bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–08–23
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  2. Recurrent Single-Nucleotide Insertions in the Mitochondrial Second Light-Strand Promoter Cause Tubulointerstitial Kidney Disease.
  3. Allosteric rewiring of mitochondrial stress signaling through Miro1.
  4. Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).
  5. Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
  6. Disease-mutations perturb proton transfer reactions in respiratory complex I.
  7. Sirtuins in mitochondrial physiology and energy homeostasis.
  8. Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
  9. Ringer Loss in Drosophila Uncovers Mitochondrial Complex I Deficits Characteristic of Human Parkinson's Disease.
  10. A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.
  11. Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
  12. Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
  13. Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
  14. Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
  15. The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
  16. Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.
  17. Severe mitochondrial cardiomyopathy with m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene: A study of large family analysis.
  18. Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
  19. Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
  20. Integrated SDH, COX histochemistry, and MHC fibre typing in skeletal muscles: Methods and interpretation.
  21. Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.
  22. When muscles matter in SORD neuropathy.
  23. Inhibition of mitochondrial complex III causes selective dopaminergic neurotoxicity by redox stress in Caenorhabditis elegans.
  24. Nocturnin drives mitochondrial NADP(H)/NAD(H) rhythms to regulate steroid rhythm amplitude and time metabolism.
  25. Dynamic S-acylation of IDH2 regulates mitochondrial redox homeostasis.
  26. Mitochondrial dynamics in Huntington's disease.
  27. Structural bases of the conformational transitions of the mitochondrial choline carrier SLC25A48 captured by molecular dynamics simulations.
  28. The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy.
  29. The hallmarks of skeletal muscle health.
  30. Fructose directly remodels the translocase of the outer membrane to impair oxidative phosphorylation in podocytes.
  31. Mitochondrial dysfunction in neurodegenerative diseases: Mechanisms and therapeutic advances.
  32. Measuring the Effects of Pharmacological Compounds on Mitochondrial Morphology in Mouse Aging Models.
  33. Novel Variants in Mitochondrial Ribosomal RNA Genes MT-RNR1 and MT-RNR2 Identified in Hereditary Optic Neuropathy Initially Presenting as Normal Tension Glaucoma: A Case Report.
  34. Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
  35. The Need for Clinical Diagnostic Proficiency in the Genomic Era.
  36. Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.
  37. Mitochondrial-neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes.
  38. When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.
  39. A head-to-tail dimeric J-aggregate probe for rapid and ratiometric imaging of mitochondrial 5-HT via dual-anchoring.
  40. Morphotype-resolved 3D morphometry reveals a structure-density-location coupling in mitochondrial networks.
  41. AMITO: An open-access application for assisted analysis of mitochondria in transmission electron microscopy images.
  42. Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.
  43. Stem Cell-Derived Mitochondria-Enriched Preservation Solutions as Organelle-Based Therapeutic Strategy for Cold Storage of Liver and Kidney.
  44. Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.
  45. A human cytokine response atlas to reconstruct underlying gene regulatory networks.
  46. Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.
  47. Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
  48. [Leber's hereditary optic nerve atrophy].
  49. A genetic switch involving EGR1 and EZH2 links aging and development across human tissues.
  50. NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection.
  51. Anti-CD320 Autoantibodies and Central Nervous System Vitamin B12 Deficiency in Idiopathic Myelopathy.
  52. Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.
  53. Human Induced Pluripotent Stem Cell-Derived Cardioids as a Model to Assess Oligonucleotide Delivery.
  54. Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis vulnerability of hepatocytes.
  55. Mice Undergo Organ-Specific Transcriptional and Metabolic Remodeling During Late Adolescence.
  56. Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.
  57. NADH FLIM reveals cellular bioenergetics and mitochondrial morphology during Drosophila convergent extension.
  58. Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
  59. Real-Time, Noninvasive Evaluation of Mitochondrial Function Using Resonance Raman Spectroscopy.
  60. mRNA translational dynamics mediates totipotent-like reprogramming.
  1. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  2. medRxiv. 2026 Aug 03. pii: 2026.07.31.26359118. [Epub ahead of print]
    Recurrent Single-Nucleotide Insertions in the Mitochondrial Second Light-Strand Promoter Cause Tubulointerstitial Kidney Disease.
    Klára Svojšová, Kendrah O Kidd, Dita Mušálková, Tereza Kmochová, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Veronika Barešová, Helena Trešlová, Martin Radina, Lea Pavlovičová, Jakub Sikora, Abbigail Taylor, Lauren Martin, Antonio Sanchez, Nelson Weller, Thomas Pinder, Megan E Astley, Xiangling Wang, Abhijit Dixit, Stephen M Korbet, Colm Rowan, Peter J Conlon, Karina Soto, Afonso Santos, Marek Mysliveček, Jiří Zeman, Hana Štufková, Hana Hansíková, Kateřina Tauchmannová, Petr Pecina, Vilma Kaplanová, Marek Vrbacký, Tomáš Mráček, Örjan Persson, Claes M Gustafsson, Maria Falkenberg, Martina Živná, Anthony J Bleyer, Stanislav Kmoch.
       Introduction: Mitochondrial DNA (mtDNA) is not routinely analyzed in inherited kidney disease. We evaluated mtDNA variation in families who remained genetically unresolved despite extensive testing.
    Methods: We reviewed pedigrees from the Wake Forest-Charles University Rare Inherited Kidney Disease Registry to identify genetically unresolved families with suspected maternal inheritance, performed mtDNA genotyping, clinically characterized variant carriers, and functionally evaluated disease-associated mitochondrial variants.
    Results: Among 33 families with evidence of maternal inheritance, 18 (55%) carried one of seven disease-associated mtDNA variant types, including homoplasmic recurrent single-nucleotide insertions in the second light-strand promoter (LSP2; 9 families), novel MT-TW and MT-TL2 variants (2 and 1 families, respectively), and previously reported MT-TF and heteroplasmic MT-ND5 variant (5 and 1 families, respectively). In 16 families, variants occurred on distinct haplotypes, consistent with independent mutational events and rapid enrichment to homoplasmy across generations. Maternal transmission was strongly supported, with below-normal kidney function observed in 54/60 (90%) offspring of affected mothers versus 1/17 (6%) offspring of affected fathers (p = 1.23 × 10 ⁻11 ). Pathogenicity was further supported by predicted deleterious structural effects and functional evidence of impaired mitochondrial transcription and translation, respiratory chain deficiency, and CoQ10 depletion. Affected individuals predominantly presented with chronic tubulointerstitial kidney disease, occasionally accompanied by gout and only sporadically with extrarenal manifestations. The rate of kidney disease progression appeared to vary both between and within families. Overall, 109/119 genetically affected individuals or obligate at-risk carriers were clinically affected; most unaffected carriers were younger than 45 years of age. Clinical status was unavailable for an additional 66 obligate at-risk carriers.
    Conclusions: These findings establish the physiological relevance of the LSP2 promoter, support routine assessment of the mitochondrial genome in inherited kidney disease, and highlight mtDNA variants as an important cause of familial and sporadic tubulointerstitial kidney disease of previously unexplained etiology.
    Lay Summary: Many inherited kidney diseases remain unexplained because routine genetic testing focuses on genes in the cell nucleus and does not examine mitochondrial DNA-the small genome in the cell's energy-providing mitochondria, inherited only from the mother. We studied 33 families with chronic kidney disease whose family histories suggested maternal inheritance and identified disease-causing mitochondrial DNA variants in 18 (55%). Nine families carried variants in LSP2, a recently discovered mitochondrial regulatory element, highlighting its importance in normal mitochondrial function and disease. Others carried pathogenic variants in mitochondrial tRNA genes required for mitochondrial protein synthesis. Laboratory studies showed that these variants impair mitochondrial energy conversion. In all families, the predominant manifestation was slowly progressive kidney disease, sometimes leading to dialysis or kidney transplantation. These findings identify pathogenic mitochondrial DNA variants as an underrecognized cause of inherited kidney disease and support the inclusion of mitochondrial DNA analysis in routine genetic testing.
    DOI:  https://doi.org/10.64898/2026.07.31.26359118
  3. Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073
    Allosteric rewiring of mitochondrial stress signaling through Miro1.
    Layla Drwesh, Julia C Fitzgerald.
      In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.011
  4. Neurotherapeutics. 2026 Aug 18. pii: S1878-7479(26)00218-7. [Epub ahead of print] e01048
    Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).
    Michio Hirano, Andres Berardo, Emanuele Barca, Valentina Emmanuele, Austin Larson, Antonella Spinazzola, Amel Karaa.
      
    Keywords:  Nucleoside therapy, POLG, Thymidine, deoxycytidine, Thymidine kinase 2, TK2d
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01048
  5. Gerontology. 2026 Aug 17. 1-21
    Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
    Chaodong Han, Zilian Zhang, Yafeng Song.
      : Background: Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades. Summary: This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming. Crucially, we examine how mitochondria act as signaling hubs for inter-organ crosstalk. Through the secretion of mitokines (e.g., FGF21, GDF15) and the release of damage-associated molecular patterns (DAMPs), dysfunctional mitochondria trigger chronic inflammation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 inflammasome (NLRP3) pathways, actively driving systemic aging within the skeletal muscle-brain and adipose/liver-cardiovascular axes. Additionally, this paper synthesizes current therapeutic interventions, ranging from lifestyle modifications and nicotinamide adenine dinucleotide (NAD+) precursors to frontier technologies like mitochondrial transplantation and gene editing. Key Messages: While promising in animal models, clinical translation of these interventions is currently hindered by limited long-term safety data and evidence gaps. Therefore, mitochondria-targeted studies incorporating integrated multi-organ phenotyping are urgently required to establish robust strategies for extending human healthspan.
    DOI:  https://doi.org/10.1159/000553430
  6. Biochim Biophys Acta Bioenerg. 2026 Aug 17. pii: S0005-2728(26)00022-8. [Epub ahead of print] 149602
    Disease-mutations perturb proton transfer reactions in respiratory complex I.
    Patricia Saura, Sofia Badolato, Andrea Gangdal, Adel Beghiah, Ville R I Kaila.
      Respiratory Complex I powers oxidative phosphorylation by a long-range proton-coupled electron transfer (PCET) reaction, with mutations linked to more than half of all human mitochondrial disorders. Yet, the molecular principles underlying the functional impairment remain difficult to test, as most mutations impede both the proton pumping and oxidoreductase activities due to the tightly coupled PCET process. Here, we probe how key disease mutations in the terminal ND5 subunit (NuoL/Nqo12), linked to the development of Leigh's syndrome (LS) and LHON/MELAS (F124L, M252T, D393N), affect the proton transport activity within the dissected antiporter module Nqo12. All constructs result in fully folded antiporter modules, with the introduced substitutions showing enhanced proton conduction rates across the proteoliposome membranes relative to the wild type module. Our molecular dynamics simulations reveal that the mutations perturb the internal water network and ion-pair dynamics that are central for the long-range PCET activity in Complex I. Taken together, we suggest that the mitochondrial disease mutations alter the redox-driven proton pumping activity of Complex I by perturbing the function of local proton gates, and result in an uncontrolled proton translocation across the antiporter module. The molecular consequences of disease mutations are discussed in the context of the proposed pumping mechanism.
    Keywords:  Cellular respiration; LHON, MELAS; Leigh syndrome; Mitochondrial disease; Molecular mechanism
    DOI:  https://doi.org/10.1016/j.bbabio.2026.149602
  7. Methods Enzymol. 2026 ;pii: S0076-6879(26)00157-6. [Epub ahead of print]733 111-142
    Sirtuins in mitochondrial physiology and energy homeostasis.
    Arshdeep Kaur, Ullas Kolthur Seetharam.
      Mitochondrial sirtuins integrate cellular metabolic and energetic state with post-translational regulation of mitochondrial proteins, thereby influencing bioenergetics, redox homeostasis, and metabolic flexibility. Despite extensive study of individual sirtuins, a comprehensive understanding of their function remains limited by methodological and conceptual challenges. These arise from the complex metabolic environment in which mitochondrial sirtuins act, including compartmentalized NAD+ pools, metabolite-driven non-enzymatic acylation, overlapping substrate specificities, and limited tools to accurately characterize enzyme-specific activity, particularly for SIRT4. This review aims to highlight current experimental approaches used to study mitochondrial sirtuins, and the need to integrate enzymatic measurements with metabolic and physiological readouts. We discuss the importance of considering mitochondrial spatial heterogeneity within cells, tissue-specific metabolic context, and temporal dynamics of metabolic state when interpreting sirtuin activity. Recent advances in quantitative proteomics, metabolite profiling, and mitochondria-specific analyses provide new opportunities to resolve these complexities. Moving forward, integrating these approaches with a systems-level and quantitative framework will be critical to fully understand how mitochondrial sirtuins orchestrate metabolic regulation across cellular and organismal scales.
    Keywords:  Enzyme kinetics; NAD(+) metabolism; Sirtuin activity; Spatio-temporal
    DOI:  https://doi.org/10.1016/bs.mie.2026.05.029
  8. Life Sci. 2026 Aug 20. pii: S0024-3205(26)00451-0. [Epub ahead of print]403 124642
    Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
    Ilitch A Marcondes-de-Castro, Thamyres Alves Sales, Thatiany Souza Marinho, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.
      Mitochondrial quality control (QC) preserves cellular homeostasis by coordinating mitochondrial structure, turnover, and bioenergetic function. Rather than operating through isolated pathways, QC is increasingly recognized as an integrated, redox-sensitive network in which reactive oxygen species (ROS), nicotinamide adenine dinucleotide (NAD+), and calcium (Ca2+) signaling regulate mitochondrial dynamics, mitophagy, biogenesis, and, ultimately, cell fate. In this narrative review, we propose a hierarchical framework in which these signaling systems function as interconnected sensors and transducers that determine whether mitochondria undergo repair, adaptive remodeling, or elimination. Under physiological conditions, controlled ROS production, adequate NAD+ availability, and tightly regulated Ca2+ flux promote a balanced mitochondrial fusion and fission, efficient mitophagic turnover, and mitochondrial biogenesis, thereby preserving bioenergetic competence and metabolic flexibility. Mitochondria-associated membranes (MAMs) emerge as key spatial platforms that integrate redox signaling, Ca2+ transfer, and lipid exchange, synchronizing communication between the endoplasmic reticulum and mitochondria. Conversely, persistent redox imbalance, characterized by excessive ROS, NAD+ depletion, and Ca2+ dysregulation, disrupts the coordination of QC pathways, resulting in mitochondrial fragmentation, defective turnover, impaired biogenesis, bioenergetic failure, and activation of apoptotic signaling. We critically discuss the mechanistic interplay among these pathways across metabolic disorders, cardiovascular disease, neurodegeneration, cancer, and aging, highlighting context-dependent adaptive and maladaptive responses. Finally, we identify unresolved questions regarding the spatiotemporal integration of redox signals, tissue-specific regulation of mitochondrial QC, and therapeutic targeting of network-level regulatory nodes. This framework provides a systems-level perspective for understanding how coordinated redox signaling governs mitochondrial adaptation and contributes to disease pathogenesis.
    Keywords:  Mitochondria-associated membranes; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Redox signaling
    DOI:  https://doi.org/10.1016/j.lfs.2026.124642
  9. bioRxiv. 2026 Jul 29. pii: 2026.07.27.741040. [Epub ahead of print]
    Ringer Loss in Drosophila Uncovers Mitochondrial Complex I Deficits Characteristic of Human Parkinson's Disease.
    Haven G Tillmon, Savannah K Boyen, Raquel Velazquez, Michelle E Urbina-Berlanga, Marco Sciortino, Swati Banerjee.
      Tubulin polymerization promoting proteins (TPPPs) are known for their cytoskeletal regulation across species; however, emerging evidence suggests broader cellular functions, including potential roles in mitochondrial biology. Here, we identify the Drosophila homolog of human TPPP, Ringer, as a previously unrecognized regulator of mitochondrial bioenergetics and electron transport chain complex I (CI) function. Ringer is enriched in the mitochondrial matrix, and its loss results in reduced levels of multiple CI subunits and assembly factors and a significant decrease in CI enzymatic activity. Notably, similar deficits are observed in postmortem human Parkinson's disease (PD) brain tissues, underscoring the translational relevance of our Drosophila model and highlighting conserved, disease-associated mechanisms. Pharmacological administration of the CI-specific reactive oxygen species (ROS) scavenger, resveratrol, ameliorates superoxide levels and improves CI enzymatic activity and ATP production in ringer mutants, demonstrating that targeted antioxidant therapeutics can improve bioenergetic function with Ringer loss. Together, these findings establish Ringer as a key regulator of mitochondrial bioenergetics and reveal CI instability as a potential mechanism underlying PD-associated mitochondrial dysfunction, providing a robust and translationally meaningful framework for future therapeutic exploration.
    DOI:  https://doi.org/10.64898/2026.07.27.741040
  10. Pediatr Neurol. 2026 Jul 31. pii: S0887-8994(26)00243-2. [Epub ahead of print]184 9-10
    A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.
    Phan Q Duy, Weilai Dong, Avram Bukhbinder, Danielle B Pier.
      
    Keywords:  Mitochondrial disease; Neuropathy; POLG; Rhabdomyolysis
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.07.033
  11. IUBMB Life. 2026 Aug;78(8): e70127
    Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
    Peng Ran, Lifang Yang.
      Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.
    Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1002/iub.70127
  12. J Lipid Res. 2026 Aug 20. pii: S0022-2275(26)00156-2. [Epub ahead of print] 101126
    Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
    Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Morgan T Canfield, Ryan D Sheldon, Sara M Nowinski.
      α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that under typical culture conditions, free LA is near-completely absent in cells. Rather, any LA generated through mitochondrial fatty acid synthesis (mtFAS) remains in a protein-bound pool, as disruption of the mtFAS pathway does not alter free LA levels despite strong loss of protein lipoylation. Conversely, supplementation with exogenous LA markedly increases free intracellular LA in both control and mtFAS-deficient cells, but is incapable of restoring protein lipoylation, mitochondrial respiration, or cell proliferation in the absence of mtFAS. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.
    DOI:  https://doi.org/10.1016/j.jlr.2026.101126
  13. bioRxiv. 2026 Aug 01. pii: 2026.07.31.742112. [Epub ahead of print]
    Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
    Youmian Yan, Lianjie Wei, Thomas Schodl, Keri-Lyn Kozul, Maria Behrens, Stephen P Plassmeyer, Alex S Holehouse, Natalie M Niemi.
      The dual targeting of mitochondrial proteins regulates a host of cellular processes, including metabolism, cofactor biosynthesis, mitophagy, and stress responsiveness. Despite this importance, the mechanisms by which proteins dually localize are incompletely defined. Here, we identify multiple sequence elements that compromise the matrix localization of the phosphatase PPTC7 to facilitate its accumulation at the outer mitochondrial membrane (OMM), where it regulates mitophagy. We find that PPTC7 has a moderately 'weak' presequence, but this feature is insufficient to promote dual targeting of a generic cargo protein. Instead, our data suggest that a recently evolved glycine stretch decreases the helical potential of the PPTC7 presequence, weakening its import efficiency in vitro and in cells. Deletion of these glycine residues improves PPTC7 in vitro import and enrichment within the mitochondrial matrix, but only partially suppresses PPTC7-mediated regulation of mitophagy at the OMM. These data suggested additional elements may contribute to PPTC7 dual localization, including its mature phosphatase domain which has robust thermal stability and becomes further stabilized to an import-incompetent state upon binding to its requisite enzymatic co-factor manganese. Simultaneous increases in presequence strength and denaturation of the PPTC7 phosphatase domain are required to promote import in vitro, underscoring the multifactorial challenges associated with its matrix targeting. These data suggest that sequence-specific features can work combinatorially to impart dual-localization capacity to mitochondrial proteins, enabling functions across cellular compartments.
    DOI:  https://doi.org/10.64898/2026.07.31.742112
  14. Metabolomics. 2026 Aug 20. pii: 140. [Epub ahead of print]22(5):
    Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
    Marianne Venter, Karin Terburgh, Jeremie Z Lindeque, Emi Ogasawara, Mirian C H Janssen, Jan A M Smeitink, Kazuto Nakada, Roan Louw.
      Pathogenic mitochondrial DNA (mtDNA) mutations contribute to a broad spectrum of both common and rare metabolic diseases. However, clinical presentation is highly variable and only partially explained by the proportion of mutant mtDNA or heteroplasmy. With the relationship between mutation burden and clinical manifestation poorly defined, controlled models are required to uncover underlying mechanisms. Here, we explore the metabolic consequences of increasing heteroplasmy in a well-characterised mouse model harbouring a pathogenic mtDNA deletion. Untargeted urinary metabolomics reveals distinct mutation load-dependent metabolic shifts with some metabolites declining early on, while others exhibit threshold-like increases beyond ~ 60% mutation load - the level at which lactic acidemia and OXPHOS defects become apparent in this model. To assess translational relevance, we examined these heteroplasmy-associated metabolites in urine from patients carrying the most common mtDNA mutation, m.3243 A > G. Several of these metabolites were differentially expressed in patients relative to controls, with conserved directionality across species. Among these, 2-hydroxyisovalerate (2-HIVA), which was most strongly affected in the mouse model, also emerged as the top discriminator in patients. Receiver operating characteristic analysis indicated that urinary 2-HIVA has strong discriminatory power, supporting its potential utility as a biomarker for mtDNA-based disorders. These findings enhance our understanding of mtDNA-related disease pathophysiology and establish a foundation for further validation studies.
    Keywords:  2-Hydroxyisovalerate; Heteroplasmy; M.3243A > G; Metabolomics; Mito-mice; Mitochondrial disease; MtDNA
    DOI:  https://doi.org/10.1007/s11306-026-02518-1
  15. Hum Reprod Update. 2026 Aug 19. pii: dmag022. [Epub ahead of print]
    The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
    Brianna L Kline, Alison G Compton, Ann E Frazier, Svenja Pachernegg, Andrew H Sinclair, Katie L Ayers, Elena J Tucker.
       BACKGROUND: Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized.
    OBJECTIVE AND RATIONALE: A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction.
    SEARCH METHODS: We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026.
    OUTCOMES: Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs.
    WIDER IMPLICATIONS: This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI.
    REGISTRATION NUMBER: N/A.
    Keywords:  POI; genetics; infertility; mitochondria; mitochondrial disease; premature ovarian insufficiency
    DOI:  https://doi.org/10.1093/humupd/dmag022
  16. Phys Biol. 2026 Aug 17. 23(4):
    Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.
    Peyman Fahimi.
      Recent studies have suggested that under high or near-maximal mitochondrial respiratory activity, ion-translocating proteins within the inner mitochondrial membrane may generate transient nonequilibrium temperature fluctuations in the adjacent mitochondrial matrix and intermembrane space. Such nonequilibrium temperature fluctuations may, in principle, influence mitochondrial mechanics and morphology. Building on elastocapillary models of mitochondrial dynamics, we investigate whether these nonequilibrium temperature fluctuations can modulate the stability of mitochondrial tubules through temperature-dependent changes in effective membrane tension and elasticity. Our numerical analysis predicts that this effect is strongly threshold-dependent: in deeply unstable states, thermal modulation remains insufficient to restore stability, whereas closer to the threshold, temperature-dependent reduction of effective membrane tension can overcome temperature-dependent elastic softening, thereby increasing the elastocapillary number, suppressing unstable modes, and shifting mitochondria toward mechanically more stable tubular states. In other words, when mitochondria begin shifting toward fission-promoting states, elevated respiratory activity, which increases the magnitude and cumulative temporal occupancy of transient thermal perturbations, tends to shift the system back toward mechanical stability. However, when mitochondria are already far within the mechanically unstable regime, transient thermal activity is no longer sufficient to restore stability. This stabilizing regime is qualitatively consistent with experimental observations linking elevated oxidative phosphorylation to mitochondrial elongation, fusion, or hyperfusion rather than fragmentation.
    Keywords:  elastocapillary stability; membrane tension and elasticity; nonequilibrium thermodynamics; temperature fluctuations
    DOI:  https://doi.org/10.1088/1478-3975/ae934f
  17. Mol Genet Metab Rep. 2026 Sep;48 101348
    Severe mitochondrial cardiomyopathy with m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene: A study of large family analysis.
    Shuichi Yatsuga.
      The m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene is a rare cause of mitochondrial cardiomyopathy (MCM). We report a Japanese family with this variant across three generations, demonstrating a wide clinical spectrum ranging from asymptomatic carriers to lethal infantile cardiomyopathy. The proband was a newborn male infant who developed severe hypertrophic obstructive cardiomyopathy, generalized hypotonia, and profound lactic acidosis (43.9 mmol/L) shortly after birth. Despite intensive care, the patient died at 11 days of age due to multiorgan failure. Autopsy revealed diffuse cardiac hypertrophy and abnormal mitochondria. Genetic analysis showed 98% heteroplasmy of the m.3303C > T variant in multiple tissues. Family screening revealed variant loads ranging from 6% to 100% in seven relatives, with clinical manifestations only appearing when the variant load exceeded 90%. One maternal uncle with 100% muscle heteroplasmy died at the age of 7 years from mitochondrial myopathy. Other family members with variant loads below 90% were asymptomatic. This study demonstrates that the m.3303C > T variant exhibited, within this family, an exceptionally high threshold effect, with severe phenotypes manifesting only at very high heteroplasmy levels (>90%), and highlights the importance of family screening for genetic counseling.
    Keywords:  Heteroplasmy; Hypertrophic cardiomyopathy; Infantile cardiomyopathy; Lactic acidosis; M.3303C > T variant; Mitochondrial DNA; Threshold effect; tRNALeu(UUR)
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101348
  18. WIREs Mech Dis. 2026 Jul-Aug;18(4):18(4): e70014
    Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
    Rosa Di Lorenzo, Rola S Zeidan, Riccardo Calvani, Vito Pesce, Emanuele Marzetti, Anna Picca.
      Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.
    DOI:  https://doi.org/10.1002/wsbm.70014
  19. Neuromuscul Disord. 2026 Aug 13. pii: S0960-8966(26)01063-1. [Epub ahead of print]67 107395
    Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
    Madalena Couto, Mafalda Delgado Soares, Pedro Coelho, Rafael Roque, Marisa Brum.
      Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.
    Keywords:  MT-TS2 gene; Mitochondrial myopathy; Novel potentially pathogenic variant
    DOI:  https://doi.org/10.1016/j.nmd.2026.107395
  20. Methods Enzymol. 2026 ;pii: S0076-6879(26)00174-6. [Epub ahead of print]733 223-251
    Integrated SDH, COX histochemistry, and MHC fibre typing in skeletal muscles: Methods and interpretation.
    Aastha Munjal, Ridhi Singh, Ashwini Bhelave, Shwetha Sekar, Ninitha Asirvatham-Jeyaraj, Nagalingam R Sundaresan.
      Skeletal muscle plays a vital role in metabolic homeostasis, accounting for the majority of glucose uptake, lipid oxidation, and adaptive thermogenesis. Its plasticity enables rapid, controlled remodelling in response to exercise, nutrients, hormonal changes, ageing, and disease. This metabolic plasticity is due to fibre-type heterogeneity. Each muscle fibre has distinct contractile and bioenergetic properties. Sirtuins are known critical regulators of skeletal muscle mitochondrial content and oxidative metabolism. Sirtuins, are NAD+-dependent acetylases and deacetylases that regulate mitochondrial biogenesis, redox balance, and cellular response to stress. Thus, studying the role of sirtuins in muscle physiology requires assays that can identify metabolic and contractile phenotypes. In this chapter, we provide a comprehensive histochemistry protocol for succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) to assess mitochondrial oxidative capacity, and Myosin Heavy Chain (MHC) immunohistochemistry to assess fibre-type classification. Additionally, we have discussed detailed guidance for troubleshooting the critical steps of the protocol, including cryoinjury, tissue sectioning, staining optimisation, and imaging.
    Keywords:  COX; MHC immunohistochemistry; Metabolism; Mitochondria; Muscle fibre typing; SDH; Sirtuins; Skeletal muscles
    DOI:  https://doi.org/10.1016/bs.mie.2026.05.046
  21. Neurol Sci. 2026 Aug 20. pii: 719. [Epub ahead of print]47(9):
    Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.
    Li-Ping Zhao, Qi-Dong Tang, Qu Li.
      A 38-year-old man presented with long-standing bilateral ptosis and new-onset paroxysmal limb weakness, which improved transiently after steroid treatment. He developed lethargy after self-discontinuation of medication. Brain MRI revealed the classic giant panda sign in the midbrain. Elevated plasma lactate and lactate peak on MRS were detected. Genetic testing identified a 7424 bp large-scale mitochondrial DNA deletion, confirming the diagnosis of single large-scale mitochondrial DNA deletion syndrome. Although the giant panda sign is classically associated with Wilson's disease, this case highlights that this characteristic imaging finding warrants mitochondrial genetic screening in adults with ophthalmoplegia and hyperlactatemia.
    Keywords:  Giant panda sign; Magnetic resonance imaging; Single Large-Scale Mitochondrial DNA Deletion Syndrome
    DOI:  https://doi.org/10.1007/s10072-026-09325-5
  22. J Neuropathol Exp Neurol. 2026 Aug 19. pii: nlag057. [Epub ahead of print]
    When muscles matter in SORD neuropathy.
    Heike Kölbel, Andreas Hentschel, Corinna Preuße, May Tiet, Maike F Dohrn, David Muhmann, Jelle van den Ameele, Lei Chen, Ulrike Schara-Schmidt, Joachim Weis, Rita Horvath, Alexander Mensch, Andreas Roos.
      Biallelic pathogenic variants in SORD (Sorbitoldehydrongenase gene), encoding sorbitol dehydrogenase, are a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (CMT2). Recent evidence suggests direct involvement of skeletal muscle in addition to peripheral nerve degeneration. We investigated muscle biopsies from 4 genetically confirmed CMT-SORD patients using an integrative approach. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, ie, non-specific neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum (SR). Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement and immunomodulatory factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodeling. Despite mitochondrial vulnerability, serum studies indicated that GDF-15 and FGF-21 did not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as intrinsic myopathic features of SORD-related CMT2. They indicate the need for therapeutic strategies targeting both neuronal and muscular compartments.
    Keywords:  SORD neuropathy; denervation-induced atrophy; mitochondrial stress; polyol pathway; skeletal muscle metabolism
    DOI:  https://doi.org/10.1093/jnen/nlag057
  23. Redox Biol. 2026 Aug 13. pii: S2213-2317(26)00350-2. [Epub ahead of print]96 104351
    Inhibition of mitochondrial complex III causes selective dopaminergic neurotoxicity by redox stress in Caenorhabditis elegans.
    Javier Huayta, Aliyah S Webster, Jay Jhaver, Joel N Meyer.
      Environmental factors including chemical exposures are important contributors to Parkinson's disease (PD). Nearly all well-validated chemicals involved in PD affect mitochondria, and the great majority of those identified inhibit mitochondrial complex I, causing ATP depletion and oxidative stress. We hypothesized that inhibition of mitochondrial complex III would also cause dopaminergic neurotoxicity. Using Caenorhabditis elegans to evaluate the in vivo effects of complex III-inhibiting pesticides antimycin A and pyraclostrobin, we found that both caused selective dopaminergic neurotoxicity. We evaluated exacerbation of dopaminergic neurotoxicity by the presence of α-synuclein, and pdr-1/PRKN and pink-1/PINK1 mutant backgrounds and found increased neurotoxicity for pdr-1. Complex III inhibition caused a more-oxidized cellular environment in those neurons and pharmacological and genetic antioxidant interventions rescued neurotoxicity, but energetic rescue attempts did not. Finally, optogenetic production of superoxide anion specifically at complex III caused dopaminergic neuronal damage. Thus, redox stress at complex III following chemical exposure causes dopaminergic neurotoxicity in vivo in C. elegans.
    DOI:  https://doi.org/10.1016/j.redox.2026.104351
  24. bioRxiv. 2026 Jul 28. pii: 2026.07.24.740574. [Epub ahead of print]
    Nocturnin drives mitochondrial NADP(H)/NAD(H) rhythms to regulate steroid rhythm amplitude and time metabolism.
    Lauren Palluth, Isara Laothamatas, Tammy-Nhu Nguyen, Emil S Rasmussen, Lauren G Zacharias, Mauricio J Velasquez, Melissa Iñigo-Vollmer, Xiaorong Fu, Thomas P Mathews, Jeffrey G McDonald, Shawn C Burgess, Joseph S Takahashi, Carla B Green.
      Circadian rhythms are conserved biological timekeeping mechanisms crucial for the temporal compartmentalization of metabolic processes. However, the molecular pathways by which circadian rhythms are regulated within metabolism are not fully understood. Nocturnin (NOCT) is a highly rhythmic, clock-controlled NADP(H) phosphatase that has been implicated in numerous metabolic phenotypes. While it is known that NOCT significantly impacts the cellular NADP(H) and NAD(H) pools in vitro , NOCT's impact on their concentrations and rhythmicity in vivo has not yet been established. In fact, the rhythmicity of NADH, NADP + , and NADPH have yet to be quantified in mammalian nucleated cells. Here, we determined both the whole cell and mitochondrial NAD(H) and NADP(H) rhythms in wild-type and Noct -/- mouse livers. Unexpectedly, we found a robust rhythm in the mitochondrial NADP(H)/NAD(H) ratio that is antiphase to the respective whole cell rhythm. While loss of NOCT increases the amplitude of the whole cell NADP(H)/NAD(H) rhythm, the mitochondrial rhythm is completely damped in Noct -/- mice. The constitutively higher relative NADP(H) within Noct -/- mitochondria drives steroidogenesis, leading to an increased amplitude of plasma corticosterone. Both the acute increase in plasma corticosterone and the disruption of mitochondrial cofactor rhythms caused by loss of NOCT lead to widespread changes in hepatic metabolism. Collectively, we found that NOCT's control of mitochondrial NADP(H)/NAD(H) rhythms is a novel regulator of steroid amplitude and downstream metabolic rhythms.
    DOI:  https://doi.org/10.64898/2026.07.24.740574
  25. Cell Rep. 2026 Aug 18. pii: S2211-1247(26)00954-X. [Epub ahead of print]45(9): 117876
    Dynamic S-acylation of IDH2 regulates mitochondrial redox homeostasis.
    Chen Miao, Zhen Wang, Jian Lin, Ziye Zhu, Jinan Wang, Baoen Chen.
      Mitochondrial redox homeostasis is fundamental for cellular function, and its dysregulation is associated with various diseases, including cancer. Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains this balance by generating NADPH. However, the mechanisms controlling IDH2 subcellular localization remain incompletely understood. Here, we identify reversible S-acylation as a critical regulator of IDH2 localization. Using chemical reporters, we demonstrate that IDH2 is S-acylated at a conserved cysteine residue, mediated by ZDHHC3 and APT1. Loss of IDH2 S-acylation disrupts its mitochondrial localization by reducing its interaction with the mitochondrial import receptor TOMM20, leading to NADPH deficiency, redox imbalance, and impaired oxidative phosphorylation. Consistently, ZDHHC3 knockout phenocopies IDH2 S-acylation deficiency, impairing its mitochondrial localization and function. Genetic ablation of IDH2 S-acylation suppresses tumor growth in vitro and in vivo. Our work establishes dynamic S-acylation of IDH2 as an essential regulator of mitochondrial redox homeostasis, thereby revealing a potential metabolic vulnerability in cancer.
    Keywords:  APT1; CP: molecular biology; IDH2; S-acylation; ZDHHC3; breast cancer; metabolic reprogramming; mitochondrial localization; palmitoylation; protein lipidation; redox homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117876
  26. J Huntingtons Dis. 2026 Aug 17. 18796397261478163
    Mitochondrial dynamics in Huntington's disease.
    Beatriz Paiva, Ana Cristina Rego.
      Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.
    Keywords:  mitochondria; mitophagy; neurotoxicity; pathogenic mechanisms; preclinical models
    DOI:  https://doi.org/10.1177/18796397261478163
  27. Int J Biol Macromol. 2026 Aug 17. pii: S0141-8130(26)04036-5. [Epub ahead of print]380 154090
    Structural bases of the conformational transitions of the mitochondrial choline carrier SLC25A48 captured by molecular dynamics simulations.
    Virginia Quadrotta, Beatrice Gasperini, Andrea Pasquadibisceglie, Fabio Polticelli.
      The mitochondrial choline carrier SLC25A48 mediates choline import into the mitochondrial matrix, supporting one‑carbon metabolism and epigenetic regulation. Despite its physiological relevance, the structural determinants of substrate recognition and conformational transitions remain poorly characterized. Here, the conformational dynamics of human SLC25A48 was investigated using deep-learning-based structure prediction combined with multiple extensive molecular dynamics simulations in a realistic mitochondrial membrane environment. Structural models representing the cytoplasmic-open (c-state), occluded and matrix-open (m-state) conformations were generated and used as starting points for MD simulations, for a total of 21 μs. Unbiased simulations captured spontaneous, bidirectional transitions between the occluded and m-state, confirmed by structural convergence and comparison with available crystal structures, and shown to remain well separated in a distinct descriptor space by a supervised classifier (LDA). Transitions were driven by an asymmetric rearrangement primarily involving Domain I, while the remaining helices behaved as a rigid scaffold, consistent with mechanistic features described for other SLC25 carriers. A matrix-side loop, whose dynamics correlated with this asymmetry, adopted distinct capping and opening conformations across states, suggesting a complementary gating role. Choline remained stably coordinated throughout the transition, indicating that the conformational change corresponds to the opening step of the transport cycle rather than substrate release. Context-dependent lipid interactions were also observed, affecting ligand position or carrier conformation. These results provide mechanistic insight into SLC25A48 conformational plasticity and a structural framework, with candidate collective variables, to guide future investigation of mitochondrial choline transport.
    Keywords:  Conformational transitions; Gating mechanism; M2 loop; Mitochondrial carrier; Mitochondrial choline carrier; Molecular dynamics simulations; SLC25; SLC25A48
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154090
  28. bioRxiv. 2026 Jul 31. pii: 2026.07.28.741372. [Epub ahead of print]
    The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy.
    Marta W Szulik, Clint Gwynn, Magnus Creed, Lina Gonzalez, Sarah Franklin.
      Infantile cardiomyopathies are rare, life-threatening disorders for which genetic diagnosis has been accelerated by next-generation sequencing approaches, including gene panel, exome, and genome sequencing. However, determining the functional consequences of identified variants remains a major challenge. Variants in SMYD1, a striated muscle-specific lysine methyltransferase critical for cardiac development and mitochondrial function, have only recently been linked to human cardiomyopathy. Here, we functionally characterize a homozygous SMYD1 variant (c.302A>G; p.Asn101Ser) identified in a patient with severe early-onset cardiomyopathy requiring cardiac transplantation. Structural modeling predicts that the N101S substitution perturbs a highly conserved residue near the cofactor binding pocket within SMYD1s catalytic domain, disrupting local interactions and modestly destabilizing the protein. Consistent with these predictions, in vitro studies demonstrate that the N101S variant impairs mitochondrial respiratory capacity in myocytes. Quantification of SMYD1 protein levels in patient cardiac tissue revealed increased SMYD1 abundance, suggesting that the N101S variant results in functional impairment rather than protein instability and may trigger compensatory upregulation of SMYD1 expression. Together, these findings support a hypomorphic mechanism in which the N101S variant disrupts SMYD1 activity, leading to mitochondrial dysfunction and cardiomyopathy. This study provides mechanistic insight into SMYD1-associated cardiomyopathy and highlights the importance of integrating genetic, structural, and functional analyses to establish the pathogenicity of rare variants.
    DOI:  https://doi.org/10.64898/2026.07.28.741372
  29. Nat Metab. 2026 Aug 20.
    The hallmarks of skeletal muscle health.
    Anna Vainshtein, Bert Blaauw, Katrien De Bock, Pura Munoz-Canoves, Eric N Olson, Coen A C Ottenheijm, Erik A Richter, Jorge L Ruas, Laurent Schaffer, Bruce Spiegelman, Marco Sandri.
      Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.
    DOI:  https://doi.org/10.1038/s42255-026-01595-9
  30. Signal Transduct Target Ther. 2026 Aug 17. pii: 332. [Epub ahead of print]11(1):
    Fructose directly remodels the translocase of the outer membrane to impair oxidative phosphorylation in podocytes.
    Wenyuan Wu, Wenhe Wang, Jingzi Zhang, Qiongdan Liang, Nannan Wang, Li Chen, Chengzhi Wang, Jiahuang Li, Yiyang Cong, Hao Hong, Xu Cheng, Maojun Yang, Lei Fang, Lingdong Kong.
      Excessive dietary fructose consumption contributes to the rapidly increasing prevalence of obesity, metabolic syndrome, and chronic kidney disease worldwide, and accumulating preclinical evidence has confirmed that excess fructose exposure provokes severe mitochondrial dysfunction, which serves as a critical upstream driver of progressive metabolic disturbance and renal tissue injury. Conventionally, fructose-induced mitochondrial damage is thought to originate from harmful intermediate metabolites produced during intracellular fructose catabolism, while the potential direct pathogenic effect of intact unmetabolized fructose is largely overlooked. It remains unclear whether free fructose can directly target core mitochondrial complexes to initiate functional defects independent of its metabolic breakdown. Here, we report a fructose metabolism-independent mechanism in which fructose structurally remodels the translocase of the outer membrane (TOM) complex, obstructing the import of nuclear-encoded mitochondrial proteins and inhibiting mitochondrial ribosome biogenesis as well as oxidative phosphorylation. In vitro biochemical assays confirm that fructose non-covalently binds to TOM22 and induces subtle but functionally critical conformational changes in the TOM complex, thereby blocking the transmembrane translocation of mitochondrial ribosome subunits. Notably, disrupting the fructose-TOM22 binding efficiently recovers abnormal ribosome trafficking, restores compromised oxidative phosphorylation, and ameliorates mitochondrial dysfunction and glomerular pathological lesions in fructose-treated podocytes and mouse injury models. Our findings establish an innovative mechanistic paradigm that fructose acts as a direct allosteric modulator of mitochondrial membrane complexes, identifying TOM structural remodeling as a previously unrecognized molecular trigger of fructose-associated mitochondrial and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41392-026-02896-x
  31. Ageing Res Rev. 2026 Aug 20. pii: S1568-1637(26)00304-1. [Epub ahead of print]122 103312
    Mitochondrial dysfunction in neurodegenerative diseases: Mechanisms and therapeutic advances.
    Zhaomin Yao, Yangwa Wei, Weiming Xie, Rui Gao, Ying Zhan, Xiaodan Wu, Wei Zhang, Yusong Pei, Guoxu Zhang, Zhiguo Wang.
      Neurodegenerative diseases associated with ageing are characterized by progressive neuronal dysfunction and loss, yet effective disease-modifying therapies remain elusive. Increasing evidence indicates that mitochondrial dysfunction is not merely a downstream consequence of neurodegeneration but represents an early and active driver of disease initiation and progression. This review addresses this critical gap by establishing an integrated framework that systematically connects mechanistic insights with translational applications. We demonstrate that mitochondrial impairment precedes classical neuropathological hallmarks, thereby positioning mitochondrial dysfunction as a primary driver rather than a secondary consequence of neurodegeneration. Through comprehensive analysis of disease-specific molecular signatures, we reveal how distinct mitochondrial regulatory failures converge on common downstream pathways: bioenergetic collapse through respiratory chain complex deficiencies, oxidative stress amplification via mitochondrial DNA damage and reactive oxygen species overproduction, calcium dysregulation, and compromised quality control through impaired mitophagy. Critically, we integrate emerging evidence demonstrating bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation, establishing a self-perpetuating pathogenic loop that accelerates disease progression. By synthesizing advances in multi-omics profiling, single-cell resolution analyses, and in vivo imaging biomarkers, we provide a systems-level perspective that transcends reductionist single-pathway models. Furthermore, we critically evaluate the translational landscape of mitochondria-targeted interventions, encompassing pharmacological agents with defined molecular targets, gene therapy approaches addressing mitochondrial DNA mutations, and lifestyle modifications promoting systemic metabolic resilience. Our comparative analysis reveals complementary mechanistic profiles and practical limitations across these modalities, supporting an integrated therapeutic paradigm that combines broad metabolic optimization with precision targeting of specific mitochondrial defects.
    Keywords:  Mitochondrial Dysfunction; Neurodegenerative Diseases; Neuronal Health; Oxidative Stress; Therapeutic Strategies
    DOI:  https://doi.org/10.1016/j.arr.2026.103312
  32. J Vis Exp. 2026 Aug 04.
    Measuring the Effects of Pharmacological Compounds on Mitochondrial Morphology in Mouse Aging Models.
    Wayne Mitchell, Cecília G de Magalhães, Praju Vikas Anekal, Vadim N Gladyshev.
      Aging-related molecular damage accumulation can contribute to changes in mitochondrial morphology and metabolic dysfunction, particularly in tissues with high energy expenditures. Pharmacological compounds that ameliorate metabolic dysfunction and restore healthy, 'young' mitochondrial morphologies may thus represent effective modalities to extend healthspan (i.e., the portion of one's lifespan free from the burden of aging-related chronic disease) in mammals. Herein, methods for performing subcutaneous osmotic pump implantations in aged mice for the stable delivery of hydrophobic pharmacological compounds are described. Then, tissues are fixed, cryosectioned, stained, and imaged using super-resolution confocal light microscopy. Finally, an automated pipeline for the three-dimensional segmentation, classification, and quantitative measurement of mitochondrial structures is presented. Thus, these methods may be useful for quantitatively assessing changes in mitochondrial three-dimensional structure in different tissues across the mouse lifespan. Moreover, these techniques may aid in the reproducible identification of small-molecule drugs that mitigate aging-related metabolic dysfunction.
    DOI:  https://doi.org/10.3791/71930
  33. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 853-859
    Novel Variants in Mitochondrial Ribosomal RNA Genes MT-RNR1 and MT-RNR2 Identified in Hereditary Optic Neuropathy Initially Presenting as Normal Tension Glaucoma: A Case Report.
    Amanda Tran, Jonathan Micieli.
       Introduction: Hereditary optic neuropathy may be caused by various mitochondrial or nuclear DNA mutations affecting the mitochondrial function. A growing body of evidence shows that mutations in non-classical mitochondrial genes, including the ribosomal RNA genes MT-RNR1 and MT-RNR2, have been reported in patients with hereditary optic neuropathy, although their pathogenicity remains uncertain. Herein, we report a case initially diagnosed as normal tension glaucoma in which whole mtDNA sequencing identified 2 novel variants in MT-RNR1 and MT-RNR2.
    Case Presentation: A 36-year-old man was referred for glaucoma assessment but was found to have bilateral symmetric temporal optic disc pallor and retinal nerve fibre layer thinning that was inconsistent with a glaucomatous pattern. Intraocular pressure (IOP), Humphrey visual fields, colour vision, and pupillary responses were normal. Genetic testing was negative for the 3 primary Leber's hereditary optic neuropathy (LHON) mutations but identified MT-RNR1:m.990T>C and MT-RNR2:m.2619A>G, both at 99.5% heteroplasmy and classified as ACMG class 3. Visual function remained stable at 6-month follow-up.
    Conclusion: Neither MT-RNR1 and MT-RNR2 variants could be definitively linked to the hereditary optic neuropathy in this patient, and they are best regarded as findings of uncertain significance. This case highlights a diagnostic pitfall as non-glaucomatous optic disc pallor can be mistaken for normal tension glaucoma and underscores the diagnostic value of whole mtDNA sequencing when primary LHON screening is negative.
    Keywords:  Hereditary optic neuropathy; MT-RNR1; MT-RNR2; m.2619A>G; m.990T>C
    DOI:  https://doi.org/10.1159/000553606
  34. Autophagy. 2026 Aug 16.
    Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
    Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.
      How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in macroautophagy/autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals > 65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by promoting autophagosome generation through TFEB, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Partial organelle recovery occurred after inducing mitophagy or inhibiting mitochondrial fission. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in mitochondria-intrinsic mechanisms to avoid loss of energy production.
    Keywords:  Aging; TFEB; autolysosome; dynamics; live-cell; longitudinal; mitochondria; mitophagy; neuronal
    DOI:  https://doi.org/10.1080/15548627.2026.2719435
  35. Pediatrics. 2026 Aug 21. pii: e2026076450. [Epub ahead of print]
    The Need for Clinical Diagnostic Proficiency in the Genomic Era.
    Salomon Vainstein, Joe Chan, Michael E March, Minjie Luo, Laura Conlin, Joseph Glessner, Dong Li, Charlly Kao, Margaret Harr, Caitlin Menello, Rebecca C Ahrens-Nicklas, Elizabeth B Rand, Elaine H Zackai, Lisa Guay Woodford, Kai Wang, Jessica I Gold, Nina B Gold, Alanna Strong.
      
    DOI:  https://doi.org/10.1542/peds.2026-076450
  36. Hum Mol Genet. 2026 Aug 10. pii: ddag080. [Epub ahead of print]35(17):
    Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.
    Paola Zanfardino, Alessandro Amati, Sharon Cox, Gennaro Agrimi, Stefano Doccini, Patricio Fernández-Silva, Apollonia Tullo, Jessica Rosati, Filippo M Santorelli, Vittoria Petruzzella.
      Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare autosomal recessive neuropathy caused by mutations in the MTMR5/SBF1 gene. In this study, we characterized dermal fibroblasts derived from a patient carrying compound-heterozygous MTMR5/SBF1 variants (R763H/G1064E) and identified alterations affecting mitochondrial metabolism and cellular stress pathways. Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved. In line with our previous evidence of enhanced mitophagy, these findings support the presence of altered mitochondrial quality control. The reduction in cellular energy production was not accompanied by increased glycolytic activity, indicating a metabolically quiescent phenotype. Transcriptomic profiling revealed dysregulation of the PI3K/AKT signalling pathway. AKT phosphorylation at Ser473 was increased in the absence of complete canonical AKT activation. These signalling changes were associated with increased expression of p53 and p21 and with features consistent with premature cellular senescence. Overall, our findings identify metabolic quiescence and premature senescence as previously unrecognized aspects of CMT4B3 cellular pathology and suggest that altered coordination between mitochondrial metabolism and intracellular signalling may contribute to disease pathogenesis.
    Keywords:  Charcot–Marie–tooth disease type 4B3; MTMR5/SBF1; mitochondria; oxidative phosphorylation; senescence; transcriptomics
    DOI:  https://doi.org/10.1093/hmg/ddag080
  37. Front Neurosci. 2026 ;20 1927695
    Mitochondrial-neuroimmune interfaces in post-stroke spasticity: from acute brain injury to chronic motor phenotypes.
    Zihang Huang.
      Post-stroke spasticity is a common and clinically consequential manifestation of the upper motor neuron syndrome, yet its mechanisms are incompletely explained by stretch reflex hyperexcitability alone. Established models emphasize corticospinal and corticoreticulospinal injury, altered brainstem descending drive, spinal reflex amplification, impaired inhibitory control, and secondary changes in skeletal muscle and connective tissue. In parallel, stroke induces profound mitochondrial stress and neuroimmune activation, including bioenergetic failure, mitochondrial reactive oxygen species production, mitochondrial quality-control disturbance, mitophagy dysregulation, mitochondrial danger signaling, glial activation, blood-brain barrier dysfunction, and peripheral immune responses. This Review examines how these mitochondrial-neuroimmune processes may interface with established neural and peripheral mechanisms to shape the onset, persistence, and heterogeneity of post-stroke spasticity. We distinguish strict reflex-mediated spasticity from broader spastic hypertonia, emphasizing that chronic clinical phenotypes often reflect mixed contributions from descending pathway imbalance, spinal disinhibition, spastic dystonia, passive muscle stiffness, pain, and contracture. We propose a brain-spinal cord-muscle framework in which mitochondrial and immune responses after stroke may modify motor-network plasticity, spinal inhibitory remodeling, skeletal muscle metabolism, autophagy-related tissue adaptation, and systemic inflammatory-metabolic vulnerability. Direct PSS-specific evidence remains limited. Accordingly, mitochondrial and neuroimmune pathways are framed here as candidate modifiers of phenotype trajectory rather than as established causes, validated biomarkers, or established therapeutic targets for PSS. The novelty of this Review lies in integrating established circuit and muscle mechanisms with broader stroke mitochondrial-immune biology to define testable interfaces and priorities for longitudinal phenotyping and mechanism-based trials.
    Keywords:  mitochondria; mitochondrial quality control; neuroimmune signaling; neuroinflammation; post-stroke spasticity; reticulospinal tract; skeletal muscle remodeling; spinal inhibition
    DOI:  https://doi.org/10.3389/fnins.2026.1927695
  38. ASN Neuro. 2026 ;18(1): 2717255
    When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.
    Aradhika Vijeev, Shaik Basha, Spandana S Nadig, Kripa Agarwal, Vibhuti Meharchandani, Aparna Ramakrishna Pai, Krishna Kishore Mahato.
      Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically heterogeneous group of rare movement disorders characterized by progressive neurodegeneration and selective basal ganglia iron deposition. Recent discoveries have fundamentally reshaped the understanding of NBIA, indicating that defects in coenzyme A metabolism, mitochondrial bioenergetics, lipid remodeling, autophagy-lysosomal pathways, and ferroptosis precede and promote secondary iron dyshomeostasis rather than resulting from primary abnormalities in iron metabolism. This review integrates recent mechanistic and translational evidence (2020-2026) across both common and underrepresented NBIA subtypes, including pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, COASY protein-associated neurodegeneration, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, β-propeller protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, neuroferritinopathy, and mitochondrial DNA-associated forms. Unlike previous reviews, this synthesis consolidates findings from patient-derived induced pluripotent stem cell neuronal and glial models, compartment-specific iron localization, advanced neuroimaging biomarkers, and emerging therapeutic strategies within a unified mechanistic framework. Collectively, the evidence supports a paradigm in which mitochondrial dysfunction and lipid metabolic failure initiate disease progression, whereas iron accumulation amplifies oxidative injury and lipid peroxidation, thereby increasing ferroptotic cell death and neuronal degeneration, providing an updated foundation for biomarker discovery, mechanistically informed therapeutic development, and precision medicine approaches in NBIA.
    Keywords:  Coenzyme A metabolism; ferroptosis; mitochondrial dysfunction; neurodegeneration with brain iron accumulation (NBIA); precision medicine
    DOI:  https://doi.org/10.1080/17590914.2026.2717255
  39. Chem Sci. 2026 Aug 17.
    A head-to-tail dimeric J-aggregate probe for rapid and ratiometric imaging of mitochondrial 5-HT via dual-anchoring.
    Chenming Chan, Yujie Han, Yu-Fei Song, Qi-Wei Zhang.
      The precise role of 5-hydroxytryptamine (5-HT) in depression remains mechanistically unresolved. While synaptic deficits dominate the monoamine hypothesis, emerging evidence points to mitochondrial dysfunction as a key factor. However, progress has been hindered by the lack of tools capable of directly, specifically, and quantitatively tracking real-time 5-HT dynamics within mitochondria. Here, we present FPY, a ratiometric fluorescent probe featuring unique head-to-tail dimeric J-aggregation via F-π interactions. FPY operates via a synergistic covalent-noncovalent dual-mode-anchoring mechanism, producing a near-infrared-to-visible ratiometric fluorescence response toward 5-HT with superior selectivity, a low detection limit (7.68 nM), and rapid kinetics (1.54 s). Leveraging its intrinsic mitochondrial localization, we achieve the first real-time visualization and ratiometric quantification of mitochondrial 5-HT dynamics in neurons. Critically, we reveal significant 5-HT depletion across key brain regions in a murine depression model and provide direct molecular evidence that the therapeutic action of monoamine oxidase inhibitors involves restoration of mitochondrial 5-HT pools, revealing a strong correlation between mitochondrial 5-HT dysregulation and depressive pathophysiology. This study provides fundamental insights into depression and introduces a novel covalent-noncovalent dual-anchoring strategy for advanced molecular probe design.
    DOI:  https://doi.org/10.1039/d6sc05216a
  40. Structure. 2026 Aug 20. pii: S0969-2126(26)00224-8. [Epub ahead of print]
    Morphotype-resolved 3D morphometry reveals a structure-density-location coupling in mitochondrial networks.
    Anshu Singh, Arun Yadav, Aneesh Deshmukh, Arjun Singh, Riva Verma, Kate White, Jitin Singla.
      Mitochondrial architecture plays a critical role in cellular function, yet how organelle structure, metabolic density, and subcellular position are jointly remodeled across whole cells remains poorly understood. We applied quantitative 3D soft X-ray tomography to analyze intact INS-1E cells in a native, cryo-hydrated state. By integrating morphometric profiling with voxel-level linear absorption coefficients (LACs) and contour-based radial mapping, we tracked the structural, biochemical, and spatial remodeling of fragmented, intermediate, and interconnected mitochondrial morphotypes under high glucose and Exendin-4 stimulation. High glucose induces morphotype-specific hypertrophy, fission, and perinuclear redistribution of low-density fragments. Co-stimulation with Exendin-4 stabilizes interconnected networks and increases metabolic density at the cell periphery. Morphotype-resolved analysis uncovers a structure-density-location coupling in which mitochondrial shape, macromolecular packing, and radial position shift in concert. These results offer a quantitative framework and high-resolution spatial constraints for whole-cell modeling of organelle dynamics.
    Keywords:  contour; exendin-4; linear absorption coefficient; mitochondrial morphometric analysis; molecular density; morphology; morphotypes; pancreatic β-cell; soft X-ray tomography; spatiotemporal distribution
    DOI:  https://doi.org/10.1016/j.str.2026.07.014
  41. Am J Physiol Cell Physiol. 2026 Aug 18.
    AMITO: An open-access application for assisted analysis of mitochondria in transmission electron microscopy images.
    Elyse Hucteau, Thomas J Hureau, Allan F Pagano, Joris Mallard.
      Analysis of mitochondrial morphology and ultrastructure from transmission electron microscopy (TEM) images is essential for understanding cellular adaptations in both physiological and pathological conditions. However, these investigations remain time-consuming, poorly standardized and therefore highly variable. We developed an open-access, standalone MATLAB-based application (AMITO) that can be run without license and integrates analyses within a single user-friendly interface. AMITO demonstrated excellent agreement with conventional manual image analysis software, high intra- and inter-experimenter reproducibility, and substantial reduction in analysis time. Therefore, AMITO provides a reliable, efficient, and accessible tool to ensure robustness and reproducibility in mitochondrial assessment.
    Keywords:  Matlab; TEM; image segmentation; mitochondrial morphology; muscle
    DOI:  https://doi.org/10.1152/ajpcell.00300.2026
  42. Mol Cell. 2026 Aug 21. pii: S1097-2765(26)00517-4. [Epub ahead of print]
    Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.
    Lisa A Vettore, Adam Boufersaoui, Yingying Lyu, Anaïs Oudin, Keene L Abbott, Sonu Subudhi, Yetiş Gültekin, Katherine L Eales, Ishana Rajgopal, Cristina Escribano-Gonzalez, Rahatil A Chowdhury, Himani Rana, Victoria Wykes, Rakesh K Jain, Anna Golebiewska, Matthew G Vander Heiden, Daniel A Tennant.
      Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent generation of mitochondrial NADPH is important for proline accumulation, maintenance of antioxidant systems, and reductive metabolism in hypoxic glioma cells in vitro and tumor progression in vivo. Collectively, these results highlight proline accumulation as a marker of mitochondrial NAD(P)(H) homeostasis and NNT as a specific metabolic dependency in human glioma.
    Keywords:  NNT; glioma; hypoxia; proline; redox
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.031
  43. Adv Healthc Mater. 2026 Aug 16. e71510
    Stem Cell-Derived Mitochondria-Enriched Preservation Solutions as Organelle-Based Therapeutic Strategy for Cold Storage of Liver and Kidney.
    Fang Lin, Jianxin Jiang, Jing Liu, Yue Ding, Kexin Ma, Jiyuan Wang, Xueyang Zheng, Yu Chen, Shu Han, Xiaoting Liang.
      Organ preservation remains a critical challenge in transplantation, primarily due to hypothermia-induced oxidative stress and metabolic dysfunction. Here, we report a mitochondria-enriched, cell-free preservation strategy by supplementing standard preservation solutions with freshly isolated mitochondria derived from human induced pluripotent stem cell-mesenchymal stem cells (MSC-mt). MSC-mt retained intact ultrastructure and functional biophysical properties. In vitro, MSC-mt were internalized by hepatocyte- and kidney-derived cells, reduced oxidative stress, preserved ATP levels, and attenuated apoptosis under cold stress. Ex vivo, MSC-mt improved liver preservation in University of Wisconsin (UW) solution, reducing sinusoidal edema, apoptosis, ALT/AST release, MDA accumulation, and oxidative DNA damage while enhancing SOD activity and preserving mitochondrial content. Human-specific mitochondrial signals remained detectable within preserved hepatic tissue. In a warm reoxygenation model, MSC-mt enhanced ATP recovery and reduced tissue injury and oxidative damage following cold storage. In kidneys, MSC-mt provided stronger protection than fibroblast- or adipose-derived mitochondria across both HC-A and UW solutions. Mechanistically, MSC-mt showed higher total and phosphorylated PINK1 levels and greater Parkin co-localization than fibroblast-derived mitochondria, while mitophagy inhibition partially reversed their antioxidant effects. These findings establish MSC-mt as a cell-free mitochondrial strategy for improving hypothermic organ preservation.
    Keywords:  liver preservation; mesenchymal stem cell‐derived mitochondria; organ preservation; renal preservation
    DOI:  https://doi.org/10.1002/adhm.71510
  44. Mol Neurobiol. 2026 Aug 17. pii: 838. [Epub ahead of print]63(1):
    Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.
    Ya-Ning Wang, Xing Wang, Qin Huang, Yun Yang, Tao Wang, Xin-Hui Qu, Xiao-Jian Han.
      M itochondria act as the energetic hub of eukaryotic cells, orchestrating cellular energy metabolism via oxidative phosphorylation and the tricarboxylic acid (TCA) cycle, thereby subjecting them to continuous environmental stress. To address these challenges, mitochondria have developed a sophisticated array of quality-control mechanisms that provide adaptive resilience. These quality-control pathways encompassing mitochondrial biogenesis, dynamic remodeling, and mitophagy collectively safeguard cellular homeostasis. Among them, mitophagy plays a continuous role in surveying, identifying, and eliminating dysfunctional mitochondria, thereby preserving the integrity of the mitochondrial network and ensuring optimal bioenergetic function. When mitophagy is dysregulated, a cascade of protein homeostatic collapse and metabolic failure ensues, disrupting physiological cellular processes. Moreover, mitophagy plays a role in the development and progression of various pathologies, including neurodegenerative disorders, cardiovascular diseases, and cancer. In the context of neurodegeneration, aberrant mitophagy aggravates disease progression at the molecular, organellar, and cellular levels. Given that neuronal metabolism critically relies on oxidative phosphorylation, which primarily occurs within mitochondria, mitochondrial functional integrity directly determines neuronal energy supply and physiological capacity. Consequently, impaired mitophagy has been identified as a key determinant in the etiology of neurodegenerative diseases. This review systematically elucidates the key molecular mechanisms regulating mitophagy and how these mechanisms contribute to the onset and progression of neurodegenerative diseases. It also summarizes potential therapeutic agents targeting mitophagy to improve neurodegenerative disorders.
    Keywords:  Mitochondria; Mitophagy; Neurodegenerative diseases; SUMOylation; Ubiquitination
    DOI:  https://doi.org/10.1007/s12035-026-06104-3
  45. bioRxiv. 2026 Jul 29. pii: 2026.07.27.740961. [Epub ahead of print]
    A human cytokine response atlas to reconstruct underlying gene regulatory networks.
    Patrick O'Connell.
      Circulating cytokines encode immune state, yet their pleiotropy and cell-type specificity make constructing a unified atlas of immune cell responses to them challenging. Here, I transformed a single-cell atlas of approximately 10 million human peripheral blood mononuclear cells from 12 donors exposed to 90 cytokines into a multiscale model of cytokine response. A GPU-accelerated implementation of dimension-scalable single-cell perturbation integration network (D-SPIN) allowed for the creation of a signed, directed model of 9.6 million cells, 1,634 immune regulatory genes, and 40 cellular programs. The gene networks and cellular programs span canonical cytokine pathways and lineage relationships and delineated cytokine-specific activation and repression across immune states. Beyond established circuitry, the model nominated candidate regulatory interactions and identified the mitochondrial antioxidant SOD2 as a prominent hub of innate immune cell signaling. Next, I developed CytoCarto, a web application that projects cytokine profiles onto these networks to prioritize dysregulated programs, candidate effector genes, cellular contexts, and disease-associated signatures. In a proof-of-concept analysis I input the cytokine profile of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) undergoing an episode of sterile inflammation and found CytoCarto prioritized metabolically reprogrammed monocytes and SOD2 , consistent with a role for mitochondrial redox signaling in innate immunity.
    DOI:  https://doi.org/10.64898/2026.07.27.740961
  46. Biomed Mater. 2026 Aug 18. 21(4):
    Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.
    Jiaenli Bolati, Junjie Yang, Yueqi Yan, Donghua Yu, Chunmiao Yu.
      Mitophagy is a selective autophagic process responsible for the elimination of damaged or dysfunctional mitochondria, playing a critical role in maintaining mitochondrial quality control and cellular homeostasis. Dysregulated mitophagy has been implicated in the pathogenesis of numerous diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, inflammatory and immune diseases, and musculoskeletal diseases. In recent years, nanotechnology-based approaches for the targeted modulation of mitophagy have emerged as promising therapeutic strategies due to their ability to achieve precise regulation, enhanced subcellular targeting, and reduced off-target effects. Building upon advances in the understanding of mitophagy mechanisms, a variety of nano-delivery systems have been developed, incorporating strategies such as mitochondria-targeting, stimuli-responsive activation, ligand-mediated targeting, and combination therapies. However, a comprehensive review integrating the molecular mechanisms of mitophagy, disease-specific therapeutic applications, nanoplatform design strategies, and translational challenges remains lacking. The present review provides an integrated overview of the molecular regulatory mechanisms of mitophagy, summarizes recent advances in nanotechnology-based therapeutic interventions across multiple disease types, and critically discusses current nanoplatform design strategies. Furthermore, key challenges associated with mitophagy evaluation, biosafety, pharmacokinetics, clinical translation, and regulatory considerations are highlighted, together with emerging technologies that may accelerate the development of next-generation mitophagy-targeting nanomedicines.
    Keywords:  mitochrial dysfunction; mitophagy; nanotechnology; targeted delivery; therapeutic strategies
    DOI:  https://doi.org/10.1088/1748-605X/ae95c8
  47. Aging Cell. 2026 Sep;25(9): e70678
    Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
    Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.
      Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.
    Keywords:  aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics
    DOI:  https://doi.org/10.1111/acel.70678
  48. Vestn Oftalmol. 2026 ;142(4): 105-111
    [Leber's hereditary optic nerve atrophy].
    O I Orenburkina, M A Frolov, A E Babushkin, I V Vorobyeva, A M Frolov, D I Koshelev.
      This review is devoted to Leber's hereditary optic neuropathy (LHON), a rare maternally inherited ophthalmic disorder presenting as optic nerve atrophy and associated with an unfavorable prognosis. LHON is the most common primary mitochondrial DNA disorder, and most patients (more than 90% of cases) carry one of three point mutations. The 11778G>A mutation in the MT-ND4 gene is the most common worldwide and causes the most severe variant of the disease. LHON typically manifests as bilateral, painless, acute or subacute significant vision loss, most often in young men. Environmental factors play a crucial role in triggering LHON and determining its severity. A preliminary diagnosis is based on family history and the initial clinical presentation, whereas genetic testing establishes the definitive diagnosis. Given the availability of specific treatment for LHON, early diagnosis is crucial for ensuring therapeutic effectiveness. The only drug currently approved for the treatment of LHON is the antioxidant, synthetic coenzyme Q10 analogue idebenone. Among alternative therapeutic strategies, gene therapy is at the most advanced stage of development.
    Keywords:  Leber hereditary optic neuropathy; bilateral visual loss; gene therapy; idebenone; optic nerve atrophy; treatment
    DOI:  https://doi.org/10.17116/oftalma2026142041105
  49. bioRxiv. 2026 Jul 30. pii: 2026.07.29.741427. [Epub ahead of print]
    A genetic switch involving EGR1 and EZH2 links aging and development across human tissues.
    Neha Khetan, Jiashun Zheng, Changhui Deng, Evan Wu, Hao Li.
      Aging is often regarded as the last chapter of development. There is growing evidence that aging and development are mechanistically linked. Here we describe a genetic switch involving EZH2 and EGR1 as opposing regulatory nodes that appears to connect aging and development across human tissues. We show that this switch defines two distinct states in fibroblasts: a proliferative (EZH2-high/EGR1-low) state and a non-proliferative and extracellular matrix-expressing (EGR1-high/EZH2-low) state. During replicative aging, cells shift from the proliferative state to the non-proliferative state and targeting either regulatory node-by overexpressing EZH2 or suppressing EGR1-rejuvenates aged fibroblasts. We provide evidence that this switch is involved in the transition from neural progenitor cells to matured neurons during brain development and becomes destabilized during aging, partially reversing the gene expression program established during development. We observed that this same switch becomes blurred and biased towards EGR1-high/EZH2-low state during the aging of muscle stem cells and hematopoietic stem cells. Since genetic switches are widely used in development to establish and reinforce cellular identity, we propose that attenuation of developmental switches may underlie aging across diverse organs and tissues, and partially accounts for the erosion of the epigenetic landscape and the loss of cellular identity.
    DOI:  https://doi.org/10.64898/2026.07.29.741427
  50. Basic Res Cardiol. 2026 Aug 19.
    NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection.
    Kielen R Zuurbier, Coert J Zuurbier.
      The mitochondrial permeability transition pore (mPTP) opening is a phenomenon in which the inner mitochondrial membrane abruptly becomes permeable when matrix calcium reaches a critical threshold. Despite 5 decades of intensive research, no protein has been universally accepted as essential for mPTP opening, limiting mechanistic understanding and raising questions about the validity of mPTP-targeted strategies to mitigate cardiac ischemia-reperfusion (I/R) injury. Here, we discuss convergent findings from two independent laboratories identifying the innate immune receptor NLRX1 as an unexpected, essential requirement for mPTP activity. NLRX1 is the only NOD-like receptor (NLR) that is targeted to the mitochondrion. NLRX1 deficiency abolishes (1) calcium-induced mPTP opening, (2) cyclosporine A sensitivity of the pore, and (3) mitochondrial calcium release following cardiac I/R. To test whether loss of mPTP function aligns with loss of NLRX1 across evolution, we performed forward and reciprocal bioinformatic (Blastp) searches and found that species reported to lack an mPTP (e.g., Artemia franciscana and Drosophila melanogaster) also lack NLRX1, further supporting a mandatory role for NLRX1 in mPTP occurrence. Notably, NLRX1-deficient hearts can exhibit increased, rather than decreased, I/R injury at specific ischemia durations. This mirrors reports that deletion of established mPTP regulators (e.g., Ppif) may also worsen injury under defined conditions, consistent with context-dependent, potentially protective roles for transient mPTP activity (e.g., mitochondrial calcium release, PI3K/Akt signaling). In summary, we propose that NLRX1 is the only currently identified protein that is strictly required for mPTP opening, and that indiscriminate inhibition of the mPTP is unlikely to represent a universally effective cardioprotective strategy against I/R injury.
    Keywords:  Cardioprotection; Innate immunity; Ischemia-reperfusion injury; Mitochondria; NLRX1; mPTP
    DOI:  https://doi.org/10.1007/s00395-026-01204-6
  51. JAMA Neurol. 2026 Aug 17.
    Anti-CD320 Autoantibodies and Central Nervous System Vitamin B12 Deficiency in Idiopathic Myelopathy.
    UCSF Neurohospitalist Division
       Importance: Disorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12% to 18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment.
    Objective: To describe a novel autoantibody associated with idiopathic myelopathy (IM) and report its clinical, radiographic, and metabolic characteristics.
    Design, Setting, and Participants: This retrospective case-control study was conducted from May 2014 to October 2025 at 4 tertiary care centers. Biofluids from 148 patients diagnosed with IM were evaluated based on clinical evidence of myelopathy without an identified etiology. Biofluids from patients with other neurological diseases (ONDs; n = 32) or known autoimmune myelitis (n = 30) were used for comparison. Proteomewide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF).
    Exposure: Autoantibody status.
    Main Outcomes and Measures: Prevalence, clinical phenotype, CSF profile, and magnetic resonance imaging pattern of autoantibody-positive IM.
    Results: Autoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 of 32 individuals with IM (56%) in a discovery cohort (mean [SD] age, 54 [14] years; 19 male). Bioactive vitamin B12 concentration was decreased in the CSF of individuals with positive anti-CD320 test results compared with that of control individuals with ONDs (mean [SD], 15.1 [2.3] pmol/L vs 22.9 [10.7] pmol/L; P = .03), indicative of autoimmune vitamin B12 central deficiency. Compared to individuals with IM and negative anti-CD320 test results, those with IM and positive anti-CD320 test results demonstrated a higher frequency of subacute time course (n = 10 [56%] vs n = 1 [7%]; P = .008), normal CSF profile (n = 15 [83%] vs n = 7 [50%]; P = .04), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (n = 11 [61%] vs n = 1 [7%]; P = .003). In 2 independent validation cohorts comprising 91 and 25 patients with IM, anti-CD320 was detected in 41 (45%) and 12 (48%) patients, respectively. Comorbid anti-CD320 antibodies were detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five individuals with IM and positive anti-CD320 test results received vitamin B12 supplementation with or without concurrent immunosuppression, and 4 of 5 showed clinical improvement.
    Conclusions and Relevance: In this study, autoimmune vitamin B12 central deficiency was associated with IM. Screening for anti-CD320 antibodies followed by metabolic confirmation of a CNS-restricted vitamin B12 deficiency may be considered in the diagnostic evaluation of myelopathy.
    DOI:  https://doi.org/10.1001/jamaneurol.2026.2778
  52. Ophthalmology. 2026 Aug 18. pii: S0161-6420(26)00586-5. [Epub ahead of print]
    Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.
    Marco Battista, Michele Carbonelli, Luigi Brotto, Giulia Amore, Catarina P Coutinho, Martina Romagnoli, Alice Galzignato, Paolo Nucci, Leonardo Caporali, Maria Lucia Cascavilla, Claudio Fiorini, Chiara La Morgia, Francesco Bandello, Valerio Carelli, Piero Barboni.
       PURPOSE: To characterize the clinical and genetic features, investigate disease triggers, and explore factors associated with visual recovery in late-onset Leber Hereditary Optic Neuropathy (LHON).
    DESIGN: Retrospective cohort study.
    SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Seventy-seven patients with late-onset LHON (onset ≥ 40 years of age) were identified from a larger cohort of 398 Italian LHON patients. Full clinical and genetic analyses were performed on 67 of these patients, while an internal control group of 562 healthy individuals was utilized for mitochondrial haplogroup comparisons.
    METHODS, INTERVENTION, OR TESTING: Patient medical records were retrospectively reviewed to assess demographics, environmental exposures (smoking history), hormonal status (menopause, hormonal therapy), systemic comorbidities, and idebenone treatment data. Genetic testing evaluated primary mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroups, and NQO1 polymorphisms. Statistical relationships were investigated using an exploratory chi-square automatic interaction detection (CHAID) analysis to generate hypothesis-generating decision tree models.
    MAIN OUTCOME MEASURES: The primary outcome measures were the identification of precipitating factors (disease triggers) for LHON conversion and the rate of visual recovery, which was defined as an improvement of at least 0.3 LogMAR or a change from off-chart to on-chart visual acuity.
    RESULTS: The m.11778G>A variant was the predominant mtDNA mutation (62.7%), and the male-to-female ratio was lower than in canonical LHON (1.48:1). Smoking history was present in 58.2% of patients, and 85.2% of women were postmenopausal. Other relevant factors included primary open-angle glaucoma (6%) and the LHON 'plus' phenotype (7.5%). The overall visual recovery rate was 38.8%. Exploratory CHAID analysis suggested that idebenone treatment at a dosage of ≥900 mg/day and the presence of a J or T mitochondrial haplogroup were associated with a higher probability of visual recovery.
    CONCLUSIONS: Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.
    Keywords:  Leber Hereditary Optic Neuropathy; haplogroups; idebenone; late-onset disease; mitochondria
    DOI:  https://doi.org/10.1016/j.ophtha.2026.08.017
  53. J Vis Exp. 2026 Aug 11.
    Human Induced Pluripotent Stem Cell-Derived Cardioids as a Model to Assess Oligonucleotide Delivery.
    Ana Da Rosa Soares, Marta Furtado, Rita Tomás, Noélia Custódio, M Carmo-Fonseca.
      Oligonucleotide-based therapeutics represent a rapidly advancing class of drugs with significant potential for treating cardiovascular diseases; however, achieving efficient delivery to cardiac tissue remains a critical and unresolved challenge. A key obstacle is the limited availability of robust, physiologically relevant human in vitro models capable of supporting quantitative assessment of oligonucleotide cellular uptake and intracellular distribution. A detailed, step-by-step protocol is presented for generating self-organizing, 3D cardioids from human induced pluripotent stem cells (iPSCs) and applying them as a platform to evaluate the uptake of fluorescently labeled oligonucleotides. The protocol guides users through directed cardiac differentiation in suspension culture by temporally modulating Wnt/β-catenin signaling, enabling sequential specification of iPSCs through the mesoderm, cardiac mesoderm, and cardiomyocyte progenitor stages. Under these conditions, cells spontaneously self-assemble into beating, cavity-containing three-dimensional structures that express canonical cardiomyocyte markers. The resulting cardioids provide a scalable, experimentally tractable platform for imaging-based assessment of oligonucleotide uptake efficiency, supporting the development and optimization of delivery strategies for cardiac applications.
    DOI:  https://doi.org/10.3791/72013
  54. Am J Pathol. 2026 Aug 19. pii: S0002-9440(26)00234-8. [Epub ahead of print]
    Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis vulnerability of hepatocytes.
    Somesh Banerjee, Jaehyun Kim, Matthew Ryan Smith, Yining Irene Wang, Michael Wang, Derrik Gratz, Gregory K Tharp, Sumin Kang, Peijian He.
      Ferroptosis is an iron-catalyzed lipid peroxidation (LP)-dependent cell death that mediates the development of many diseases, including liver injury. Compelling evidence has suggested a crucial role of mitochondrial reactive oxygen species (mtROS) in the induction of ferroptosis, but the underlying mechanism remains poorly defined. In this study, the impact of mtROS-driven signaling on cellular metabolism, redox state, and ferroptosis vulnerability of the hepatocytes was investigated by utilizing mtROS inducers, including iron overload and pharmacological inducers. Elevations in mtROS production and LP suppressed glycolysis, fatty acid oxidation, and tricarboxylic acid (TCA) cycle activity, protecting hepatocytes from ferroptosis. In contrast, mtROS-induced signaling downregulated genes involved in glutathione biosynthesis, and coenzyme Q10 (CoQ) biosynthesis, including those in the mevalonate pathway, and CoQ8A, a key stabilizer of the CoQ biosynthetic complex. Importantly, silencing CoQ8A expression enhanced, whereas overexpression of CoQ8A reduced, ferroptosis susceptibility of the hepatocytes. Further analysis showed that mtROS-mediated downregulation of CoQ8A is dependent on farnesoid X receptor (FXR) and retinoid X receptors (RXRs). Collectively, these findings suggest that mtROS induces downregulation of glutathione and CoQ biosynthesis, thereby promoting ferroptotic death in hepatocytes.
    Keywords:  CoQ8A; Coenzyme Q10; fatty acid oxidation; glutathione; glycolysis; iron overload
    DOI:  https://doi.org/10.1016/j.ajpath.2026.07.010
  55. Res Sq. 2026 Aug 05. pii: rs.3.rs-10171816. [Epub ahead of print]
    Mice Undergo Organ-Specific Transcriptional and Metabolic Remodeling During Late Adolescence.
    Qing-Xia Huang, Ahmad Al Ajami, Eva Kohnert, Temel Kilic, Christina Engel, Melanie Boerries, Clemens Kreutz, Katharina Moos, Gerd Walz.
      Mouse models aimed at deciphering human aging have typically focused on early development or late-life stages. Much less is known about the transition from late adolescence to young adulthood, spanning 8 to 12 weeks of age. Here, we show that C57Bl6 mice undergo a comprehensive developmental transition characterized by significant transcriptional and metabolic reprogramming during this time. Transcriptional analysis revealed substantial, organ-specific changes: the heart shifts toward a maintenance-focused phenotype with down-regulated oxidative phosphorylation (OXPHOS) and increased expression of genes supporting structural remodeling. Conversely, the kidney adopts an immunologically active state, reflecting progressive immune cell colonization, while the liver shifts from a hematopoietic role to one dominated by lipid metabolism, detoxification, and ketogenesis. These transcriptional changes correspond to a coherent metabolic maturation driven by the gut-liver axis. Intestinal maturation enhances lipid absorption and microbial fermentation, leading to increased circulating levels of short-chain fatty acids, poly-unsaturated glycerolipids, and sphingomyelins. Elevated hepatic production of ketone bodies, driven by up-regulated fatty acid metabolism genes, provides an efficient alternative energy substrate for peripheral tissues like the heart. Urinary metabolite profiles, marked by increased acylglycines and tricarboxylic acid (TCA) cycle intermediates, further confirm heightened mitochondrial energy turnover and fatty acid β-oxidation. Collectively, this coordinated maturation from 8 to 12 weeks signifies the transition from a highly plastic developmental state to a stable, energy-efficient, and metabolically flexible adult phenotype.
    DOI:  https://doi.org/10.21203/rs.3.rs-10171816/v1
  56. Transl Res. 2026 Aug 18. pii: S1931-5244(26)00171-4. [Epub ahead of print]
    Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.
    Jia Li, Hongmei Duan, Peng Hao, Wen Zhao, Yudan Gao, Zhaoyang Yang, Xiaoguang Li.
      In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.
    Keywords:  Regenerative medicine; cell therapy; neurodegenerative diseases; reprogramming
    DOI:  https://doi.org/10.1016/j.trsl.2026.08.005
  57. Dev Biol. 2026 Aug 19. pii: S0012-1606(26)00184-3. [Epub ahead of print]
    NADH FLIM reveals cellular bioenergetics and mitochondrial morphology during Drosophila convergent extension.
    Maria Espana-Pena, Alan Woessner, Kyle P Quinn, Adam C Paré.
      Mitochondria are dynamic organelles that can fragment or fuse to support different bioenergetic demands and cellular processes, although the role of mitochondrial fission and fusion during embryonic development is not well understood. Fluorescence lifetime imaging (FLIM) of the mitochondrial cofactor NADH can be used to visualize mitochondrial networks and infer aspects of cellular bioenergetics in a label-free manner. We used NADH FLIM to test whether germband cells undergo changes in cellular metabolism during Drosophila convergent extension (CE)--a process in which hundreds of epithelial cells undergo coordinated intercalation to elongate the embryo. Contrary to our expectations, we did not observe significant changes in NADH lifetime or mitochondrial topology during CE, suggesting that germband cells do not need to alter their baseline metabolism to fuel intercalation. Inhibiting mitochondrial fission led to hyper-fused basal networks and robustly increased NADH lifetime, whereas inhibiting fusion led to hyperfragmented apical networks and decreased NADH lifetime. Inhibiting either mitochondrial fission or fusion increased cell intercalation errors during CE, suggesting that a precise network topology is required for proper tissue elongation. These defects could be rescued by knocking down ROS scavengers, suggesting that one of the roles of mitochondria during CE is to create a ROS-rich environment to support cell motility. This study demonstrates the utility of NADH FLIM for visualizing mitochondria and characterizing bioenergetics during development in live embryos, and this technique should be broadly applicable to many other systems.
    Keywords:  Drosophila; NADH FLIM; convergent extension; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.ydbio.2026.08.011
  58. Mov Disord. 2026 Aug 18.
    Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
    Hari Prasad.
      
    Keywords:  GBA1; Parkinson's disease; lysosomal pH; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1002/mds.70492
  59. J Vis Exp. 2026 Aug 07.
    Real-Time, Noninvasive Evaluation of Mitochondrial Function Using Resonance Raman Spectroscopy.
    Yasemin Altug, Rohil Jain, Khanh T Nguyen, Padraic Romfh, Shannon N Tessier.
      Although mitochondria are central to pathogenesis and disease progression, mechanistic insight into mitochondrial health dynamics remains costly and inaccessible. To address this gap, this study employs Resonance Raman Spectroscopy (RRS) to assess mitochondrial function, using a portable system that delivers real-time, noninvasive, and quantitative measurements of mitochondrial cytochrome redox states in rat livers. In this protocol, we demonstrate the use of this technology, including setup, data acquisition, and data processing. This study presents a proof-of-concept experiment that highlights RRS's ability to measure real-time changes in mitochondrial redox state- and, by extension, mitochondrial function. Briefly, the RRS device was connected to a laser pump as well as a data acquisition computer and placed 1 cm away from the rat liver.  Acquisition parameters were selected in accordance with the rat liver protocol; redox states were measured in oxygenated and ischemic conditions utilizing an oxygen stress test. Changes in mitochondrial redox states were tracked throughout the oxygen stress test.
    DOI:  https://doi.org/10.3791/71290
  60. J Biol Chem. 2026 Aug 19. pii: S0021-9258(26)02336-7. [Epub ahead of print] 113464
    mRNA translational dynamics mediates totipotent-like reprogramming.
    Lingci Huang, Jun Zhang, Xinwei Wu, Haotian Zhang, Wanting Cai, Xiaoyan Sun, Yuanhui Mao, Jun Zhou, Xiao-Min Liu.
      Embryonic stem cells (ESCs) are characterized by their dual capacity for self-renewal and differentiation into all cell types of the embryonic lineage. A subpopulation known as 2-cell-like cells (2CLCs), which recapitulate key molecular and metabolic features of totipotent 2-cell blastomeres, has been identified within cultured mouse ESC populations. While transcriptional regulation, epigenetic modifications, and chromatin reorganization are known to be critical for the reprogramming of pluripotent ESCs into a totipotent-like state, the role of translational control in this process remains poorly understood. Using an inducible 2CLC model, we performed transcriptome-wide profiling of mRNA translation and found that global translation efficiency dynamically decreases during the early phase of totipotent-like reprogramming, correlating with reduced TORC1 signaling and translation initiation. In the later phase, although overall mitochondrial mass declines, mitochondrial translation is selectively upregulated and exhibits high translational efficiency. Importantly, pharmacological inhibition of mitochondrial translation suppressed the expression of canonical 2-cell transcripts and impaired the transition from ESCs to 2CLCs. Together, these results demonstrate that coordinated regulation of both cytosolic and mitochondrial translation during totipotent-like reprogramming, offering a new perspective for understanding cell fate determination.
    Keywords:  2CLCs; mRNA translation; mitochondrial translation; totipotent
    DOI:  https://doi.org/10.1016/j.jbc.2026.113464
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