bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–09–06
fifty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
  2. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  3. Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
  4. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  5. Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
  6. Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
  7. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  8. Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
  9. A single-amino-acid cleavage controls global mitochondrial complex integrity.
  10. Guanosine 10 methylation by TRMT11-TRMT112 optimizes human mitochondrial tRNAs for efficient translation.
  11. Mitochondrial Lipids in Cellular Adaptation.
  12. Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
  13. Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
  14. Unusual Variants in NDUFAF6-Associated Mitochondrial Disease.
  15. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  16. Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.
  17. Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
  18. Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
  19. Immunosuppression in children with primary mitochondrial diseases after kidney transplantation: insight from case series of RMND1-related disease.
  20. Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome.
  21. Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
  22. Algebraic Representation of Mitochondrial Dynamics.
  23. SLIRP differentially modulates RNA binding of pathogenic LRPPRC variants.
  24. Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration.
  25. Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
  26. Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.
  27. Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.
  28. MICOS13-Related Combined Oxidative Phosphorylation Deficiency 37: A Case Report and Systematic Review of the Literature.
  29. Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study.
  30. From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
  31. Mutation rate heterogeneity biases variant effect prediction and reveals genuine mutational robustness.
  32. Dietary effects on cytosolic and mitochondrial tRNA abundance and modification patterns across mouse tissues.
  33. Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
  34. Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
  35. Phenotypic overlap masking MELAS in Turner syndrome: a diagnostic challenge.
  36. Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.
  37. Tissue mitochondrial activity dictates the macrophage pool size.
  38. Nucleic acid sensing pathways in kidney disease development.
  39. Mitochondrial molecular diversity in the brain.
  40. Analysis of mtDNA Methylation.
  41. Airway administered artificial mitochondria-enriched nanovesicles for efficient and selective mitochondria transfer to intervene in pulmonary fibrosis.
  42. RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
  43. An adult case of acute encephalopathy associated with general anaesthesia and the m.11232T > C MT-ND4 variant.
  44. The mitochondrial deacetylase SIRT3 is nonessential for cyclophilin D-dependent procoagulant platelet formation in mice.
  45. Mitochondrial reprogramming of neutrophil extracellular traps in chronic obstructive pulmonary disease and asthma: toward a phenotype-driven therapeutic framework.
  46. Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.
  47. Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
  48. Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
  49. Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
  50. Carotid body mitochondria exhibit normal oxygen affinity despite COX4I2 enrichment.
  51. T-rex: standardized analysis of germline variants in whole-exome sequencing trios.
  52. APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.
  1. Ann Hum Genet. 2026 Aug 30.
    Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
    Enchi Yuan, Ning Zhang, Haoyu He, Tao Zhang, Enze Chen, Qidi Zhang, Dongmei Ji.
       BACKGROUND: Variants in the MT-TI gene, which encodes mitochondrial transfer RNA for isoleucine, have been associated with neuromuscular, cardiac, auditory, renal, and metabolic disorders, but their clinical interpretation remains difficult.
    OBJECTIVE: To integrate clinical, familial, heteroplasmy, and functional evidence across the reported MT-TI variant spectrum and clarify its implications for variant interpretation and diagnosis.
    METHODS: We conducted a narrative review of reported MT-TI variants, with detailed comparison of seven representative variants and synthesis of phenotypic, familial, tissue-specific heteroplasmy, and functional findings.
    RESULTS: Evidence was derived mainly from case reports and small pedigrees. Heteroplasmy differed markedly among blood, skeletal muscle, and myocardium, indicating that blood may not represent variant loads in energy-demanding tissues. Reported values generally reflected the lowest observed levels in affected individuals or family-specific boundaries rather than validated pathogenic cutoffs. Functional findings support a staged mechanism involving disturbed transfer RNA processing, structure, stability, or aminoacylation, followed by impaired mitochondrial protein synthesis and respiratory-chain dysfunction. Integrated mechanistic support was limited to a few variants, including m.4295A>G; evidence for most variants remained incomplete or indirect.
    CONCLUSION: Diagnosis requires tissue-informed heteroplasmy assessment integrated with phenotype, maternal family history, and functional evidence. Current treatment is supportive, and proposed reproductive and molecular strategies lack MT-TI-specific clinical-trial evidence.
    Keywords:  Ile; RNA; heteroplasmy; mitochondrial; mitochondrial diseases; oxidative phosphorylation; transfer
    DOI:  https://doi.org/10.1111/ahg.70056
  2. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  3. J Inherit Metab Dis. 2026 Sep;49(5): e70247
    Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
    Lea Isermann, Aleksandra Trifunovic.
      Mitochondrial CLPP has emerged as an unusual therapeutic target because both increasing and decreasing its proteolytic activity can be beneficial, depending on the cellular and disease context. Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma. Conversely, reduced CLPP activity can preserve respiratory-chain components and promote adaptive metabolic and redox remodelling in selected models of mitochondrial disease, neurodegeneration and metabolic dysfunction, with emerging potential in ischaemia-reperfusion injury. These opposing outcomes reflect the broader role of CLPXP in controlling mitochondrial translation, respiratory-chain integrity and metabolism rather than acting simply as a general protein quality-control system. In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness.
    DOI:  https://doi.org/10.1002/jimd.70247
  4. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
  5. Sci Adv. 2026 Sep 04. 12(36): eaec8606
    Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
    Kristina Bubb, Giovanni Rigoni, Polyxeni Papadea, Gianluigi Pironti, Jelena Misic, Shan Jiang, David Alsina, Diana Rubalcava-Gracia, Daniel C Andersson, Roberta Filograna, Camilla Koolmeister, Patrick Giavalisco, Anna Wredenberg, Matthias Mann, Florian A Rosenberger, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8606
  6. Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381
    Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
    Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.
      Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
    DOI:  https://doi.org/10.1016/j.redox.2026.104381
  7. Cell Rep. 2026 Aug 29. pii: S2211-1247(26)00927-7. [Epub ahead of print]45(9): 117849
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.
    Keywords:  CP: metabolism; NAD(+) metabolism; anemia; erythropoiesis; metabolism; mitochondria; post mitotic tissues; progeria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117849
  8. Free Radic Biol Med. 2026 Sep 04. pii: S0891-5849(26)01137-8. [Epub ahead of print]
    Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
    Mei Ma, Jinze Tian, Zhe Wang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Intercellular mitochondrial transfer has been recognized as an important mechanism for maintaining tissue homeostasis and adapting to stress. Mitochondria can cross cellular boundaries through tunneling nanotubes, extracellular vesicles, and free mitochondrial release. However, the physiological signals coordinating these pathways remain poorly defined. Exercise is a potent inducer of transient redox signaling, generating superoxide and hydrogen peroxide while modulating mitochondrial dynamic remodeling. This review integrates exercise redox biology with redox regulation of transfer machinery characterized in non-exercise models, proposing that exercise-induced redox signaling may function as a candidate regulatory mechanism. The framework emphasizes bidirectional redox coordination, in which oxidant pulses may activate export in donor cells and prepare recipient cells for uptake and antioxidant defense. Exercise-induced mitochondrial transfer has been directly demonstrated in the brain, while observations in skeletal muscle, adipose tissue, and heart remain suggestive but have not been confirmed in exercise models. These findings support a framework in which intercellular mitochondrial transfer contributes to metabolic signaling, antioxidant defense, and distributed quality control across organs. This model represents a working hypothesis requiring direct experimental validation through lineage tracing, tissue-specific mitochondrial reporters, and intravital imaging.
    Keywords:  exercise; mitochondrial biogenesis; mitochondrial quality control; mitochondrial transfer; redox signaling; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.003
  9. Nat Struct Mol Biol. 2026 Aug 31.
    A single-amino-acid cleavage controls global mitochondrial complex integrity.
    Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.
      Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.
    DOI:  https://doi.org/10.1038/s41594-026-01876-7
  10. Nucleic Acids Res. 2026 Aug 24. pii: gkag859. [Epub ahead of print]54(16):
    Guanosine 10 methylation by TRMT11-TRMT112 optimizes human mitochondrial tRNAs for efficient translation.
    Jonny Petrosyan, Mehmet Yilmaz, Carolin P M Scheitl, Nicolas Lemus-Diaz, Angela Boshnakovska, Laurianne L E Tay, Wanwan Hu, Olga Beine-Golovchuk, David Touboul, Ricarda Richter-Dennerlein, Claudia Höbartner, Marc Graille, Peter Rehling, Katherine E Bohnsack.
      Modified nucleotides are essential determinants of RNA function, and identifying the enzymes that install them is fundamental to understanding their cellular roles. Here, we show that the human RNA methyltransferase TRMT11 and its cofactor TRMT112 are imported into mitochondria via N-terminal targeting signals. Using a recently developed N2-methylguanosine (m2G)-sensitive DNAzyme, we demonstrate that TRMT11 catalytic activity and interaction with TRMT112 are required for installation of m2G at position 10 in 13 mitochondrial (mt-)tRNAs. The crosslinking profile of TRMT11 on mt-tRNAs experimentally supports a model of the TRMT11-TRMT112-mt-tRNATrp complex in which the THUMP domain contacts the 3' end of the acceptor stem, and G10 is flipped into the S-adenosylmethionine binding pocket for methylation. Transcriptome-wide mapping reveals that TRMT11 interacts with most nuclear-encoded and mt-tRNAs, but only methylates a subset. In vitro reconstitution of TRMT11-TRM112-mediated methylation defines key structural requirements for m2G10 installation across different mt-tRNAs, and reveals how pathogenic mutations influence this modification. TRMT11-TRMT112 recognizes folded mt-tRNAs, and in the degenerate mt-tRNALys, m1A9 strongly enhances m2G10 methylation efficiency. Loss of m2G10 modifications alters the conformation of numerous mt-tRNAs, perturbs mitochondrial protein synthesis, and impairs oxidative phosphorylation, highlighting an essential role of this modification in maintaining mitochondrial function.
    DOI:  https://doi.org/10.1093/nar/gkag859
  11. ACS Chem Biol. 2026 Aug 26.
    Mitochondrial Lipids in Cellular Adaptation.
    Mária Balážová, Lili Jiang, Cunqi Ye.
      Mitochondria serve as central hubs of cellular bioenergetics and signaling, yet the dynamic role of their lipid composition in cellular adaptation remains underappreciated. Unlike most organelles, mitochondria possess a unique dual-bilayer membrane architecture shaped by lipid transport and de novo synthesis. The mitochondrial lipidome, dominated by phosphatidylcholine, phosphatidylethanolamine, and the signature phospholipid cardiolipin, influences cristae organization, oxidative phosphorylation capacity, and metabolite transport, collectively determining whether mitochondria undergo stabilization, remodeling, or degradation. In this review, we explore how mitochondrial lipid dynamics sustain organelle-wide homeostasis while coordinating cellular adaptation across multiple temporal scales and how failure of lipid homeostasis drives rare monogenic disorders and complex pathologies. We propose that environmental shifts transiently disrupt the balance between phospholipid biosynthesis and utilization, generating changes in mitochondrial lipid homeostasis that promote cellular adaptation through complementary biophysical and biochemical signaling mechanisms. Specifically, membrane lipid remodeling rapidly alters membrane biophysical properties to regulate membrane protein activity, whereas bioactive phospholipid intermediates and side-products support long-term adaptive reprogramming. Mitochondrial lipids therefore function not merely as passive structural components but as active regulatory nodes that drive cellular plasticity, positioning lipid dynamics at the nexus of metabolic adaptation and human disease.
    DOI:  https://doi.org/10.1021/acschembio.6c00615
  12. Psychophysiology. 2026 Sep;63(9): e70383
    Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
    Darshana Kapri, Gabriel Sturm, Catherine Kelly, Ke Bo, Cynthia C Liu, Tor D Wager, Michio Hirano, Caroline Trumpff, Martin Picard.
      Time perception-the subjective sense of how quickly or consistently time passes-shows striking variability across individuals, yet its physiological basis remains poorly understood. We hypothesized that internal clock speed and trial-to-trial variability in time perception would be linked to physiological and behavioral states. In a cohort of healthy adults (n = 59) and individuals carrying rare mitochondrial DNA mutations affecting mitochondrial energy transformation (n = 36), we explored the associations between time perception (time estimation and production) with measures of immune mitochondrial bioenergetics, blood catecholamines, working memory, and structural and functional neuroimaging. We found weak evidence suggesting that internal clock speed and time perception variability correlated with age and physiological metrics including resting energy expenditure, serum and urine norepinephrine levels, mood and fatigue, working memory performance, and neuroimaging measures of brain structure and function. Individuals with mitochondrial disorders and those with healthy mitochondria exhibited no main difference in time perception. However, they exhibited differential relations with physiological and neural variables, suggesting that mitochondria may moderate how specific processes influence time perception. These results provide a foundation for future studies to examine how cellular bioenergetics relate to time perception in humans.
    Keywords:  mitochondrial disease; norepinephrine; resting energy expenditure; time perception
    DOI:  https://doi.org/10.1111/psyp.70383
  13. Mol Genet Metab. 2026 Aug 27. pii: S1096-7192(26)00530-5. [Epub ahead of print]149(1-2): 110247
    Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
    Merve Setenay Akyüzlüer Güneş, Merve Koç Yekedüz, Engin Köse, İlknur Sürücü Kara, Fatma Tuba Eminoğlu.
       BACKGROUND: Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort.
    MATERIALS AND METHODS: We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation.
    RESULTS: Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement.
    CONCLUSION: Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.
    Keywords:  Biotin; Carnitine; Coenzyme Q10; Primary mitochondrial disease; Riboflavin; Thiamine
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110247
  14. Rare. 2026 ;pii: 100129. [Epub ahead of print]5
    Unusual Variants in NDUFAF6-Associated Mitochondrial Disease.
    Yuka Aoyama, Julia Grafstein, Parker Houston, Marisa W Friederich, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Johan Van Hove, William Gahl, David R Adams, Lynne Wolfe, Ellen F Macnamara.
      A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6, i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.
    Keywords:  Mitochondrial disease; NDUFAF6; complex 1 deficiency
    DOI:  https://doi.org/10.1016/j.rare.2026.100129
  15. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  16. Exp Gerontol. 2026 Sep 02. pii: S0531-5565(26)00282-2. [Epub ahead of print]224 113303
    Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.
    Margaret-Jade Searles, Debanjali Dasgupta, Trace A Christensen, Gary C Sieck, Matthew J Fogarty.
      Declining aerodigestive neuromotor function is a major aspect of human aging, with impaired airway defense and swallow manoeuvres implicated in pneumonia and dysphagia. Hypoglossal motor neurons (MNs) innervate tongue muscles, essential for these behaviours. Their degeneration contributes to age-related aerodigestive dysfunctions. In neurodegenerative diseases, the ubiquitin-proteasome system (UPS) is altered, disturbing mitochondrial proteostasis. We have previously shown reduced mitochondrial abundance, dysfunction and mitochondrial fragmentation in aging hypoglossal MN somas and dendrites. However, the relationship between the UPS (pUBS65 and ubiquitinated proteins), mitochondrial fragmentation (pDRP1S616) and fusion promoting proteins (MFN2) in MN aging is unexplored. In other neurons, aging changes mitochondria within axons in an opposite way to somas and dendrites. We used Western blotting to show impairment in mitophagy-related pUBS65, increased fragmentation-promoting pDRP1S616 and unchanged MFN2. Serial Block-Face Scanning Electron Microscopy showed increased mitochondrial volume density and larger, more simplistic mitochondria in old, myelinated hypoglossal axons, while somas and dendrites showed reduced mitochondrial volume density and increased fragmentation. Our results suggest that a more nuanced compartment-specific evaluation of mitochondrial structure and function is required to fully elucidate the pathophysiology underlying age-related neuromotor dysfunction.
    Keywords:  Aging; Axon; Brainstem; Dendrite; Hypoglossal; Mitochondria; Motor neuron; Proteostasis
    DOI:  https://doi.org/10.1016/j.exger.2026.113303
  17. Sci Adv. 2026 Sep 04. 12(36): eaef8132
    Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
    Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.
      Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef8132
  18. J Vis Exp. 2026 Sep 03.
    Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
    Teresa Kloimboeck, Thomas Ebner, Kateryna Makova, Barbara Arbeithuber.
      Oocytes are densely packed with mitochondria, the energy-producing organelles that contain their own genome, mitochondrial DNA (mtDNA). Each cell contains multiple copies of mtDNA, with copy number varying among tissue types. Oocytes possess the highest mtDNA copy number, containing hundreds of thousands of mtDNA molecules per cell. Because mitochondria are inherited exclusively through the maternal lineage, accurate detection of mtDNA variants is essential for studies of inheritance, aging, and disease. The presence of multiple mtDNA copies allows wild-type and mutant molecules to coexist within the same cell, a condition known as heteroplasmy, in which low-frequency and de novo variants may occur at frequencies below 1%. Conventional next-generation sequencing (NGS) lacks sufficient accuracy to reliably distinguish these rare variants from errors introduced during library preparation and sequencing. Here, we present a protocol for enriching mtDNA from single human oocytes using Exonuclease V to remove linear DNA, followed by duplex sequencing library preparation for highly accurate mtDNA analysis. This workflow enables error-corrected sequencing of individual oocytes, facilitating reliable detection of low-frequency mtDNA variants and analysis of heteroplasmy and de novo mutagenesis. The protocol provides a reproducible approach for investigating mitochondrial genome variation in single oocytes using Illumina-compatible sequencing platforms.
    DOI:  https://doi.org/10.3791/73071
  19. Pediatr Nephrol. 2026 Sep 04.
    Immunosuppression in children with primary mitochondrial diseases after kidney transplantation: insight from case series of RMND1-related disease.
    Sze Wa Wong, Fred Tomlin, Jelena Stojanovic.
      While successful kidney transplantation has been reported in pediatric patients with primary mitochondrial diseases, immunosuppression regimen and its effect on systemic disease were not described. We present four pediatric patients with genetically confirmed RMND1 disease in a quaternary nephrology center. They presented at a very young age and progressed rapidly to stage 5 chronic kidney disease. All underwent successful kidney transplantation. Their allograft function remained stable throughout the follow-up period, and they did not manifest any major systemic deterioration.
    Keywords:  Immunosuppression; Kidney transplantation; Primary mitochondrial diseases; RMND1 disease
    DOI:  https://doi.org/10.1007/s00467-026-07527-9
  20. HGG Adv. 2026 Sep 04. pii: S2666-2477(26)00110-7. [Epub ahead of print] 100670
    Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome.
    Alicia N Campbell, Kendall N Jung, Steven J Doyle, Ekaterina Lebayle, Barbara Corneo, Joanna Feng, Christopher L Ricupero, Jennifer M Bain, Randy Strich.
      The Mediator Kinase Module (MKM) coordinates transcriptional programs regulating cellular metabolism, stress responses, and differentiation. Heterozygous variants of MED13L, a core MKM component, cause a neurodevelopmental disorder characterized by variable intellectual disability, developmental delay, hypotonia and motor impairment, and congenital anomalies. However, the molecular basis underlying this clinical heterogeneity is poorly defined. Previously, we identified mitochondrial dysfunction and aberrant nuclear release of another MKM component, cyclin C (CCNC), in a single fibroblast line derived from an individual with MED13L syndrome. Here, we expand these studies across 12 fibroblast lines derived from individuals with 11 distinct MED13L variants. We identify mitochondrial dysfunction as a consistent feature of MED13L variation, characterized by reduced mitochondrial ATP production, decreased mitochondrial DNA abundance, elevated reactive oxygen species, and impaired transcription of genes involved in mitochondrial biogenesis. In parallel, all variant lines exhibit aberrant cytoplasmic CCNC localization, consistent with its established role in mitochondrial fission. Longitudinal analyses further reveal progressive declines in mitochondrial function along with markers associated with premature cellular aging. Importantly, the severity of mitochondrial dysfunction shows an association with variant position within MED13L and with clinical functional measures, suggesting that mutation location may partially predict disease severity. Together, these findings establish mitochondrial dysfunction as a consistent cellular feature of MED13L heterozygosity and identify CCNC mis-localization as a candidate biomarker of MKM disruption. More broadly, this work reveals an intersection between transcriptional control and mitochondrial homeostasis in MED13L syndrome, forming the framework for biomarker-driven therapeutic development in MED13L-associated and related neurodevelopmental disorders.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100670
  21. Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14
    Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
    Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.
    Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse
    DOI:  https://doi.org/10.7554/eLife.106976
  22. Bull Math Biol. 2026 Sep 04. pii: 176. [Epub ahead of print]88(10):
    Algebraic Representation of Mitochondrial Dynamics.
    Raphael Mostov, Greyson Lewis, Gabriel Sturm, Wallace F Marshall.
      This paper addresses the increasing need for comprehensive mathematical descriptions of cell organization by examining the algebraic structure of mitochondrial network dynamics. Mitochondria are cellular structures involved in metabolism that take the form of a network of membrane-based tubes that undergo continuous re-arrangement by a set of morphological processes, including fission and fusion, carried out by protein-based machinery. Because of their network structure, mitochondria can be represented as graphs, and the morphological operations that take place in the cell, referred to as mitochondrial dynamics, can be represented by changes to the graphs. Prior studies have classified mitochondrial graphs based on graph-theoretic features, but an alternative approach is to focus not on the graphs themselves but on the set of morphological operations inducing mitochondrial dynamics, since this may provide a simpler representation. Moreover, the operations are what determine the graphs that will be generated in a biological system. Here we show that mitochondrial dynamics give rise to a category in which the objects are equivalence classes of graphs defined by one of the morphological operations and morphisms are mappings between these equivalence classes defined by the remaining morphological operations. For mitochondria consisting of a single component this gives rise to a particularly simple representation. Using these formalisms we define a distance metric for similarity between mitochondrial structures based on an edit distance, and demonstrate how this representation can be used for visualization and statistical analysis of biological data. In the course of defining these structures we provide a mathematical motivation for new experimental questions regarding mitochondrial fusion, the impacts of cell division on mitochondrial morphology, and the presence of a single giant component in some cell types. This work points to a general strategy for formulating a cell structure state-space, based not on the shapes of cellular structures, but on relations between the dynamic operations that produce them.
    Keywords:  Algebraic graph theory; Budding yeast; Cell representation; Mitochondrial fission; Mitochondrial fusion; Morpholomics; Planar graphs; Spatial statistics
    DOI:  https://doi.org/10.1007/s11538-026-01738-9
  23. NAR Mol Med. 2026 Jul;3(3): ugag040
    SLIRP differentially modulates RNA binding of pathogenic LRPPRC variants.
    Louise Lambert, Urška Rovšnik, Amandine Moretton, Katarina Johansson, Mãdãlina Sãcultanu, Mathilde Chéron, Adèle Porcan, Bertil Macao, Siet van den Wildenberg, Xuefeng Zhu, Maria Falkenberg, Géraldine Farge.
      The LRPPRC/SLIRP complex is a key post-transcriptional regulator of mitochondrial gene expression, stabilizing mitochondrial mRNAs and promoting their polyadenylation and translation. Mutations in LRPPRC cause mitochondrial disorders, including Leigh syndrome French-Canadian type (LSFC), primarily affecting oxidative phosphorylation. Here, we examined the RNA-binding properties of wild-type LRPPRC and three pathogenic variants (A354V, K909del, and R1276_K1300del) using electrophoretic mobility shift assays, acoustic force spectroscopy, and AlphaFold 3 modeling. All three mutations reduced intrinsic RNA binding, with R1276_K1300del showing no detectable interaction in the absence of SLIRP. Remarkably, SLIRP restored RNA binding of this mutant to near wild-type levels, likely through conformational stabilization, as supported by single-molecule and structural analyses. These findings highlight SLIRP's critical role in modulating LRPPRC function and suggest that enhancing SLIRP activity represents a potential therapeutic strategy for LRPPRC-related mitochondrial disorders.
    DOI:  https://doi.org/10.1093/narmme/ugag040
  24. Mol Biol Cell. 2026 Sep 02. mbcE26060250
    Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration.
    Breanne R Hewitt, Jacob J Duggan, Ryan J Petrie.
      Cells migrating through three-dimensional (3D) tissues adapt their mechanical properties in response to extracellular matrix architecture through migratory plasticity. In primary human dermal fibroblasts, matrix elasticity drives distinct low- and high-pressure migration modes in which forces either push or pull the nucleus, respectively. How these mechanically distinct modes of nuclear translocation influence mitochondrial organization and function is not known. Here, we show that mitochondria become enriched anterior to the nucleus during 3D migration and segregate into spatially distinct populations with different motility and energetic states. During high-pressure, nuclear-pulling migration, a highly energized mitochondrial pool forms immediately anterior to the nucleus. This mitochondrial pool occupies a specialized perinuclear compartment organized by ROCK-dependent contractility and vimentin intermediate filaments and is selectively lost when this machinery is disrupted. Together, these findings reveal that extracellular matrix mechanics spatially organize mitochondrial dynamics and energetics during 3D migration, coupling localized mitochondrial function to the mechanical requirements of nuclear translocation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E26-06-0250
  25. Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00343-9. [Epub ahead of print]232 108428
    Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
    Ester Zito, György Hajnóczky.
      Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.
    Keywords:  CHOP; Ca²⁺ handling; ER stress; ERO1; ER–mitochondria contact sites (ERMCs); IP₃ receptor (IP₃R); Mitochondrial permeability transition pore (mPTP); Pharmacological therapy; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.phrs.2026.108428
  26. J Neurosci. 2026 Sep 03. pii: e0515262026. [Epub ahead of print]
    Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.
    Dobromila Pekala, Maurice Safar, Madeline Lampert, Duc Doung, Stephanie Zlatic, Victor Faundez, Peter Wenner.
      Neural function is maintained through homeostatic mechanisms that are engaged following perturbations to the nervous system. Homeostatic plasticity is thought to be critical for establishing and stabilizing appropriate levels of network function. Neurons are proposed to detect deviations in activity through intracellular calcium signaling, such that changes in calcium levels initiate compensatory mechanisms that restore activity and calcium to baseline. This sensing process is generally assumed to occur in the cytoplasm, however, recent work suggests that it may reside inside mitochondria. We test this in the chick embryo (either sex) spinal cord. We show that perturbations known to induce homeostatic plasticity preferentially alter the mitochondrial proteome, including components of the tricarboxylic acid (TCA) cycle, a pathway sensitive to calcium entry into mitochondria. We then tested whether calcium influx into the mitochondrial matrix contributes to the induction of homeostatic plasticity in motoneurons. Pharmacological blockade of the mitochondrial calcium uniporter (MCU), which mediates calcium entry into the matrix, produced a robust and sustained increase in spontaneous network activity (SNA). Using Ru265 to inhibit MCU function, we confirmed a reduction in mitochondrial calcium, while cytoplasmic calcium levels were largely unchanged or slightly elevated. MCU blockade was accompanied by an increase in excitatory synaptic strength consistent with homeostatic synaptic plasticity. The underlying mechanisms overlapped with those previously described in this preparation following activity or neurotransmitter blockade. Together, these findings support a model in which mitochondria contribute to the initiation of homeostatic synaptic plasticity, potentially by sensing changes in calcium transients within the mitochondrial matrix.Significance Statement Homeostatic plasticity is thought to play a critical role in maintaining circuit function. Although substantial progress has been made in identifying the mechanisms underlying the expression of homeostatic plasticity, the upstream triggers remain poorly understood. Cytoplasmic calcium has been proposed as a key signal in the detection of perturbations in neural circuit activity and in initiating compensatory responses. Here, we present findings consistent with the idea that the sensor for network activity and homeostatic synaptic plasticity tracks mitochondrial calcium. Identifying the sensor that initiates homeostatic mechanisms will be essential for understanding the functional objectives of this form of plasticity and may provide a foundation for pharmacologically targeting this pathway in conditions characterized by altered network activity.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0515-26.2026
  27. Methods Enzymol. 2026 ;pii: S0076-6879(26)00237-5. [Epub ahead of print]734 29-53
    Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.
    Karthick Chennakesavan, Thangavel Samikkannu.
      Cellular pathways for experimental discovery provide a comprehensive overview of sirtuin biology and its critical involvement in HIV-associated neurocognitive disorders (HAND) and related neurodegenerative diseases, highlighting the translational potential of sirtuin-targeted therapeutic strategies. As NAD+-dependent deacetylases and ADP-ribosyl transferases, sirtuins regulate diverse cellular processes, including stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, autophagy, oxidative stress responses, and genomic stability, all of which contribute to neuronal dysfunction and disease progression. This chapter focuses on key mammalian sirtuins, including SIRT1 and SIRT2, which are primarily localized within the nucleus and cytosol; mitochondrial sirtuins SIRT3, SIRT4, and SIRT5; and nuclear/nucleolar sirtuins SIRT6 and SIRT7. Here, a method with a detailed protocol to isolate compartment-specific sirtuin expression and activity was used: subcellular fractionation was performed using a subcellular fractionation kit to obtain cytosolic and nuclear fractions, while mitochondrial isolation was carried out using Tom20 antibody-conjugated magnetic microbeads. These approaches were applied to brain tissues from HIV-positive individuals, as well as to HIV-Tat-treated human microglial (HMC3) cells and astrocytes. This experimental framework enables accurate assessment of compartment-resolved sirtuin regulation in disease-relevant models. Collectively, the chapter highlights the protective roles of sirtuins in mitigating key pathogenic mechanisms underlying HAND and related neurodegenerative diseases. These findings support the emerging concept that sirtuins represent promising pharmacological targets for the development of novel therapeutic interventions in neurodegeneration and HIV-associated brain disorders.
    Keywords:  Epigenetics; HIV-associated neurodegenerative disorders; Histone deacetylases; Mitochondria; Sirtuins
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.023
  28. Fetal Pediatr Pathol. 2026 Sep 02. 1-15
    MICOS13-Related Combined Oxidative Phosphorylation Deficiency 37: A Case Report and Systematic Review of the Literature.
    Khdir H Hamad, Sadraldin A Braim, Dyari Q Hamad, Shadan A Hamad, Karukh K Mohammed, Honar O Kareem, Karzan M Hasan, Bilal A Mohammed, Ayman M Mustafa, Fahmi H Kakamad.
       BACKGROUND: Mitochondrial Contact Site and Cristae Organizing System (MICOS13)- related combined oxidative phosphorylation deficiency 37 is a rare autosomal recessive disorder caused by disruption of mitochondrial structure and function, leading to early-onset multisystem disease. Case report: A genetically confirmed case is described in a 5-month-old female infant born to consanguineous Iraqi parents, presenting with hypotonia, developmental delay, feeding difficulties, laryngomalacia, and recurrent cyanotic episodes. Clinical findings included diminished reflexes and a small atrial septal defect, while laboratory tests revealed hypoalbuminaemia and mild coagulopathy. Whole-exome sequencing identified a homozygous MICOS13 splice-site variant (c.260-2A >G). Despite supportive care, progressive respiratory failure developed, resulting in death at 5months. Review of 13 reported cases demonstrates consistent early onset, universal hepatic and neurological involvement, frequent respiratory compromise, and, among reported cases, uniformly fatal outcomes. Most identified variants are loss-of-function, predominantly frameshift, with no missense variants reported to date.
    CONCLUSION: The present report adds a genetically confirmed case and reinforces the value of considering MICOS13 deficiency in consanguineous infants with early encephalopathy and hepatic dysfunction.
    Keywords:  COXPD37; MICOS13; QIL1; consanguinity; cristae architecture; mitochondrial disease
    DOI:  https://doi.org/10.1080/15513815.2026.2726271
  29. EBioMedicine. 2026 Sep 01. pii: S2352-3964(26)00342-7. [Epub ahead of print]131 106458
    Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study.
    GENOMIT study group
       BACKGROUND: Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking.
    METHODS: In this multinational cohort study, we analysed longitudinal data of patients with a genetically confirmed MD from the GENOMIT registry included at German, Austrian, and Italian sites between 07/2009-01/2025. Our objectives were to (1) expand the genetic spectrum of mitochondrial diabetes mellitus (mDM), (2) identify risk factors, (3) delineate the clinical course, and (4) characterise real-world use of antidiabetic therapies.
    FINDINGS: Of 2399 patients, 1225 (51%) were female, and 281 (12%; 172 female) had mDM. Diabetes occurred across 31 genotypes and exhibited marked genotype dependence, with the highest prevalence in m.3243A>G carriers (177/360 [49%]). Only the m.3243A>G variant was associated with a significantly increased risk of mDM (HR = 10.3; 95% CI 5.2-20.4, p < 0.0001), whereas single mtDNA deletions, multiple mtDNA deletions, and primary LHON variants, as well as sex, BMI, ethnicity, smoking, hypertension and dyslipidaemia did not show a significant association. Median diabetes onset in patients with the m.3243A>G variant was at 47.7 years (SD 45.2-52.0). Among patients with mDM, 140/281 (50%) used insulin, and 111/281 (40%) received non-insulin antidiabetic drugs, most commonly metformin, which was discontinued in 8/50 users. Literature review revealed neurological events temporally linked to metformin application in m.3243A>G carriers, though long-term use without adverse events was likewise reported.
    INTERPRETATION: mDM is frequent in patients with MD, and the individual risk is strongly genotype dependent. While caution is warranted, our data do not justify universal avoidance of metformin; prospective, genotype-informed studies are needed to guide management.
    FUNDING: German Ministry of Research, Technology and Space; Italian Ministry of Health; European Union.
    Keywords:  Diabetes mellitus; Metformin; Mitochondrial diabetes; Mitochondrial disease; m.3243A>G
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106458
  30. Front Mol Neurosci. 2026 ;19 1921079
    From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
    Qiaoqiao Cui, Ke Zheng, Qiyun Liu, Lizhen Wang, Yixin Liu, Ruifang Bai, Wei Zhang, Junhong Guo, Xueli Chang, Juan Wang.
      Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.
    Keywords:  amino acid metabolism; disease-associated microglia; glucose metabolism; immunometabolism; lipid metabolism; microglia; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2026.1921079
  31. Am J Hum Genet. 2026 Sep 03. pii: S0002-9297(26)00312-5. [Epub ahead of print]
    Mutation rate heterogeneity biases variant effect prediction and reveals genuine mutational robustness.
    Hossameldin Loay, Prathitha Kar, Evan Koch, Vladimir Seplyarskiy, Donate Weghorn.
      Variant effect predictors (VEPs) are widely used to interpret the functional consequences of human genetic variation. Because most methods rely on sequence conservation, they implicitly treat conservation as evidence of functional constraint. However, substitution patterns across a phylogeny reflect not only selection but also differences in underlying mutation rates. Here, we show that this creates a systematic confounding: most VEPs capture mutation rate variation and misinterpret it as variation in functional importance. Widely used conservation metrics exhibit a related bias; in particular, phyloP scores correlate strongly with mutation rate even at putatively neutral sites. Consequently, variants at low-mutation-rate sites tend to be predicted as more damaging, and variants at highly mutable sites as more tolerated, than warranted by their true functional impact. We also identify a distinct biological signal in experimental measurements of mutational effects on protein stability: amino acid substitutions that are more likely to arise are, on average, less destabilizing than rarer substitutions. This provides empirical support for mutational robustness in the context of protein stability. However, this relationship is insufficient to explain the mutation-rate dependence observed in current VEP outputs. Together, our findings show that mutation rate heterogeneity systematically biases current variant effect prediction frameworks, highlight the need to model mutation probabilities explicitly in future VEPs, and reveal a genuine biological signal of mutational robustness.
    Keywords:  conservation scores; human genetics; mutation rate variation; variant effect prediction
    DOI:  https://doi.org/10.1016/j.ajhg.2026.08.011
  32. Genome Res. 2026 Sep 01. 36(9): 1902-1920
    Dietary effects on cytosolic and mitochondrial tRNA abundance and modification patterns across mouse tissues.
    Simeiyun Liu, Andrew D Holmes, Ruoxia Zhao, Cassandra Herbert, Patrick A Limbach, Todd M Lowe, Upasna Sharma.
      Transfer RNAs (tRNAs) are central to protein synthesis and are increasingly recognized as dynamic regulators of gene expression whose abundance and chemical modifications are subject to precise biological control. Here, we systematically investigate how two distinct dietary interventions, low-protein and high-fat diets, reshape the tRNA landscape across multiple mouse tissues, using RNA mass spectrometry and ordered two-template relay sequencing (OTTR-seq) to comprehensively profile cytosolic and mitochondrial tRNAs at single-nucleotide resolution. We reveal pronounced tissue-specific biases in tRNA isodecoder expression, including the unexpected presence of full-length cytosolic tRNAs in mature sperm with a distinct isotype composition. In somatic tissues such as liver and heart, dietary conditions alter both tRNA abundance and key modifications known to regulate decoding efficiency, whereas in reproductive tissues diet primarily affects the abundance of select tRNAs with comparatively limited changes in modification profiles. We further demonstrate that mitochondrial tRNAs are subject to diet-responsive changes in both abundance and modification status and that even subtle differences in dietary fat composition are sufficient to alter tRNA modification signatures. Together, these findings establish the tRNA epitranscriptome as a sensitive and tissue-specific sensor of nutritional state and provide a resource for understanding how dietary cues interface with translational regulation in somatic and reproductive tissues.
    DOI:  https://doi.org/10.1101/gr.281159.125
  33. Methods Enzymol. 2026 ;pii: S0076-6879(26)00199-0. [Epub ahead of print]734 121-149
    Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
    Chitrakshi Pant, Vidya Jyothi Alli, Genji Sukumar, Abhijit Mohapatra, Surender Singh Jadav, Srihari Pabbaraja, Shasi V Kalivendi.
      Mitochondrial dysfunction is one of the significant aspects of Parkinson's disease (PD) pathophysiology, marked by a gradual decline in oxidative phosphorylation, an abnormal increase in free radical species, dysfunctional mitochondrial quality control, and faulty mitochondrial biogenesis. Sirtuin 1 (SIRT1), a NAD+-dependent class-III deacetylase, acts as a crucial metabolic sensor that orchestrates transcriptional programs related to mitochondrial biogenesis, respiratory chain assembly, and stress resilience, mainly by way of deacetylation and activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). While screening for the small molecule activators, we have identified that 2,4-dihydroxy-Azaflavanone allosterically activates SIRT1. This chapter outlines a detailed, multi-layered methodological framework for assessing the allosteric activation of SIRT1 by 2,4-dihydroxy-azaflavanone and its downstream effects in a cellular models of PD. The validation process involves synthesis of small molecules, molecular docking studies utilizing crystallographic SIRT1 coordinates (PDB: 5BTR), in vitro fluorometric deacetylase assays with recombinant enzyme, and cellular thermal shift assays (CETSA) to confirm direct, isoform-selective target engagement. The activation of downstream pathways is evaluated by immunoblotting and quantitative PCR for PGC-1α, TFAM, and quantification of mitochondrial DNA (mtDNA) copy number. Functional restoration of mitochondria in cells is analyzed by assessing the overall mitochondrial bioenergetics parameters using Seahorse extracellular flux analyzer. Overall, this integrated approach offers robust, reproducible results for exploring SIRT1-activators in the mechanisms mediating neurodegenerative disease models.
    Keywords:  Azaflavanone; CETSA; Mitochondrial biogenesis; Mitochondrial membrane potential; MtDNA copy number; PGC-1α; Parkinson’s disease; SIRT1; Seahorse assay
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.011
  34. FEBS Open Bio. 2026 Sep 01.
    Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
    Lishen Wang, Mingqiang Deng, Dongmei He, Diqin Lai, Dongjun Liu, Dengyong Zhu, Zhenhua Zhang, Peng Tang, Chuanman Zhou, Menghui Yin, Xichen Bao.
      The Warburg effect has long suggested that oxidative phosphorylation (OXPHOS) is dispensable for tumor growth. However, recent studies have shown that the mitochondrial RNA polymerase inhibitors IMT1 and IMT1b, which impair OXPHOS, are potent anticancer agents. Here, we demonstrate that ionomycin, a selective ionophore known to modulate mitochondrial homeostasis, similarly inhibits mitochondrial gene expression across cancer cell lines. Specifically, gene expression and nascent RNA profiling revealed a global downregulation of mitochondrial gene transcription in Jurkat T, THP-1, HeLa, and NCI-H441 cells. Thus, we conclude that ionomycin suppressed mitochondrial gene transcription, impaired OXPHOS, and thereby inhibited cancer cell proliferation and growth, providing a novel insight into the function of ionomycin.
    Keywords:  OXPHOS; cell proliferation; ionomycin; mitochondrial gene transcription
    DOI:  https://doi.org/10.1002/2211-5463.70297
  35. Eur Heart J Case Rep. 2026 Sep;10(9): ytag578
    Phenotypic overlap masking MELAS in Turner syndrome: a diagnostic challenge.
    Tomoya Shinozaki, Hironobu Sumiyoshi, Daisuke Ueshima, Joe Onaka, Kazue Tajima.
       Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic disorder that can present with diverse clinical features, including cardiomyopathy and chronic intestinal pseudo-obstruction. However, diagnosing MELAS can be challenging when its manifestations overlap with other genetic syndromes, leading to diagnostic anchoring and potential mismanagement.
    Case summary: A 51-year-old woman with mosaic Turner syndrome presented with concentric left ventricular hypertrophy and mildly reduced systolic function (left ventricular ejection fraction 45%). Her medical history included childhood-onset hearing loss, hypothyroidism, and recurrent intestinal obstruction of unknown etiology, which had been previously attributed to Turner syndrome or its comorbidities. Despite resolution of bowel symptoms during prior hospitalizations, she exhibited persistent hyperlactataemia (4.55 mmol/L), a diagnostic red flag. Cardiac magnetic resonance imaging showed patchy mid-wall late gadolinium enhancement, suggesting a non-ischaemic process. Family history revealed a maternal pattern of cardiomyopathy and stroke-like episodes. Genetic analysis confirmed the m.3243A > G mitochondrial DNA mutation (heteroplasmy 23%), establishing a diagnosis of MELAS. Earlier recognition of mitochondrial dysfunction might have avoided a previous unnecessary laparotomy performed for suspected intestinal ischaemia.
    Discussion: This case illustrates the clinical challenge of phenotypic masking; features of Turner syndrome masked the underlying MELAS, resulting in a significant diagnostic delay. The coexistence of unexplained cardiomyopathy, recurrent pseudo-obstruction, and persistent hyperlactataemia should prompt consideration of mitochondrial disease, even in patients with an established genetic diagnosis. Clinicians must remain vigilant for multisystemic 'red flags' to avoid diagnostic anchoring and ensure appropriate metabolic and genetic evaluation.
    Keywords:  Cardiomyopathy; Case report; Chronic intestinal pseudo-obstruction; Hyperlactataemia; Left ventricular hypertrophy; MELAS; Mitochondrial disease; Turner syndrome
    DOI:  https://doi.org/10.1093/ehjcr/ytag578
  36. Nat Neurosci. 2026 Sep 02.
    Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.
    Jun Gao, Haixin Zhao, Xiao Han, Lingmin Zeng, Jingqi Pan, Guangqin Liu, Xuechen Wei, Changwei Liu, Wenjun Wu, Siqi Chen, Jiayi Chen, Ting Li, Jiye Yin, Tao Zhou, Xue-Min Zhang, Ai-Ling Li, Teng Li, Xin Pan.
      Addictive substances hijack the brain's reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a therapeutic target for addiction treatment.
    DOI:  https://doi.org/10.1038/s41593-026-02421-x
  37. Sci Immunol. 2026 Sep 04. 11(123): eaeb9244
    Tissue mitochondrial activity dictates the macrophage pool size.
    Laura Pena-Couso, Jon Sicilia, Sofía Vieto, Roberto Silva-Rojas, María Sánchez-Díaz, Enrique Calvo, Rafael Romero-Becerra, Cintia Folgueira, Leticia Herrera-Melle, Raquel Justo-Méndez, Xiaotong Hong, Silvia Campanario, Juan A López, Georgiana Crainiciuc, María Gil, Sandra Martín-Salamanca, Vera Lukesova, Jessica Segalés, Antonio L Serrano, Iván Ballesteros, Marta León, Macarena de Andrés-Laguillo, Sebastian A Stifter, Lorena Esteban-Martínez, Joan Isern, Jorge Alegre-Cebollada, Miguel Torres, Melanie Greter, Jesús Vázquez, José A Enríquez, Guadalupe Sabio-Buzo, Pura Muñoz-Cánoves, Andrés Hidalgo, José A Nicolás-Ávila.
      Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration-including heart, skeletal muscle, and brown adipose tissue-and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1-CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb9244
  38. Nat Rev Nephrol. 2026 Sep 01.
    Nucleic acid sensing pathways in kidney disease development.
    Magaiver Andrade-Silva, Chaelin Kang, Yena Jang, Katalin Susztak.
      Sterile inflammation triggered by mislocalized self-nucleic acids has emerged as an important mechanism linking cellular injury to progressive kidney dysfunction. Among the key molecular pathways implicated in this response, those underlying nucleic acid sensing represent a central signalling mechanism, particularly the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). In both glomerular and tubular compartments, mitochondrial dysfunction, genotoxic stress and epigenetic dysregulation lead to the accumulation of cytosolic nucleic acids, including mitochondrial DNA and RNA, nuclear DNA fragments and reactivated endogenous retroelements. These signals converge on nucleic acid sensors, including STING, absent in melanoma 2 (AIM2) and endosomal Toll-like receptors (TLRs), activating proinflammatory cascades, cell death programmes and fibrotic remodelling. The latest research highlights the context-dependent engagement of these pathways across human kidney disease and in experimental models of acute kidney injury and chronic kidney disease, linking cellular damage to immune activation and fibrosis. Here, we synthesize emerging insights into the molecular programming of nucleic acid sensing in kidney disease and evaluate the therapeutic landscape, outlining opportunities and challenges for clinical translation.
    DOI:  https://doi.org/10.1038/s41581-026-01120-x
  39. Curr Opin Neurobiol. 2026 Sep 03. pii: S0959-4388(26)00106-6. [Epub ahead of print]101 103270
    Mitochondrial molecular diversity in the brain.
    Alva G Sainz, Xinnan Wang.
      Mitochondria are not uniform organelles. Across the brain, they exhibit profound molecular, biochemical, and functional diversity shaped by cell type, anatomical region, subcellular compartment, and lived experience. Recent advances in cell-type- and subcellular domain-targeted proteomics, transcriptomics, advanced live imaging, and functional biochemistry have begun to map this landscape with unprecedented resolution. Together, these findings challenge the conventional view of mitochondria as generic metabolic engines and position mitochondrial molecular diversity as a fundamental feature of brain organization, with direct relevance to behavior, aging, and neurological disease. This mini review synthesizes key recent studies in this field, highlighting their findings, methodological novelty, and significance, and formulates theories and hypotheses for future investigations.
    DOI:  https://doi.org/10.1016/j.conb.2026.103270
  40. Methods Mol Biol. 2026 ;3038 295-307
    Analysis of mtDNA Methylation.
    Camila Bruna de Lima, Marc-André Sirard.
      Whole-genome methyl sequencing facilitates the characterization of DNA methylation profiles within a reference genome. Recent identification of mitochondrial DNA (mtDNA) as an additional regulatory pathway within embryos paves the way for examining the impact of assisted reproductive technologies and other environmental factors on gamete and embryo developmental programming. Here, we describe the protocol for preparing libraries tailored to detect cytosine methylation in mtDNA extracted from minimal input, typical of experiments involving reproductive samples such as oocytes and embryos.
    Keywords:  Cytosine methylation; Epigenetics; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1007/978-1-0716-5292-3_17
  41. Nat Commun. 2026 Aug 05. pii: 9412. [Epub ahead of print]17(1):
    Airway administered artificial mitochondria-enriched nanovesicles for efficient and selective mitochondria transfer to intervene in pulmonary fibrosis.
    Jinsong Zhang, Siying Fu, Jiawen Wang, Honghui Wu, Zhuoting Li, Ruyi Lin, Hao Sun, Seungho Choe, Yuhuan Kong, Donghang Xu, Jinqiang Wang, Zhen Gu, Jianqing Gao, Tianyuan Zhang.
      Mitochondrial transplantation is a promising therapeutic approach involving the transfer of exogenous mitochondria into diseased cells to restore impaired mitochondrial homeostasis. However, its clinical translation is severely limited by the lack of efficient methods for precise and potent mitochondria transfer. Inspired by natural mitochondria-containing vesicles, we develop mesenchymal stem cell-derived biomimetic nanovesicles with high mitochondrial loading capacity and augmented extracellular mitochondrial stability. These nanovesicles exhibit an ability to efficiently and selectively deliver mitochondrial cargo to injured cells, which is potentially ascribed to the specific interaction between very late antigen-5 on the nanovesicle surface and pathologically upregulated fibronectin on injured cells. In a mouse pulmonary fibrosis model, these nanovesicles successfully deliver healthy mitochondria to injured lung epithelial cells through airway administration, resulting in a significant reduction in fibrotic progression. This study introduces a design of mitochondria-enriched biomimetic nanovesicles for effective and targeted mitochondria transfer, offering a nanotechnology-based strategy to advance mitochondrial transplantation therapy.
    DOI:  https://doi.org/10.1038/s41467-026-76330-9
  42. Autophagy. 2026 Sep 01.
    RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
    Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.
      Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.
    Keywords:  Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2728346
  43. Rev Esp Anestesiol Reanim (Engl Ed). 2026 Sep 02. pii: S2341-1929(26)00179-4. [Epub ahead of print] 502103
    An adult case of acute encephalopathy associated with general anaesthesia and the m.11232T > C MT-ND4 variant.
    I Arranz Chamorro, P Blanco-Schweizer, E Ruiz Pesini, M Busto Busto, T Ticona Espinoza, J Rodríguez Jiménez.
      We report the case of a 20-year-old woman who developed acute encephalopathy after uneventful general anaesthesia with sevoflurane, propofol, and opioids. The patient presented neurological impairment followed by metabolic acidosis and hyperlactatemia and neuroimaging findings involving the basal ganglia, brainstem, and cerebellum. Genetic testing confirmed the mitochondrial variant m.11232T > C in the MT-ND4 gene, previously described only in paediatric patients. This case could be one of the first cases described in the literature of acute encephalopathy associated with this mutation in an adult patient, possibly precipitated by exposure to volatile anesthetics. The patient's favorable clinical and radiological evolution after intensive neuroprotective management and suboccipital decompressive craniectomy highlights the importance of early diagnosis and individualized treatment. Mitochondrial dysfunction should be considered in atypical neurological presentations following general anesthesia, especially when accompanied by lactic acidosis and unusual neuroimaging findings.
    Keywords:  CHANTER syndrome; Encefalopatía tóxico-metabólica; Enfermedad mitochondrial; Mitochondrial DNA mutation; Mitochondrial disease; Mutación MT-ND4; Mutación del ADN mitochondrial; Perioperative metabolic disorders and lactic acidosis; Sevoflurane; Sevoflurano; Síndrome de CHANTER; Toxic–metabolic encephalopathy; Trastornos metabólicos perioperatorios y acidosis láctica; Variante m.11232T > C; m.11232T > C variant; mtND4 mutation
    DOI:  https://doi.org/10.1016/j.redare.2026.502103
  44. Platelets. 2026 Dec;37(1): 2721783
    The mitochondrial deacetylase SIRT3 is nonessential for cyclophilin D-dependent procoagulant platelet formation in mice.
    Jens Van Bael, Anne-Sophie Delmote, Inge Pareyn, Laurence Pirotton, Emma de Cartier d'Yves, Sandrine Horman, Yotis A Senis, Johan Auwerx, Simon F De Meyer, Karen Vanhoorelbeke, Claudia Tersteeg.
      Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD)-dependent mitochondrial deacetylase that regulates protein acetylation and maintains mitochondrial homeostasis in nucleated cells. By deacetylating cyclophilin D (CypD), SIRT3 limits mitochondrial permeability transition pore (mPTP) opening and protects against mitochondrial dysfunction. Although SIRT3 is present in murine and human platelets, its contribution to platelet mitochondrial regulation and procoagulant platelet formation remains unknown. This study investigated whether platelet SIRT3 modulates CypD-dependent procoagulant platelet formation. Platelets obtained from platelet-specific Sirt3 knockout mice (Sirt3plt-/-) and littermate controls (Sirt3plt+/+) were analyzed under resting conditions and after activation with CRP-XL and thrombin. Flow cytometry was used to analyze platelet (activation) markers and procoagulant platelet formation, and mitochondrial respiration was assessed using a Seahorse extracellular flux analyzer. Platelets lacking SIRT3 showed no alterations in basal or agonist-stimulated mitochondrial respiration. Likewise, platelet Sirt3 deletion did not affect the generation of procoagulant platelets in response to strong dual agonist stimulation. These findings indicate that, despite its role in regulating mPTP opening in nucleated cells, platelet SIRT3 is not required for procoagulant platelet formation, suggesting that platelets rely on distinct mechanisms for mPTP regulation.
    Keywords:  Mitochondria; SIRT3; platelet; procoagulant
    DOI:  https://doi.org/10.1080/09537104.2026.2721783
  45. Front Immunol. 2026 ;17 1920684
    Mitochondrial reprogramming of neutrophil extracellular traps in chronic obstructive pulmonary disease and asthma: toward a phenotype-driven therapeutic framework.
    Pei Xu, Fen Xia.
      Chronic obstructive pulmonary disease (COPD), severe asthma, and asthma-COPD overlap (ACO) represent a major global burden of chronic airway inflammation, often remaining inadequately controlled by current corticosteroid and biologic therapies. Neutrophil extracellular traps (NETs) have emerged as a shared effector mechanism in these phenotypes, with neutrophil mitochondria acting as the upstream switch for sustained NET release and corticosteroid resistance. This review consolidates evidence that mitochondrial reprogramming of NETosis operates through four interlinked facets: mitochondrial reactive oxygen species (mtROS) production, the mitochondrial permeability transition pore, mitochondrial DNA release (mtDNA-DAMP), and PINK1/Parkin-PGC-1α-controlled mitophagy. These mechanisms drive a downstream spectrum including suicidal NETosis, vital mtDNA-NETosis, and gasdermin-mediated discharge. Disease-specific drivers (e.g., Nrf2-SLC7A11-GPX4 in COPD; IL-33/TSLP in asthma) reweight this common axis, resulting in distinct effector repertoires and steroid-response profiles. Therapeutically, the landscape is asymmetric: whilst NET-dissolution agents and type-2 biologics are approved, they address distal nodes. Conversely, mitochondrial-targeted antioxidants and metabolic regulators target the convergent root but remain in early development. We argue that translating this framework requires phenotype-enriched trials randomizing molecularly selected patients, coordinated bedside biomarker panels, and explicit inclusion of the ACO subgroup. A coherent framework, a set of candidate targets, and an explicit stratification logic are now defined, and the pivotal preclinical and early-phase clinical data needed to deliver such a programme are the necessary next step.
    Keywords:  chronic airway inflammation; corticosteroid resistance; mitochondrial reprogramming; neutrophil extracellular traps (NETs); phenotype-enriched trials
    DOI:  https://doi.org/10.3389/fimmu.2026.1920684
  46. Redox Biol. 2026 Aug 20. pii: S2213-2317(26)00359-9. [Epub ahead of print]97 104360
    Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.
    Nian Cao, Haijing Zhao, Zhengfeng Wu, Shuanglei Li, Wei Tong, Lihao Jin, Ming Wu, Jie Liu, Aihong Liu, Meng Wang, Changfu Liu, Yuqi Liu, Yundai Chen.
      The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNAIle4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNAIle destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis-using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)-rescues vascular abnormality. This study highlights mt. tRNAIle4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.
    Keywords:  Hypertension; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial Ca(2+) overload; ROS; Vascular organoids; mt.DNA mutation
    DOI:  https://doi.org/10.1016/j.redox.2026.104360
  47. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015
    Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
    Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.
      High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
    Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
  48. Cancer Discov. 2026 Sep 01. 16(9): 1727-1729
    Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
    Silvia Tiberti, Katayoun Rezvani, May Daher.
      Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1267
  49. iScience. 2026 Sep 18. 29(9): 117230
    Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
    Stefania De Santis, Monica Rutigliano, Federica Simone, Letizia Larocca, Maria Laura Matrella, Martina Milella, Antonio Vavallo, Pasquale Ditonno, Nicola Marrano, Anna Mestice, Stefano Battaglia, Michele Battaglia, Antonio Moschetta, Peter Seibel, Elena Piccinin, Gaetano Villani.
      Antibiotics with off-target mitochondrial toxicity can impair host immunity, yet their impact on human adaptive immunity in vivo remains unclear. Because T cell activation and differentiation depend on mitochondrial metabolism, antibiotic-induced mitochondrial stress may alter T helper cell function. We investigated whether uridine and pyruvate (UP) supplementation modulates immune responses in patients receiving mitotoxic antibiotics. In a pilot observational study, 67 patients undergoing prophylactic antibiotic therapy received either antibiotics alone or antibiotics plus daily UP supplementation. Antibiotic exposure increased circulating growth differentiation factor-15 (GDF15), indicating mitochondrial stress, and altered T cell response. UP supplementation was associated with immune features consistent with preserved inflammatory competence, including a trend toward Th1 polarization. These findings suggest that mitotoxic antibiotics can influence human T cell programs and support the hypothesis that UP supplementation may preserve pro-inflammatory T cell responses during antibiotic therapy, representing a potential metabolic strategy to mitigate antibiotic-induced immunotoxicity.
    Keywords:  GDF15; OXPHOS; T cells; antibiotics; immunometabolism; mitochondria; pyruvate; uridine
    DOI:  https://doi.org/10.1016/j.isci.2026.117230
  50. Free Radic Biol Med. 2026 Sep 03. pii: S0891-5849(26)01145-7. [Epub ahead of print]
    Carotid body mitochondria exhibit normal oxygen affinity despite COX4I2 enrichment.
    Agnieszka Swiderska, Michael P Murphy, Gina L J Galli, Andrew W Trafford.
      The carotid body (CB) is the key peripheral oxygen sensor. CB mitochondria are hypothesised to be uniquely adapted with unusually low intrinsic oxygen affinity which, in association with nitric oxide (NO) and reactive oxygen species signalling, enables acute responsiveness to hypoxia. However, CB mitochondrial physiology or intrinsic oxygen affinity have never been measured directly. We sought to address this key gap by isolating sheep CB mitochondria and comprehensively characterising their phenotype and contrasting them to a non-oxygen sensing tissue, left ventricular myocardium (LV). High resolution respirometry, liquid chromatography mass spectrometry, enzymatic assays and in silico modelling were used to characterise mitochondrial content, aerobic capacity, oxygen affinity, complex subunit abundance and activity, H2O2 production and NO sensitivity in ovine CB and LV. Mitochondrial oxygen affinity (P50 = 0.089 mmHg) was lower in the CB than the LV (P50 = 0.058 mmHg; p = 0.005). Whilst mitochondrial content was lower in the CB, CB mitochondria had higher respiratory rates and enzymatic activity than LV. H2O2 production and NO sensitivity were similar in the two tissues. While intrinsic mitochondrial oxygen affinity is slightly lower in the oxygen sensing CB than in the non-oxygen sensing LV, this difference is small. Hence, any role of mitochondria in CB oxygen sensing is not due to an intrinsic difference in the O2 affinity of cytochrome oxidase due to differential expression of its subunits. Instead, this work suggests that differences in O2 affinity in vivo are secondary to other factors, perhaps including NO, that alter mitochondrial O2 affinity.
    Keywords:  Carotid body; heart disease; left ventricle; mitochondria; mitochondrial reactive oxygen species; oxygen sensing
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.005
  51. Sci Rep. 2026 08 31. pii: 27284. [Epub ahead of print]16(1):
    T-rex: standardized analysis of germline variants in whole-exome sequencing trios.
    Sara-Luisa Reh, Carolin Walter, Judith Lohse, Tabita Ghete, Markus Metzler, Julia Hauer, Franziska Auer.
      Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n = 13) confirmed quick learning across clinicians and researchers. Application to a cohort of n = 121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF ≤ 0.1% in gnomAD v4.1), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing reproducible, end-to-end workflows for clinical genomics, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers.
    Keywords:  Genetic predisposition; Germline variants; Rare disease; Trio-based sequencing; WES analysis platform
    DOI:  https://doi.org/10.1038/s41598-026-67762-w
  52. Free Radic Biol Med. 2026 Aug 29. pii: S0891-5849(26)01056-7. [Epub ahead of print]256 312-322
    APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.
    Firoz Akhter, Asma Akhter, Jasmine Zhou, Michelle Xi, Donghui Zhu.
      Advanced glycation end products (AGEs) accumulate with aging and have been implicated in neurodegeneration, yet their relationship with the APOE4 genotype and downstream inflammatory signaling remains poorly understood. Here, we show that APOE4 is associated with greater age-dependent AGE accumulation and APOE glycation in the aging brain compared with APOE3 in animal models. These changes are accompanied by mitochondrial dysfunction and increased release of mitochondrial DNA (mtDNA) into the cytosol, providing a potential trigger for innate immune activation. Consistent with enhanced innate immune signaling, APOE4 brains exhibit increased cGAS expression and phosphorylation of STING, TBK1, and IRF3, together with elevated type I interferon and pro-inflammatory responses. This activation is particularly prominent in microglia, as demonstrated by increased cGAS-DNA interactions and greater colocalization of cGAS signaling with Iba1-positive cells. APOE4 mice further display increased levels of cGAMP and IFN-β, as well as enhanced expression of pro-inflammatory cytokines and interferon-stimulated genes. Mechanistically, exposure of primary microglia to AGEs induces cytosolic mtDNA release and activates cGAS-STING signaling, whereas pharmacological inhibition of the receptor for advanced glycation end products (RAGE) attenuates these responses. Together, these findings identify an association between the APOE4-AGE axis, mitochondrial dysfunction, mtDNA release, and enhanced cGAS-STING-related inflammatory signaling in the aging brain, while the in vitro studies support a functional contribution of AGE-RAGE signaling to these responses in primary microglia.
    Keywords:  APOE4; Advanced glycation end products (AGEs); Microglia; Mitochondrial DNA; Neuroinflammation; cGAS-STING signaling
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.054
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