10.1113/JP292108
  30. Mol Ther Adv. 2026 Dec 10. 34(4): 201835
    Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.
    Keiko Imamura, Shin Yoshioka, Kota Kamizato, Ryosuke Oki, Hiroyuki Hioki, Kayoko Tsukita, Ikuyo Inoue, Rina Shimizu, Mako Takiguchi, Tomoki Sakasai, Aya Okusa, Ran Shibukawa, Takeshi Niki, Satoko Sakurai, Taro Okunomiya, Takayuki Kondo, Tomohisa Kato, Atsushi Miyanohara, Manabu Kakinohana, Takuya Yamamoto, Martin Marsala, Keiji Nishida, Yuishin Izumi, Haruhisa Inoue.
      In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.
    Keywords:  AAV; ABE; ALS; HMSN-P; MND; base editing therapy; gene therapy; iPSCs; organoids; subpial injection
    DOI:  https://doi.org/10.1016/j.omta.2026.201835
  31. Yeast. 2026 Sep 14.
    CryoBN-PAGE: A Rapid and Cost-Effective Method for the Analysis of Yeast Respiratory Complexes and Their Dynamic Organization.
    Lizeth J Camacho Lopez, Mazzen H Eldeeb, Elliana G Mohrhardt, Flavia Fontanesi.
      Over the last three decades, blue native polyacrylamide gel electrophoresis (BN-PAGE), a technique that allows the resolution of large protein complexes in their native conformations, has profoundly impacted the study of mitochondrial biology and our understanding of oxidative phosphorylation (OXPHOS) system's biogenesis and organization. However, while protein samples for BN-PAGE can be prepared from permeabilized mammalian cells, the analysis of yeast OXPHOS complexes requires the prior isolation of mitochondria from whole yeast cells. This requirement limits high-throughput studies and prevents short time-course analyses. We therefore combined BN-PAGE techniques with the cryogenic milling of snap-frozen cells to develop cryoBN-PAGE, which allows for the preparation of BN-PAGE samples from whole-cell yeast lysates and avoids the cost and time associated with mitochondrial isolation. Here, we show the optimization of the method and demonstrate that it can be efficiently paired with a number of downstream applications, such as immunoblots, second-dimension SDS-PAGE, and in gel enzymatic activity assays. Furthermore, by avoiding the time-consuming mitochondrial isolation, cryoBN-PAGE allows for precise time-course assays and the investigation of rapid changes in the properties of the OXPHOS system in response to alterations in environmental conditions.
    Keywords:  BN‐PAGE; Saccharomyces cerevisiae; cryo‐milling; electron transport chain; mitochondria; respiratory supercomplex
    DOI:  https://doi.org/10.1002/yea.70043
  32. Sci China Life Sci. 2026 Sep 09.
    A new role of iridium(III) complexes in regulating pluripotency acquisition via mitochondrial remodulation.
    Hao Wu, Wei Li, Yanshuang Zhou, Jimiao Sang, Yi Wu, Shubin Yu, Jianjun Cao, Yingzhe Ding, Yile Huang, Shiwei Du, Yaohang Xie, Cai-Ping Tan, Zong-Wan Mao, Shicheng Su, Xingguo Liu, Qi Long.
      Induced pluripotent stem cells (iPSCs) hold great potential in regenerative medicine, disease modeling and cell biology studies. Reprogramming of mouse and human cells can be achieved through the introduction of transcription factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM), or by chemical stimulation via exposure to small molecules. However, the role of ion compounds in reprogramming has remained relatively unexplored. Herein, we identify iridium (Ir)(III) complexes that enhance iPSC generation by promoting the perinuclear clustering of mitochondria. Mechanistically, Ir(III) complexes promote the nuclear localization of TCA cycle enzyme Pdha1 and increase the cellular acetyl-CoA, leading to chromatin remodeling at pluripotency genes by enhancing histones H3 and H4 acetylation. Our results reveal an important role for Ir(III) complexes in epigenetic regulation of cell fate and suggest a novel approach for iPSC generation.
    Keywords:  TCA cycle; epigenetics; histone acetylation; iridium; mitochondria; pluripotency; somatic cell reprogramming; stem cell
    DOI:  https://doi.org/10.1007/s11427-025-3300-x
  33. Dis Model Mech. 2026 Sep 01. pii: dmm052890. [Epub ahead of print]19(9):
    Mitochondrial defects in the cAMP-PKA-DRP1 pathway in a Crppa deletion model of dystroglycanopathy.
    Jihang Luo, Yidan Liu, Danyu Song, Shiqi Yang, Xiaona Fu, Lin Ge, Cuijie Wei, Liya Cui, Yanwei He, Jin Xu, Qiang Shen, Yuxuan Guo, Motoi Kanagawa, Tatsushi Toda, Jingmin Wang, Hong Zhang, Hui Xiong.
      Dystroglycanopathies (DGPs) are autosomal recessive muscular dystrophies caused by abnormal α-dystroglycan glycosylation. CRPPA is one causative gene, with deletion of exons 6-9 identified as a founder variant in Chinese patients. Our previous study revealed mitochondrial abnormalities in patient muscle biopsies, although the underlying mechanism(s) remained unclear. A Crppa knockout mouse (dyC/dyC) was generated based on the founder variant, displaying muscle weakness, cerebellar hypoplasia, retinal abnormalities and neonatal lethality within 24 h. Electron microscopy showed mitochondrial structural defects in skeletal muscle, consistent with patient findings. RNA sequencing revealed dysregulation of the cAMP-PKA pathway, accompanied by decreased ATP and reduced phosphorylation of PKA and DRP1 (Ser637). To verify the link between CRPPA deficiency and mitochondrial dysfunction, Crppa knockdown C2C12 cells and CRPPA-related DGP patient-derived fibroblasts were examined. Both models exhibited reduced DRP1 Ser637 phosphorylation and ATP levels. Treatment with cAMP-PKA activators restored DRP1 phosphorylation and ATP production in a time-dependent manner. Recovery of mitochondrial membrane potential was confirmed by JC-1 staining. These findings suggest that CRPPA deficiency is associated with mitochondrial dysfunction involving the cAMP-PKA-DRP1 axis, suggesting a candidate pathway warranting further investigation for DGPs.
    Keywords:   CRPPA ; Dystroglycanopathies; Mitochondrial; Mouse model; cAMP-PKA-DRP1
    DOI:  https://doi.org/10.1242/dmm.052890
  34. Elife. 2026 Sep 18. pii: RP104055. [Epub ahead of print]13
    Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.
    Grzegorz Walkiewicz, Siyu Chen, Chienhui Lo, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Benjamin Lawson, Yang Sun.
      Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.
    Keywords:  Lowe syndrome; ROS; cell biology; cilia formation; human; mitochondria; mouse; neuronal differentiation; oxidative stress; zebrafish
    DOI:  https://doi.org/10.7554/eLife.104055
  35. Bioinformatics. 2026 Sep 15. pii: btag684. [Epub ahead of print]
    "NanoDel": Identification of large-scale mitochondrial DNA deletions using long-read sequencing.
    C Fearn, J Poulton, C Fratter, C Oliva, C Griguer, R A Baldock, S C Robson, R E McGeehan.
       MOTIVATION: Traditional methods for detecting large-scale mitochondrial DNA (mtDNA) deletions (LSMDs) in cells present challenges, i.e. requiring a priori information, high DNA inputs, and are not always sensitive and/or quantitative. Mitigation can be achieved through high-throughput DNA sequencing using e.g. Illumina and Oxford Nanopore Technologies (ONT), in combination with LSMD breakpoint identification and quantification using bioinformatics. Splice-aware RNA alignment tools increase the sensitivity for detecting LSMD breakpoints compared with DNA aligners. Long-read sequencing (LRS) also offers potential advantages over short-read sequencing (SRS), e.g. greater read lengths and capturing variants on single reads. Here we aimed to capture the benefits of both a splice-aware alignment tool and LRS.
    RESULTS: We developed "NanoDel", a LRS pipeline, to sensitively and accurately detect cellular LSMDs. Using artificial datasets, "NanoDel" was more sensitive and accurate than other pipelines. In samples diagnosed with mitochondrial disease, it identified both known and previously uncharacterised (including mixtures) of LSMDs, without a priori information. Analysis of selected LSMDs revealed proximity to repeat, putative G-quadruplex motifs, and the "contact zone". Together with occurrence in a range of healthy and pathological tissues, indicates potential for a shared vulnerability landscape in mtDNA, shaped by sequence motifs and structural constraints. This proof-of-concept study shows that "NanoDel" combined with one-amplicon LR-PCR offers a robust strategy for detecting LSMDs across a variety of cell/tissue samples. Applying "NanoDel" to a larger and broader range of samples would confirm this, yielding new mechanistic insights into LSMD formation, and further our understanding of mtDNA instability in the future.
    AVAILABILITY AND IMPLEMENTATION: "NanoDel" is available at https://github.com/uopbioinformatics/NanoDel (DOI: 10.5281/zenodo.20119070) and raw read data are available through the NCBI Sequence Read Archive (SRA) under BioProject accession code PRJNA1369153 (https://www.ncbi.nlm.nih.gov/bioproject/1369153).
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag684
  36. Channels (Austin). 2026 Dec;20(1): 2728231
    Functional evidence of Hv1-mediated proton flux in cardiac mitochondria.
    Rayen De Fazio, Clara Ventura, Paulina Finochietto, Ernesto A Aiello, Carolina Jaquenod De Giusti, Verónica Milesi.
      Mitochondria are essential for cardiac myocyte function, providing the continuous ATP supply required for contraction and cellular homeostasis. Regulation of the proton motive force, which is critical for ATP synthesis, depends on multiple ion transport mechanisms, including those mediating H+ flux. The voltage-gated proton channel (Hv1), encoded by the Hvcn1 gene, is known to regulate cytosolic pH and membrane potential in several cell types. Here, using isolated mouse cardiac mitochondria, we demonstrate for the first time that Hv1 is functionally expressed in cardiac mitochondria. Pharmacological inhibition of Hv1 enhanced matrix alkalinization and induced mitochondrial hyperpolarization during succinate-driven mitochondrial energization. Importantly, a similar hyperpolarization was also observed under basal conditions in intact cardiac myocytes.
    Keywords:  Hv1 channel; heart; membrane potential; mitochondria; pH
    DOI:  https://doi.org/10.1080/19336950.2026.2728231
  37. iScience. 2026 Sep 18. 29(9): 117457
    A novel mitochondrial microprotein reprograms cellular bioenergetics and protects against hepatic steatosis.
    Yilu Xu, Quan Yuan, Yang Wang, Qiumin Liao, Xiaochuan Fu, Zhen Cao, Bin Pan, Kaixuan Zheng, Jifeng Wang, Tiemin Liu, Pingsheng Liu, Shuyan Zhang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge with limited therapeutic options. To identify new regulators of lipid metabolism, we developed a novel proteomic strategy combining organelle enrichment with a custom sORF database to explore the "dark proteome". Using this approach, we discovered MNP33, a previously uncharacterized 28-amino acid microprotein. This novel protein protects against metabolic disease in mice by potently reducing body weight gain, improving glucose homeostasis, and decreasing hepatic triacylglycerol (TAG) accumulation. Mechanistically, MNP33 localizes to the inner mitochondrial membrane, interacts with adenine nucleotide translocase 2 (ANT2), and induces a bioenergetic remodeling characterized by increased proton leak, elevated basal respiration, and a paradoxically elevated membrane potential. This promotion of energy dissipation provides a direct basis for the observed reduction in TAG. Our findings establish MNP33 as a key regulator of hepatic lipid metabolism with therapeutic potential for treating MASLD.
    Keywords:  ANT2; MASLD; MNP33; energy dissipation; hepatic steatosis; lipid metabolism; microprotein; mitochondrial energetics
    DOI:  https://doi.org/10.1016/j.isci.2026.117457
  38. Neurotherapeutics. 2026 Sep 16. pii: S1878-7479(26)00235-7. [Epub ahead of print]23(6): e01065
    Targeting prostaglandin catabolism via topical nanotherapy rescues vision in ischemic optic neuropathy.
    Shweta Modgil, RuSiou Hsu, Mohammad Ali Shariati, Juan A Oses-Prieto, Al Burlingame, Yaping Joyce Liao.
      Ischemic optic neuropathy is a leading cause of acute vision loss and currently lacks effective therapy. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for prostaglandin degradation, as a metabolic checkpoint in ischemic optic neurodegeneration. Analysis of human ischemic optic nerve tissue and a murine model of optic nerve ischemia reveals marked upregulation of retinal 15-PGDH, suggesting dysregulated prostaglandin homeostasis after ischemic injury. To therapeutically target this pathway, we develop a nano-micellar formulation of the hydrophobic 15-PGDH inhibitor SW033291 (SW@NM) that enables efficient topical ocular delivery and retinal penetration. Topical administration of SW@NM suppresses retinal 15-PGDH activity, restores PGE2 levels, preserves retinal ganglion cells and optic nerve axons, and significantly improves visual function after ischemic injury. Mechanistically, 15-PGDH inhibition suppresses ferroptosis-associated lipid peroxidation and preserves mitochondrial integrity, thereby mitigating ischemia-induced neurodegeneration. Collectively, these findings establish 15-PGDH-mediated prostaglandin catabolism as a therapeutic target in ischemic optic neuropathy and demonstrate a clinically translatable nanotherapeutic strategy for protecting the central nervous system from ischemic neurodegeneration.
    Keywords:  15-PGDH; AION; Nano-micelle; Neuroprotection; Optic neuropathy; SW033291
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01065
  39. Int J Mol Sci. 2026 Aug 28. pii: 7734. [Epub ahead of print]27(17):
    Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.
    Xing Yang, Kun Cheng, Chen Chen, Yuxin Zhang, Dao Wen Wang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD-HF overlap.
    Keywords:  cardio-hepatic crosstalk; heart failure; metabolic dysfunction-associated steatotic liver disease; mitochondrial distress signaling; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms27177734
  40. Dis Model Mech. 2026 Sep 01. pii: dmm052757. [Epub ahead of print]19(9):
    PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.
    Ignacio Simó, Katherine J Robinson, Julia Y Kam, Yvonne Wang, Andrea Kuriakose, Esmeralda Paric, Flora Cheng, Anastasiya Potapenko, Yousun An, Maxinne Watchon, Albert Lee, Angela S Laird.
      Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD), is a fatal neurodegenerative disease caused by an expanded CAG repeat in ataxin-3 (ATXN3). Here, we investigated mitochondrial alterations across complementary MJD models, including transgenic zebrafish, CMVMJD135 mice and primary neuronal cultures. Proteomic profiling of brain lysates from male and female wild-type and CMVMJD135 mice identified mitochondrial alterations and altered oxidative phosphorylation-associated protein abundance as major shared features in both male and female MJD mice. Primary neuron cultures derived from CMVMJD135 mice were examined, validating the proteomic findings and revealing alterations in mitochondrial morphology. We further examined a transgenic zebrafish model of MJD that expresses EGFP-fused human ataxin-3 containing 84 glutamines in neurons (driven by the pan-neuronal elavl3/HuC promoter). The MJD zebrafish model also exhibited altered levels of mitochondrial electron transport chain complex proteins and enhanced sensitivity to rotenone. Notably, complex II-associated alterations featured across most assays, supporting complex II-linked dysregulation as a convergent, potentially targetable component of MJD. These phenotypes provide a robust platform for evaluating potential mitochondrial-targeted therapies and support growing evidence that disrupted mitochondrial homeostasis contributes to MJD pathogenesis.
    Keywords:  Mitochondria; Neurodegeneration; Polyglutamine; Trinucleotide repeat disorder
    DOI:  https://doi.org/10.1242/dmm.052757
  41. Ann Neurol. 2026 Sep 17.
    Patient-Derived Fibroblasts as a Clinically Relevant Model of Kearns-Sayre Syndrome.
    Laura Valls-Roca, Adrià Vilaseca-Capel, Judith Cantó-Santos, Ester Tobías, Félix Andújar-Sánchez, Laia Farré-Tarrats, Frederic Tort, Carles Rentero, Carlos Enrich, Virginia López, Juan R Tejedor, Anna Esteve-Codina, Cristina Núñez de Arenas, Pedro J Moreno-Lozano, José C Milisenda, Mar O'Callaghan, Teresa García-Silva, Montserrat Morales-Conejo, Mario F Fraga, Rafael Artuch, Miguel Á Martín, José M Cuezva, Ana Matas, Glòria Garrabou, Mariona Guitart-Mampel.
       OBJECTIVE: Kearns-Sayre syndrome (KSS) is characterized by single large-scale mitochondrial DNA deletions and by severe early-onset clinical manifestations with neurological involvement. Reliable disease models, as well as validated biomarkers or effective treatments, are lacking. We aimed to determine whether patient-derived fibroblasts represent a suitable cellular model for translational research.
    METHODS: In a cross-sectional multicenter study, fibroblasts from 12 patients with KSS, and 10 age- and sex-matched controls were analyzed to comprehensively characterize their genetic and transcriptomic profiles, mitochondrial functional signature, and secretion of soluble signaling molecules (lactate and growth differentiation factor-15).
    RESULTS: Fibroblasts derived from patients with KSS harbored single large-scale mitochondrial DNA deletions in 75% of cases and showed significant mitochondrial DNA depletion. Transcriptomic profiling identified 71 differentially expressed genes and multiple significantly enriched pathways. Despite mitochondrial respiratory chain enzymatic activities being preserved, ubiquinol-cytochrome c reductase core protein 2 complex III and MTCO1 complex IV protein expression was significantly decreased, and mitochondrial respiration was markedly impaired. Total adenosine triphosphate production rate was conserved, likely due to a metabolic shift toward glycolysis. Patient fibroblasts showed abnormal mitochondrial network organization and morphology, significant altered expression of fusion and fission proteins, a tendency to increase mitochondrial reactive oxygen species, and notably dysregulated antioxidant defenses. Mitochondrial content did not affect the functional signature. Lactate and growth differentiation factor-15 secretion were significantly increased, and demonstrated high sensitivity and specificity scores in distinguishing KSS.
    INTERPRETATION: Patient-derived fibroblasts show a reproducible mitochondrial phenotype in KSS, supporting their use as a translational model for mechanistic studies, biomarker discovery, and therapeutic screening. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78351
  42. Nat Metab. 2026 Sep 18.
    m6A mRNA methylation regulates pancreatic α-cell plasticity.
    Dario F De Jesus, Natalie K Brown, Garrett Fogarty, Guilherme Gabriel, Shirong Wang, Shen Wang, Lenee Shrestha, Kristin Kendall, Lily Young, Jiang Hu, Jermaine Austin, Joan Sabadell-Basallote, Sevim Kahraman, Ling Xiao, Rohit N Kulkarni.
      Pancreatic α-cells are central regulators of glucose and amino acid homeostasis, yet the mechanisms that preserve α-cell identity and function remain incompletely understood. N6-methyladenosine (m6A) is a widespread mRNA modification that is essential for β-cell biology and pancreatic endocrine differentiation. Here we show that m6A is a key regulator of α-cell function and plasticity. In α-cells, metabolic cues that stimulate glucagon secretion such as L-arginine increase METTL3, METTL14 and m6A levels. Loss of m6A impairs amino acid-stimulated glucagon secretion, disrupts α-cell identity programmes and induces metabolic rewiring. In mice, α-cell-specific Mettl14 deletion reduces α-cell mass, increases β-cell mass and promotes α-to-β-cell conversion, accompanied by the emergence of late β-like states with features of incomplete maturation. Mechanistically, m6A-eCLIP identifies Yy1 as a direct m6A-sensitive target, and elevated YY1 links m6A loss to signalling rewiring and erosion of α-cell identity. These findings identify m6A as a central regulator of α-cell state and reveal an epitranscriptomic mechanism controlling endocrine cell plasticity.
    DOI:  https://doi.org/10.1038/s42255-026-01591-z
  43. Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01133-2. [Epub ahead of print]45(10): 118054
    Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
    Zeng Zhang, Quan Guo, Zhihan Yang, Yukai Sun, Shuaiming Jiang, Yangli He, Jiahe Li, Jiachao Zhang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.118054
  44. Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):
    Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
    Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.
      Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-77423-1
  45. Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):
    Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
    Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.
      Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-76619-9
  46. Free Radic Biol Med. 2026 Sep 15. pii: S0891-5849(26)01161-5. [Epub ahead of print]256 516-530
    Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
    Gaoge Wang, Zhen Ni, Jingzheng Zhang, Qian Li, Yunfu Tan, Hao Yu, Enliang Hong, Chunmei Guang, Shu Wang, Huan Chen, Hongwei Hou.
      Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration accompanied by mitochondrial dysfunction and oxidative stress, yet the metabolic mechanisms underlying these pathological changes remain incompletely understood. Here, we investigated whether nicotine preserves dopaminergic integrity by modulating ceramide homeostasis through α7 nicotinic acetylcholine receptor (α7nAChR) signalling. In an MPTP mouse model, nicotine improved motor and exploratory deficits, preserved striatal tyrosine hydroxyl positive fibres, and selectively reversed ceramide accumulation in the striatum and plasma. Transcriptional analysis further showed that nicotine suppressed the induction of ceramide biosynthetic genes, suggesting regulation of sphingolipid remodelling in vivo. In MPP + challenged SH-SY5Y cells, nicotine restored cell viability, mitochondrial membrane potential, respiratory function, and mitochondrial morphology while reducing reactive oxygen species (ROS) production and apoptosis. Time-resolved analyses revealed that nicotine modulated an evolving stress response, in which early oxidative stress preceded detectable ceramide accumulation, while later ceramide dysregulation was associated with sustained mitochondrial vulnerability. Targeted lipidomics confirmed that nicotine directly restrained ceramide accumulation in stressed neuronal cells. Genetic (siSPTLC1 or siCHRNA7), pharmacological (Myriocin or MLA), and exogenous ceramide supplementation studies further supported a model in which nicotine limits this ceramide associated mitochondrial stress response through α7nAChR associated metabolic regulation. Mechanistically, nicotine restored AKT signalling and the BCL2 to BAX balance while suppressing cleaved caspase-3. Together, these findings identify ceramide dysregulation as a functionally relevant component of Parkinsonian mitochondrial stress responses and support an α7nAChR associated ceramide regulatory mechanism through which nicotine limits neuronal vulnerability.
    Keywords:  Ceramide; Mitochondrial dysfunction; Nicotine; Parkinson's disease; ROS; α7nAChR
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.010
  47. Clin Epigenetics. 2026 Sep 17. pii: 167. [Epub ahead of print]18(1):
    Nanopore long-read sequencing facilitates accurate diagnosis of KMT2B-related dystonia.
    Ugo Sorrentino, Nazanin Mirza-Schreiber, Martin Pavlov, Fatemeh Peymani, Petra Havrankova, Elisabetta Indelicato, Tereza Serranová, Lukas Kunc, Sandy Lösecke, Erik Tilch, Sebastian Eck, Holger Prokisch, Juliane Winkelmann, Sylvia Boesch, Robert Jech, Elisabeth Graf, Konrad Oexle, Michael Zech.
      Diagnosis of KMT2B-related dystonia remains challenging due to the high prevalence of variants of uncertain significance and technological constraint of short-read pipelines. To overcome these limitations, we integrated nanopore-based long-read sequencing with a validated KMT2B-episignature classifier to perform simultaneous genetic and epigenetic profiling for three cases with prior uncertain KMT2B-related findings. Our workflow detected characteristic deviations in the KMT2B-episignature score in two cases with previously unresolved or missed KMT2B variants, while refuting an ambiguous indel call. Combining genomic-variant detection with DNA-methylation analysis eliminated the need for sequential testing and enhanced accurate diagnosis of KMT2B-related dystonia, offering a basis for streamlined epigenetics-guided diagnostics.
    Keywords:   KMT2B ; Challenging variation; Episignature; Long-read sequencing; Nanopore; Streamlined diagnostics
    DOI:  https://doi.org/10.1186/s13148-026-02243-5
  48. Int J Mol Sci. 2026 Aug 25. pii: 7606. [Epub ahead of print]27(17):
    LRRK2: Molecular Mechanisms in Parkinson's Disease.
    Oscar Arias-Carrión, Magdalena Guerra-Crespo, Daniel Ortuño-Sahagún, Emmanuel Ortega-Robles.
      Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson's disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry-most prominently Rab8 and Rab10-yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase-phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges-including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune-neuronal crosstalk-and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson's disease.
    Keywords:  LRRK2; Parkinson’s disease; Rab GTPases; conformational regulation; cryo–electron microscopy; lysosomal stress
    DOI:  https://doi.org/10.3390/ijms27177606
  49. Small Methods. 2026 Sep 16. e71046
    Stimulus-Responsive Nanozymes for Mitochondria-Targeted Therapy: Design, Mechanisms, and Biomedical Applications.
    Yongxiang Wei, Ziyi Yuan, Yuanke Zhang, Peng Zhang, Guixia Ling.
      Mitochondrial dysfunction represents a common pathological hub in tumors, neurodegenerative diseases, cardiovascular diseases, and inflammatory degenerative diseases. Nanozymes offer new opportunities for precision intervention. However, inadequate targeting and uncontrollable activity remain major obstacles to their clinical translation. This review proposes a "trinity" synergistic design paradigm, which exploits pathological mitochondrial signals as dual-functional cues for both subcellular navigation and catalytic activation, thereby achieving temporal coupling of "targeting enrichment" and "responsive activation." Within this framework, we first summarize the three major categories of nanozyme material systems and their mitochondrial targeting strategies. Subsequently, we systematically analyze the structural design and activation mechanisms of endogenous, exogenous, and multi-stimulus synergistic responsive nanozymes. We also establish a cross-scale effect chain model that cascades from catalytic events to mitochondrial metabolic remodeling, programmed cell death, and immune regulation. On this basis, we comprehensively review the therapeutic applications of these nanozymes in oncology, neurological disorders, cardiovascular diseases, and inflammatory degenerative diseases. Finally, we analyze the critical challenges confronting this field and provide perspectives on future directions, with the aim of offering theoretical references and research ideas for the development of mitochondria-targeted intelligent nanomedicines.
    Keywords:  ROS homeostasis; biomedical applications; cell death; immune regulation; mitochondrial targeting; stimulus‐responsive nanozymes
    DOI:  https://doi.org/10.1002/smtd.71046
  50. Clin Chim Acta. 2026 Sep 14. pii: S0009-8981(26)00525-5. [Epub ahead of print]594 121343
    Beyond copy number: circulating cell-free mitochondrial DNA Fragmentomics and structural states in liquid biopsy.
    Muhammad Tahir Naseem, Wajid Zaman, Aziz Ullah.
      Circulating cell-free mitochondrial DNA (cf-mtDNA) is commonly treated as a concentration-based biomarker, yet the measured signal is a composite of biologically distinct molecular states that are differentially affected by blood collection, platelet activation, centrifugation, storage, extraction, amplification, and sequencing. This analytical heterogeneity has become more consequential as cf-mtDNA research moves from copy-number assays toward fragmentomics, topology, heteroplasmy, oxidative lesions, and carrier-resolved measurements. Recent multi-cohort studies indicate that fragment size, 5'-end composition, motif diversity, and regional breakage patterns can support cancer detection and tissue-of-origin inference, while clinical chemistry studies demonstrate that routine preanalytical choices can markedly alter the mitochondrial fraction recovered from plasma. This review develops a laboratory-medicine framework in which cf-mtDNA is considered a multidimensional analyte rather than a single abundance variable. We integrate mitochondrial release biology with the extracellular carrier states of mtDNA; explain how TFAM, membrane pores, mitophagy, extracellular vesicles, platelets, and nucleases shape the observed fragmentome; evaluate preanalytical and analytical sources of bias; and assess translational evidence across oncology, critical illness, cardio-renal disease, metabolic inflammation, transplantation, and neuroinflammatory disorders. Particular emphasis is placed on distinguishing true biological variation from procedure-induced redistribution of cf-mtDNA between soluble, vesicular, platelet-associated, and cell-free mitochondrial compartments. We propose minimum analytical descriptors, quality-control priorities, and validation steps required before cf-mtDNA fragmentomic signatures can become transportable clinical tests. The central implication is that the next phase of cf-mtDNA diagnostics will depend less on measuring more DNA than on measuring the correct molecular fraction with traceable preanalytics, orthogonal characterization, and clinically locked computational models.
    Keywords:  Cell-free mitochondrial DNA; Extracellular vesicles; Fragmentomics; Laboratory medicine; Liquid biopsy; Preanalytics
    DOI:  https://doi.org/10.1016/j.cca.2026.121343
  51. Nature. 2026 Sep 14.
    Drug firms' secret data supercharge AI protein models.
    Ewen Callaway.
      
    Keywords:  Drug discovery; Machine learning; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-02882-x
  52. Neuromuscul Disord. 2026 Aug 26. pii: S0960-8966(26)01069-2. [Epub ahead of print]67 107401
    Mitochondrial abnormalities in Charcot-Marie-Tooth disease: insights from a family harbouring a novel GDAP1 variant.
    Shivani Sharma, Madhu Nagappa, Gayathri Narayanappa, Kuldeep Kumar Sharma, Binukumar Bhaskarapillai, Yasha T Chickabasaviah, Arun B Taly.
      Charcot-Marie-Tooth disease is an inherited peripheral neuropathy marked by progressive loss of motor and sensory function. GDAP1 mutations are implicated in Charcot-Marie-Tooth disease, but the precise mechanism is not fully understood. This study aims to decipher the underlying genetic variant and its functional consequences in a consanguineous Indian family with two children (an 8-year-old boy and 3-years old girl) who presented with progressive motor and sensory limb involvement secondary to severe distal axonal neuropathy. Whole-exome sequencing identified a novel homozygous frameshift variant (c.503_504delAG) in GDAP1 in proband that was segregated among the family members. Patient-derived fibroblasts demonstrated complete loss of protein expression and swollen mitochondria with disrupted cristae in the cultured fibroblasts of affected individuals. Altered mitochondrial membrane potential with elevated reactive oxygen species levels, and significantly reduced ATP production and oxygen consumption rate in affected individuals compared to unaffected parents and controls, indicated impaired mitochondrial bioenergetics. We report a novel GDAP1 frameshift variant that disrupts mitochondrial structure and bioenergetics, underscoring GDAP1's role in mitochondrial quality control. However, the other downstream mechanisms implicated in axonal degeneration remains to be elucidated.
    Keywords:  CMT; Hereditary axonal neuropathy; Mitochondrial dysfunction; Novel GDAP1 variant; Patient-derived fibroblasts
    DOI:  https://doi.org/10.1016/j.nmd.2026.107401
  53. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70380
    Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies.
    Ana Bermejo-Moriñigo, Paloma Martín-Jiménez, Violeta González-Méndez, Laura Bermejo-Guerrero, Luz Edith Ochoa, Cristina Martín-Arriscado, Andrea Alcalá-Galiano, Cristina Casado-Pérez, María Navarro-Riquelme, Rocío Garrido-Moraga, Adrián González Quintana, Alberto Blázquez, Cristina Domínguez-González.
       BACKGROUND: Quantitative muscle MRI is increasingly used to assess structural muscle damage in inherited myopathies, but its application in primary mitochondrial myopathies (PMM) has not been systematically evaluated in large cohorts. Because PMM are clinically and genetically heterogeneous, objective imaging biomarkers are needed to quantify skeletal-muscle involvement and define meaningful subgroups. We assessed whether MRI-derived proton density fat fraction (PDFF) captures genotype- and phenotype-specific patterns of fatty replacement and reflects disease severity using motor function outcomes and circulating biomarkers.
    METHODS: We performed a cross-sectional analysis of 49 adults with genetically confirmed PMM enrolled in a prospective natural history study. Participants underwent standardised lower-limb MRI, including T1-weighted sequences and mDIXON-QUANT fat fraction imaging. Muscle involvement was assessed semi-quantitatively with the modified Mercuri scale and quantitatively by PDFF measurement in selected pelvic girdle and thigh muscles. A total fat fraction score (FF sum) was calculated. PDFF was compared across genotypes and phenotypes and against MRC score, NSAA, 6-min walk test, 100-m run test, CK, serum creatinine, GDF15 and disease duration.
    RESULTS: Mean age at onset was 26.3 ± 15.1 years, mean age at MRI was 50.0 ± 12.3 years, and median disease duration was 23 years (IQR 15-31). Genetic diagnoses included mtDNA variants in 29 patients (59.1%; single large-scale deletions, n = 19; point mutations, n = 10), nuclear variants in POLG (n = 8), TK2 (n = 8) and TWNK (n = 4). Phenotypes were exercise intolerance without overt weakness (n = 7), isolated progressive external ophthalmoplegia (PEO; n = 16), PEO-plus (n = 16) and progressive myopathy (n = 8). Highest median PDFF values were observed in tensor fasciae latae (31%), gluteus maximus (30%), sartorius (25%) and gracilis (20%). FF sum correlated with MRC score (r = -0.567, p < 0.0001), NSAA (r = -0.731, p < 0.0001), 100-m run test time (r = 0.629, p < 0.0001), 6-min walk distance (r = -0.311, p = 0.0476) and serum creatinine (r = -0.715, p < 0.0001), but not with CK or GDF15. TK2 deficiency showed the highest fat replacement, particularly in gluteus maximus and gracilis (p < 0.001). Progressive myopathy showed greater fatty replacement than other phenotypes (p < 0.001), while exercise intolerance showed higher fat fraction than isolated PEO (p = 0.033).
    CONCLUSIONS: Quantitative muscle MRI provides objective and clinically meaningful measures of muscle involvement in PMM. MRI-derived fat fraction reflects disease severity, discriminates between genotypes and phenotypes, and detects subclinical muscle damage. These cross-sectional findings support PDFF as a candidate imaging biomarker for patient stratification and disease characterisation; prospective longitudinal studies will be required to establish its sensitivity to change and its validity as an outcome measure for therapeutic trials.
    Keywords:  MRI‐derived fat fraction; biomarkers; mitochondrial myopathies; quantitative muscle MRI
    DOI:  https://doi.org/10.1002/jcsm.70380
  54. Methods Mol Biol. 2027 ;3074 141-157
    Skeletal Muscle Tissue Engineering: Methods and Analysis for the Bio-Fabrication and Validation of a 3D Scaffold-Free Muscle Construct.
    Marianna Cosentino, Desiree Genovese, Antonio Musarò.
      The development of three-dimensional (3D) tissue constructs that accurately replicate the morphology and function of native tissues is critical for advancing tissue engineering and regenerative medicine. Two primary strategies are currently employed: scaffold-based and scaffold-free approaches. Both aim to reproduce a biomimetic microenvironment that supports cell-cell and cell-matrix interactions, enabling the formation of functional tissues. To circumvent the immunological and toxicological limitations related to the use of exogenous scaffold materials, scaffold-free tissue engineering has emerged as a promising alternative. This method utilizes multicellular aggregates that fuse into cohesive structures while naturally producing extracellular matrix (ECM). Harnessing the intrinsic capacity of cells to self-organize and assemble into sheets enhances cell-cell connectivity and promotes spontaneous ECM remodeling, facilitating the formation of scaffold-free tissues. This study outlines the methodology for generating a 3D skeletal muscle tissue in vitro without the use of scaffolds. Here, we describe key analytical techniques, including flow cytometry, immunofluorescence, and histological staining, used to evaluate tissue functionality in physiological and pathological contexts. The proposed protocols enable the creation of a mouse skeletal muscle model suitable for drug screening and testing, considering its advantages and limitations. Furthermore, the integration of patient-derived biopsies or induced pluripotent stem cells (iPSCs) establishes a basis for personalized therapeutic applications in clinical settings.
    Keywords:  Drug screening models; Flow cytometry; Histological staining; Immunofluorescence; Personalized regenerative medicine; Scaffold-free tissue engineering; Three-dimensional tissue
    DOI:  https://doi.org/10.1007/978-1-0716-5539-9_9
  55. Am Heart J Plus. 2026 Oct;70 100882
    Human cardiovascular organoids: Biomedical applications and ethical challenges.
    Koushik Sen, Suravi Majumder, Dragana Stanisic, Avisek Majumder.
      Cardiovascular disease (CVD) remains the leading cause of global mortality, yet traditional in vitro and animal models often fail to recapitulate the integrated structural, cellular, and functional complexity of the human heart. Recent advances in human pluripotent stem cell technology, developmental bioengineering, and microphysiological systems have enabled the development of diverse three-dimensional cardiac tissue models, including self-organizing cardiovascular organoids and engineered cardiac platforms, three-dimensional constructs that partially recapitulate key myocardial features. These platforms facilitate mechanistic and disease-relevant modelling of congenital and acquired cardiac disorders, allow interrogation of arrhythmogenic mechanisms, and reproduce pathophysiological processes such as ischemia-reperfusion injury, fibrotic remodelling, and inflammatory cardiomyopathy with increasing physiological relevance. In translational contexts, these models are emerging as valuable tools in drug discovery pipelines, enabling high-throughput cardiotoxicity assessment and supporting regenerative medicine strategies, thereby bridging mechanistic research with preclinical validation. Integration with cutting-edge modalities-such as single-cell and spatial multi-omics, CRISPR-based genome editing, synthetic biology circuits, and artificial intelligence-driven phenomics further enhances their maturation and predictive accuracy, although their clinical applicability remains under active investigation. Despite these advances, challenges including batch-to-batch variability, limited vascularization, metabolic immaturity, and incomplete immune system incorporation continue to constrain physiological fidelity. Additionally, ethical and regulatory considerations spanning donor consent, genetic data privacy, biobanking governance, and model-specific translational and societal implications remain critical for responsible innovation. This review presents a comprehensive synthesis of current cardiovascular organoid research, highlights emerging biomedical applications, and provides a critical perspective on the ethical frameworks essential for advancing the field responsibly.
    Keywords:  Cardiac bioengineering; Cardiac organoids; Disease modelling; Drug screening; Engineered cardiac tissues; Human pluripotent stem cells; Precision medicine; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.ahjo.2026.100882
  56. J Physiol Sci. 2026 Sep 14. pii: S1880-6546(26)00048-X. [Epub ahead of print]76(3): 100102
    Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
    Motohiro Nishida.
      Cardiovascular homeostasis is increasingly understood not as the output of isolated pathways, but as an emergent and history-dependent property of interactions across biological scales. Cutting-edge technologies have revealed coupling between transcription and metabolism, signaling within molecular microdomains, organelle networks, communication between cardiomyocytes and non-myocytes, neurovascular regulation, and interorgan interactions. This special issue brings together five perspectives that examine how such interactions preserve physiological function and, under stress, redirect the cardiovascular system toward adaptation or disease. As a representative multiscale example, this Editorial highlights hierarchical mitochondrial quality control. Biogenesis, fusion-fission dynamics, proteostasis, mitochondria-derived vesicles, organelle contacts, and mitophagy form a graded defense network that matches the response to the burden and location of damage. The same network connects mitochondrial dysfunction to innate immunity and tissue remodeling. Defining directionality, spatial context, temporal order, and flux within these interactions will be essential for converting descriptive interaction maps into causal physiology and selective therapies.
    Keywords:  Cardiovascular homeostasis; Cellular circuits; Functional interaction; Heart failure; Microdomains; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100102
  57. Annu Rev Pathol. 2026 Sep 17.
    Friedreich Ataxia: From Genetics to Mechanism to Clinical Features.
    David R Lynch, Sanjay I Bidichandani, Jill S Napierala, Marek Napierala.
      Friedreich ataxia is a slowly progressive neurodegenerative disorder caused by GAA expansions in the FXN gene that lead to decreased transcription of the mRNA coding for frataxin protein. Such deficiency leads to impaired iron sulfur cluster synthesis and various components of mitochondrial dysfunction. These events have been modeled in cellular and animal models, leading to assessment of many potential therapeutic agents based on enhancement of mitochondrial function or mitigation of frataxin deficiency. One agent, though not curative, has been approved for adults with Friedreich ataxia, but many approaches remain in therapeutic development.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-032025-035253
  58. Int J Mol Sci. 2026 Aug 30. pii: 7771. [Epub ahead of print]27(17):
    Annexin A5 Maintains Mitochondrial Integrity by Inhibiting mPTP Opening to Protect Against Acetaminophen-Induced Acute Liver Injury.
    Xiaowen Zhang, Wenwei Li, Luqi Li, Ying Wang, Wei Tang, Jing Zhang, Zichun Hua.
      Acetaminophen (APAP) represents a major cause of drug-induced liver injury (DILI), and effective pharmacological interventions remain limited. Annexin A5 (AnxA5), a Ca2+-dependent phospholipid-binding protein, participates in diverse biological processes related to tissue repair. In this study, we evaluated AnxA5 expression in APAP-challenged mouse livers and clinical samples from patients with liver injury. Using hepatic cell lines AML12 and HepG2, we performed overexpression-based functional assays to assess the cytoprotective effects of AnxA5 against APAP toxicity. Co-immunoprecipitation assays were applied to characterize protein interactions, and mitochondrial functional parameters were measured to dissect the underlying molecular mechanism. We found that AnxA5 was significantly upregulated in both APAP exposed mice and APAP DILI patients. Cellular functional assays showed that AnxA5 overexpression mitigated APAP triggered cytotoxicity in AML12 and HepG2 cells. Mechanistically, AnxA5 bound to voltage dependent anion channel 1 (VDAC1), restrained VDAC1 mediated mitochondrial Ca2+ influx, and suppressed VDAC1 oligomerization, which further inhibited mitochondrial permeability transition pore (mPTP) opening. In an APAP-induced liver injury mouse model, exogenous recombinant AnxA5 treatment maintained mitochondrial integrity and ameliorated hepatic inflammation and liver damage. Collectively, our data reveal AnxA5 as an endogenous mitochondrial protective factor and support its therapeutic potential against APAP-induced liver injury.
    Keywords:  APAP toxicity; AnxA5; liver injury; mPTP opening; mitochondria
    DOI:  https://doi.org/10.3390/ijms27177771
  59. Small Sci. 2026 Sep;6(9): e70386
    A Biomimetic 3D Human Skeletal Muscle Microtissue for Modeling Biological and Functional Hallmarks of Aging.
    Sohae Yang, Jeong Sik Kong, Hyun Young Shin, Sung Chun Cho, Aseer Intisar, Min Young Kim, Yeong-Jin Choi, Yun-Il Lee, Dong-Woo Cho, Minseok S Kim.
      Skeletal muscle is one of the largest organs in the human body, playing a central role in mobility, metabolism, and endocrine regulation. The aging global population underscores the need to understand skeletal muscle aging, which is bottlenecked by the lack of in vitro models that recapitulate biological and functional features of aged human muscle as well as discrepancies between humans and animal models. Here, we present a 3D biomimetic aged skeletal muscle model using human primary skeletal muscle cells (SkMCs) embedded in a skeletal muscle-derived decellularized extracellular matrix (dECM) scaffold. Constructs fabricated from aged and young SkMCs were systematically evaluated across structural, molecular, mitochondrial, calcium-handling, and contractile readouts. Compared with young constructs, aged constructs recapitulated several aging-associated biological and functional phenotypes, including smaller myotubes, altered myogenic and inflammatory marker expression, mitochondrial alterations, delayed calcium responses, and weakened contractile forces. This human-relevant platform enables simultaneous assessment of biological and functional aspects of muscle aging and may serve as a translational tool to study mechanisms and screen therapies for age-associated muscle disorders. This aligns with the FDA Modernization Act 2.0-which recognizes in vitro human systems as alternatives to animal testing-underscoring the practical relevance of this model.
    Keywords:  3D skeletal muscle constructs; aged skeletal muscle; contractile function; decellularized extracellular matrix; human‐derived skeletal muscle cells; in vitro model
    DOI:  https://doi.org/10.1002/smsc.70386
  60. Curr Pharmacol Rep. 2026 ;12(1): 38
    The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.
    Md Salman Shakil, Matthew J McBride.
       Purpose of Review: This article describes the recent discoveries on how the amino acid methionine alters mitochondrial metabolism to support tumor function and growth. A detailed understanding of these mechanisms of cross-talk between the methionine cycle and mitochondria will empower the discovery and development of new metabolism-targeting cancer therapies.
    Recent Findings: Methionine and metabolites of the methionine cycle are increasingly appreciated to have both direct and indirect roles in regulating mitochondrial metabolism, which are critical for survival, growth, and treatment-resistance in tumors. Recent work has discovered multiple mitochondrial transporters that directly connect tumor use of methionine-derived S-adenosylmethionine (SAM) to mitochondrial function. Carnitine is synthesized from SAM-mediated methylation of lysine and is critical for tumor energy generation by fatty acid oxidation. Tumors depend on mitochondrial transport of SAM to support methylation reactions and oxidative phosphorylation. Purine synthesis is supported by mitochondrial one-carbon units from the folate cycle in tumors, which requires remethylation of homocysteine to form methionine to prevent folate trapping. Preclinical and clinical studies investigating both pharmacological and nutritional interventions are uncovering the mechanisms by which mitochondrial function depends on methionine metabolism. Further exploration in this area will define both the targets and specific interventions with the greatest promise for the treatment of cancer patients.
    Summary: Methionine metabolism influences many aspects of mitochondrial function, including energy generation, antioxidant defenses, and lipid composition. Understanding how tumors co-opt these processes and their dependence on the amino acid nutrient methionine provides an opportunity for new cancer therapies.
    Keywords:  Cancer; Metabolism; Methionine; Methylation; Mitochondria; S-adenosylmethionine
    DOI:  https://doi.org/10.1007/s40495-026-00481-y
  61. J Nanobiotechnology. 2026 Jul 28. pii: 859. [Epub ahead of print]24(1):
    Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.
    Yue Zhang, Fei Han, Yixuan Yuan, Mengyang Li, Linbin Yi, Yujie Xiao, Dongliang Zhang, Zhi Zhang, Yunchuan Wang, Hongtao Wang, Dahai Hu.
      Chronic diabetic wounds are trapped in a persistent inflammatory state, largely due to macrophage failure to transition from pro-inflammatory (M1) to pro-reparative (M2) phenotypes. Here, we show that adipose-derived stem cell extracellular vesicles (ADSC-EVs) deliver functional mitochondria into diabetic wound macrophages, thereby restoring tricarboxylic acid (TCA) cycle-driven M2 polarization. Mechanistically, ADSC-EV-mediated mitochondrial transfer reactivates pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), increases TCA cycle flux, and suggests enhanced glutamine anaplerosis, as evidenced by ¹³C-glucose isotope tracing. This metabolic rewiring restores oxidative phosphorylation (OXPHOS), elevates oxygen consumption rate (OCR) and suppresses glycolysis. Consequently, ADSC-EV treatment reduces M1 macrophages and increases M2 macrophages, lowers pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, MCP1, p < 0.0001), and upregulates IL-10 in vitro, p < 0.0001). In a diabetic mouse wound model, a single course of ADSC-EVs accelerates wound closure at day 14 (p < 0.05), enhances re-epithelialization and collagen deposition, and reduces local oxidative stress and inflammation. Mitochondria‑depleted Rho-ADSC-EVs show markedly diminished effects, confirming that functional mitochondrial transfer is the primary driver. Our findings establish ADSC-EV-mediated mitochondrial transfer as a central metabolic reprogramming strategy that breaks the inflammatory lock in diabetic wounds and promotes healing.
    Keywords:  ADSC-EVs; Diabetic wound; Macrophages; Metabolic remodeling; Mitochondrial transfer; TCA cycle
    DOI:  https://doi.org/10.1186/s12951-026-04846-9
  62. Nature. 2026 Sep 16.
    Transplanted human brain-tissue takes root in mice without a cortex.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Neuroscience; Publishing; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02927-1
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