bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–07–12
fifty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondria setting the stage for ferroptosis.
  2. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  3. Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
  4. Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
  5. Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
  6. Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
  7. Research progress on VDAC2 in mitochondrial dysfunction-related diseases.
  8. Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.
  9. Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
  10. A Molecular Engineering Strategy to Fine-Tune Phototoxicity of AIE Probes for Super-Resolution Imaging of Mitochondrial Cristae Dynamics.
  11. Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation Deficiency.
  12. Intercellular Mitochondrial Transfer and Mitochondrial Transplantation in Cardiovascular Disease.
  13. N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
  14. Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
  15. The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate.
  16. The human LRRK2-R1441G mutation drives age-dependent oxidative stress and mitochondrial dysfunction in dopaminergic neurons.
  17. Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
  18. Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
  19. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  20. Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.
  21. Mitochondria produce lactate to vent redox pressure.
  22. A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
  23. Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD.
  24. RankVar: machine learning-based variant ranking and reinterpretation for rare genetic diseases.
  25. TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.
  26. SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
  27. Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
  28. Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.
  29. Droplet Microfluidics-Enabled Mitochondrial Transfer from Young to Senescent MSCs to Ameliorate Cellular Senescence.
  30. R1398 is the GTP-𝛾-phosphate sensor that drives the ROC G-domain switching mechanism unique to Parkinson's disease-associated LRRK2.
  31. ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
  32. Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
  33. Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
  34. Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
  35. Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
  36. Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
  37. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  38. De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
  39. Interplay between Neuronal Metabolism and Signaling in Model Systems with Impaired α-Ketoglutarate Dehydrogenase Complex Activity.
  40. Mitochondrial translocation of DNMT3L suppresses oxidative phosphorylation and restrains megakaryopoiesis.
  41. A human-specific microRNA controls the timing of excitatory synaptogenesis.
  42. Resolving cellular signaling in space and time: From organelle proteomics to spatial phosphoproteomics.
  43. Restoring the powerhouse: mitochondrial transplantation in regenerative medicine and cancer therapy.
  44. Decoding the Hot-Mitochondrion Paradox.
  45. Interaction of G2019S LRRK2 and metabolic syndrome in a two-hit mouse model of Parkinson's disease: LRRK2-driven systemic depletion of pyrimidine nucleosides.
  46. Using human 3D organoid models to gain mechanistic insight in motor neuron diseases.
  47. Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.
  48. The role of mitochondrial proteases in inflammation and immunity.
  49. Long-Chain Fatty Acid Oxidation Disorder Genes: A Comprehensive Genetic Database of LC-FAOD Variants, Genotypes, and Phenotypes.
  50. Addendum: In situ architecture of the human prohibitin complex.
  51. COQ2-Associated Primary Coenzyme Q10 Deficiency Presenting With Proteinuria: A Case Report and Literature Review.
  1. Trends Endocrinol Metab. 2026 Jul 07. pii: S1043-2760(26)00150-5. [Epub ahead of print]
    Mitochondria setting the stage for ferroptosis.
    Sofia Ahola.
      Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron-sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.
    Keywords:  coenzyme Q; ferroptosis; iron–sulfur cluster; lipid peroxidation; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2026.06.006
  2. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  3. Protein Sci. 2026 Aug;35(8): e70703
    Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
    Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.
      Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.
    Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling
    DOI:  https://doi.org/10.1002/pro.70703
  4. Mol Genet Metab. 2026 Jun 26. pii: S1096-7192(26)00481-6. [Epub ahead of print]148(4): 110198
    Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
    Atsuko Okazaki, Yukiko Yatsuka, Takuya Fushimi, Takanori Onuki, Yuko Aida, Hisato Aihara, Toshiyuki Imasawa, Akira Ohtake, Kei Murayama, Yasushi Okazaki.
       BACKGROUND: Mitochondrial diseases present diagnostic challenges due to variations in heteroplasmy levels of mitochondrial DNA (mtDNA) in different tissues. Current diagnostic approaches primarily rely on blood testing, which may miss pathogenic variants present at higher levels in other accessible tissues.
    METHODS: We analyzed tissue samples from 164 individuals (125 probands and 39 family members) with genetically confirmed mitochondrial diseases using droplet digital PCR (ddPCR). We quantified heteroplasmy levels in five tissue types: blood, urine, cardiac muscle, skeletal muscle, and kidney tissue.
    RESULTS: Among the 108 blood samples and 87 urine samples from patients carrying the m.3243A>G variant, urine samples demonstrated significantly higher heteroplasmy levels than blood samples (median: 76.6% [interquartile range (IQR): 50.8-91.8%] vs. 20.9% [IQR: 11.3-41.4%], p < 0.001). In a paired analysis of 80 patients with the m.3243 A > G variant who provided both blood and urine samples, urine heteroplasmy exceeded blood levels in all cases (median difference: 44.6% [interquartile range (IQR): 26.9-56.7%], p < 0.001). Moderate positive correlations were observed between blood and urine heteroplasmy (all variants: r = 0.68, n = 94 pairs; m.3243 A > G: r = 0.66, n = 80 pairs; both p < 0.001). Using an exploratory 10% heteroplasmy threshold based on prior reports for m.3243A>G, blood classified 24 of the 94 paired cases (25%, or one in four patients) as <10% while urine was ≥10%. Cardiac tissue exhibited the highest heteroplasmy levels (mean: 86% ±8% in m.3243A>G patients), though this likely reflects selection bias, as cardiac biopsies were obtained only from patients with cardiac involvement.
    CONCLUSIONS: Urine specimens demonstrate higher heteroplasmy levels and more often place individuals above an exploratory 10% heteroplasmy threshold compared with blood specimens for certain mitochondrial DNA (mtDNA) variants, most notably m.3243A>G. Using this exploratory threshold, 24 of 94 paired blood-urine samples (25%) had blood heteroplasmy <10% while urine heteroplasmy was ≥10%, supporting the use of urine as an important noninvasive complementary specimen, and in many cases a preferred specimen, for suspected m.3243A>G. However, blood testing remains appropriate for variants that typically show high blood heteroplasmy and a relatively high threshold for clinical expressivity, such as m.8993 T > G. These findings support the implementation of urine-based screening protocols for suspected m.3243A>G cases, which may reduce underestimation of variant load and improve diagnostic evaluation.
    Keywords:  Droplet digital PCR; Heteroplasmy; Inherited metabolic disorder; Mitochondrial disease; Tissue-specific diagnosis; m.3243A>G
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110198
  5. Nat Metab. 2026 Jul 08.
    Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
    Ankur Garg, Brandon R Desousa, Raju Roy, Amy Flis, Skyler Y Blume, Yohei Abe, Arthur A Melo, Ryan R Cupo, Gabriela Grigorean, Daniel R Southworth, James Shorter, Isha H Jain.
      Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.
    DOI:  https://doi.org/10.1038/s42255-026-01566-0
  6. Nat Metab. 2026 Jul 08.
    Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
    Anthony S Grillo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01569-x
  7. Mol Biol Rep. 2026 Jul 10. pii: 1138. [Epub ahead of print]53(1):
    Research progress on VDAC2 in mitochondrial dysfunction-related diseases.
    Miao Wang, Yuanyuan Cui, Yili Sun, Jia Li.
      Mitochondrial dysfunction contributes to numerous human diseases. Voltage‑dependent anion channel 2 (VDAC2) is an essential outer mitochondrial membrane porin with distinct structural and functional properties that are non-redundant with those of VDAC1 and VDAC3. VDAC2 precisely controls ATP, ADP, NADPH and Ca2+ transport, thereby acting as a key hub for energy metabolism, calcium homeostasis, redox balance and cell fate. It directly binds BAX/BAK to differentially regulate apoptosis and is also involved in ferroptosis, necroptosis, Parkin‑dependent mitophagy, and lipid transport through protein interactions and post‑translational modifications. Aberrant expression or dysfunction of VDAC2 promotes tumorigenesis, neurodegenerative diseases, and cardiovascular disorders through metabolic reprogramming, apoptotic imbalance, immune evasion, and impaired mitochondrial quality control. Several small‑molecule compounds and peptides targeting VDAC2 have been developed, providing valuable tools for mechanistic studies and potential therapies for mitochondrial dysfunction‑related diseases. Several major challenges remain, including poor isoform selectivity, a lack of tissue‑specific conditional knockout models, and unclear cross‑species conservation. This review systematically summarizes the structure of VDAC2, its versatile roles in mitochondrial function, disease mechanisms, and advances in pharmacological targeting. We also highlight current limitations and future directions, with the aim of providing a theoretical basis for VDAC2‑targeted drug development and clinical translation.
    Keywords:  Apoptosis; Mitochondrial dysfunction; Myocardial injury; Neurodegenerative diseases; Tumor; VDAC2
    DOI:  https://doi.org/10.1007/s11033-026-12336-2
  8. Cureus. 2026 Jun;18(6): e110551
    Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.
    Víctor J Altares, María Castro Rebollo, Julio González Martín-Moro.
      Leber hereditary optic neuropathy (LHON) constitutes a mitochondrial disorder characterized by subacute, bilateral central vision impairment, secondary to mitochondrial DNA (mtDNA) mutations. These mutations compromise Complex I, subsequently precipitating the degeneration of retinal ganglion cells (RGCs). While traditionally manifesting in young males, contemporary literature has documented a small number of cases of late-onset presentation. Numerous studies have suggested the existence of a distinct clinical phenotype, particularly concerning the funduscopic features of the optic disc. Elucidating this atypical manifestation is paramount to preclude diagnostic inaccuracies and to refine therapeutic intervention. In this context, we describe the case of a 70-year-old male presenting with progressive bilateral vision loss and diffuse thinning of the ganglion cell complex on optical coherence tomography (OCT), notably lacking the hyperaemic phase typical of younger patients. Genetic analysis confirmed the homoplasmic m.14484T>C mutation; however, despite the traditionally favourable prognosis associated with this variant, the patient progressed to permanent optic atrophy with no functional recovery. By reporting this case of late-onset LHON and providing a comprehensive review of clinical cases documented in recent literature, our objective is to ascertain whether late-onset presentation endows this clinical entity with additional distinguishing characteristics.
    Keywords:  age-related; case report; late-onset; leber hereditary optic neuropathy; lhon; mitochondrial disease; optic disc findings; senile
    DOI:  https://doi.org/10.7759/cureus.110551
  9. CNS Neurosci Ther. 2026 Jul;32(7): e71013
    Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
    Zou Pan, Li Yang, Haiyan Tang, Chen Chen, Qian Yang, Tenghui Wu, Fang He, Zhanwei Zhang, Fangyun Liu, Jing Peng.
       AIM: To delineate the clinical features of AFG3L2-related developmental and epileptic encephalopathy (DEE) and explore its pathogenic mechanisms.
    METHODS: Whole-genome and blood transcriptome sequencing were performed in undiagnosed DEE patients. Patient-derived skin fibroblasts were established for the analysis of RNA and protein expression as well as for mitochondrial functional assays, including OPA1 processing, mtDNA copy number, membrane potential, ATP production, mitochondrial morphology analysis, and mitochondrial stress testing. Additionally, published AFG3L2-related epilepsy cases were systematically reviewed.
    RESULTS: We identified four novel AFG3L2 variants in four DEE patients from two unrelated families, including splice-site/intronic variants in one family and exon-deletion/intronic variants in the other, fitting a recessive model of disease. In these patients, plus six additional previously reported DEE patients, symptoms included severe developmental delay, intractable seizures, microcephaly, generalized spasticity, and progressive cerebral atrophy. Transcriptome and fibroblast functional analyses revealed aberrant splicing, reduced AFG3L2 expression, defective OPA1 processing, decreased mtDNA content, impaired membrane potential and ATP production, fragmented mitochondrial networks, and diminished respiratory capacity, supporting a loss-of-function mechanism. Compared with spastic ataxia 5-usually involving null-missense or missense-missense genotypes-DEE predominantly features null-null combinations.
    SIGNIFICANCE: We implicate AFG3L2 as a novel causative gene for DEE, likely through mitochondrial proteostasis failure and bioenergetic compromise, expanding the phenotypic and genotypic spectrum of AFG3L2-related disorders.
    Keywords:   AFG3L2 ; developmental and epileptic encephalopathy; genomic and transcriptomic sequencing; mitochondrial dysfunction; m‐AAA protease
    DOI:  https://doi.org/10.1002/cns.71013
  10. Adv Sci (Weinh). 2026 Jul 06. e24281
    A Molecular Engineering Strategy to Fine-Tune Phototoxicity of AIE Probes for Super-Resolution Imaging of Mitochondrial Cristae Dynamics.
    Kongqi Chen, Mengjie Wang, Chuen Kam, Zhiming Wang, Qinrong Zhang, Sijie Chen.
      Understanding mitochondrial morphology and function is critical for investigating mitochondrial diseases, yet fluorescent probes that label the inner mitochondrial membrane (IMM) and report dysfunction at high spatiotemporal resolution remain limited. Here, we rationally designed aggregation-induced emission-active probes with tunable alkyl chain lengths and carboxyl groups, allowing us to fine‑tune phototoxicity and achieve a controlled, mild level of reactive oxygen species (ROS) generation. Two probes, named OTS-7C and OTS-12C, enabled super‑resolution imaging of mitochondrial cristae using stimulated emission depletion microscopy (STED), while OTS-12C further supported Hessian-structured illumination microscopy (Hessian-SIM) imaging in living cells. Importantly, the controllable ROS output of OTS‑12C supports prolonged time-lapse imaging of mitochondrial stress responses, including swelling, cristae remodeling, and recovery. We further demonstrated that it could serve as a platform for evaluating antioxidant effectiveness, using Vitamin C and Astaxanthin as model antioxidants. Meanwhile, fluorescence lifetime imaging of OTS-12C revealed that ROS-induced oxidation of unsaturated lipids increased its fluorescence lifetime within the IMM, permitting real-time monitoring of mitochondrial functional states. This work presents a simple yet effective strategy to fine-tune the phototoxicity of AIE photosensitizers and provides OTS-12C as a versatile fluorescent probe for high-resolution visualization of mitochondrial ultrastructure, investigating mitochondrial stress management and evaluating drug antioxidant efficacy in living cells.
    Keywords:  aggregation‐induced emission; fluorescent probes; mitochondrial ultrastructure; phototoxicity; super‐resolution imaging
    DOI:  https://doi.org/10.1002/advs.202524281
  11. J Inherit Metab Dis. 2026 Jul;49(4): e70222
    Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation Deficiency.
    Pranavi Hegde, Aakanksha Anand, Rita Rani, Namanpreet Kaur, Ami Shah, Shilpa Kulkarni, Janani Supraja Mallavaram, Raghavender Medishetti, Amoolya Kandettu, Huzail Shaikh, Shahyan Siddiqui, Purvi Majethia, Vivekananda Bhat, Periyasamy Radhakrishnan, Aarti Sevilimedu, Sanjiban Chakrabarty, Anju Shukla.
      ATP synthase (complex V) catalyzes ATP synthesis and is composed of the F1 catalytic sector and the F0 proton-conducting sector. The e subunit of the F0 sector, encoded by ATP5ME, is essential for complex V dimerization and cristae organization; however, genetic variants in ATP5ME have not yet been implicated in human disease. We ascertained a 4-year-old male, born of a consanguineous marriage, who presented with neuroregression, feeding difficulty, spasticity, encephalopathy, bilateral sensorineural hearing loss and optic atrophy. Exome sequencing identified a biallelic 62 bp deletion, c.-48_14del in ATP5ME (NM_007100.4; NC_000004.12: g.674234_674295del), spanning the upstream sequence, the 5' untranslated region, and part of exon 1. Patient-derived fibroblasts exhibited markedly decreased ATP5ME transcript and protein levels, accompanied by a reduction in the expression of complex I, IV, and V subunits. In vitro assays demonstrated reduced activities of complexes I, IV, and V, impaired mitochondrial respiration, reduced reactive oxygen species levels, decreased mitochondrial membrane potential, and reduced ATP levels. Additionally, atp5me knockout zebrafish demonstrated a severe developmental phenotype characterized by craniofacial defects, reduced locomotion, and decreased ATP levels. This was accompanied by reduced protein levels of complex II and IV subunits, mild decrease in mtDNA, and upregulation of genes associated with glycolysis and oxidative stress. All observed phenotypes were rescued by human ATP5ME mRNA complementation, thereby validating the pathogenicity of ATP5ME deficiency in vivo.
    Keywords:   ATP5ME ; ATP synthase; OXPHOS; complex V deficiency; mitochondrial bioenergetics; mitochondrial encephalopathy; oxidative phosphorylation; subunit e; zebrafish
    DOI:  https://doi.org/10.1002/jimd.70222
  12. Can J Cardiol. 2026 Jul 07. pii: S0828-282X(26)00654-9. [Epub ahead of print]
    Intercellular Mitochondrial Transfer and Mitochondrial Transplantation in Cardiovascular Disease.
    Fatemeh Farhid, Farshad Heydari, Michael R Hamblin, Saman Masoudifar, Amirhossein Sahebkar, Jalal Naghinezhad.
      Mitochondria have traditionally been regarded as intracellular powerhouses; however, they are now recognized as dynamic intercellular signaling organelles capable of moving between cells to coordinate tissue adaptation and repair. This Review examines the emergence of mitochondria transfer as a fundamental mechanism of cardiovascular communication, integrating current evidence for the exchange of intact mitochondria, mitochondrial DNA, and mitochondrial components among cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts, and immune cells. We discuss the major routes of mitochondria transfer, including tunneling nanotubes, extracellular vesicles, gap junction-associated pathways, and extracellular mitochondrial release, together with the molecular machinery governing mitochondrial trafficking, such as MIRO proteins, TRAK adaptors, and cytoskeletal motor complexes. By reshaping cellular bioenergetics, redox homeostasis, metabolic signaling, and innate immune responses, transferred mitochondria exert profound effects on cardiovascular homeostasis and disease, influencing ischemia-reperfusion injury, heart failure, vascular remodeling, and inflammatory vascular disorders. We further evaluate recent advances in mitochondria transplantation, engineered mitochondrial donor platforms, and emerging imaging technologies that enable tracking of mitochondrial fate in vivo. Finally, we propose an integrated mechanistic framework in which the biological consequences of mitochondria transfer and mitochondria transplantation are determined by donor-recipient compatibility, mitochondrial quality, and the surrounding microenvironment, thereby explaining their context-dependent protective, maladaptive, and immunomodulatory effects. By identifying critical gaps in molecular mechanisms, methodological standardization, and clinical validation, this Review outlines a roadmap for translating mitochondria-based therapeutic strategies into precision cardiovascular medicine.
    Keywords:  Bioenergetics; Cardiovascular disease; Extracellular vesicles; Heart failure; Mitochondrial transfer; Mitochondrial transplantation; Regenerative cardiology
    DOI:  https://doi.org/10.1016/j.cjca.2026.06.032
  13. bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]
    N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
    Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.
      N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.
    DOI:  https://doi.org/10.64898/2026.06.29.735215
  14. Annu Rev Genet. 2026 Jul 09.
    Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
    Zhe Chen, Hong Xu.
      The mitochondrial genome resides in a highly mutagenic environment and is typically maternally inherited with little recombination, features that should render mitochondrial DNA (mtDNA) prone to the accumulation of deleterious variants. Contrary to this expectation, mtDNA integrity is remarkably well-preserved over evolution. Purifying selection in the female germline that limits transmission of deleterious mtDNA mutations has been documented in various animal models and in humans. Here, we synthesize the literature, with an emphasis on insights from Drosophila, revealing that replication competition-the preferential propagation of healthy genomes over deleterious ones-is the main mechanism driving mtDNA purifying selection in the germline. We highlight developmentally orchestrated mitochondrial processes that couple genome function to replication, enabling selection based on the bioenergetic performance of individual genomes during oogenesis. Finally, we discuss how replication competition can generate genetic conflicts, particularly through the emergence of selfish mtDNA, and how such conflicts may have shaped mtDNA evolution and features of mitochondrial genetics, including maternal inheritance and the mitochondrial bottleneck.
    DOI:  https://doi.org/10.1146/annurev-genet-011626-033825
  15. bioRxiv. 2026 Jun 30. pii: 2026.06.29.733391. [Epub ahead of print]
    The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate.
    Alva G Sainz, Chulhwan S Kwak, Kwang Bog Cho, Sejal A Sripadanna, Brandon H Bergsneider, Zoe Zizzo, Aarooran S Durairaj, Zehui Du, Ian Cooney, Anthony Venida, Nike Bharucha, Ioannis Karakikes, Wah Chiu, Michael Lim, Michael C Bassik, Xinnan Wang.
      BAX macropores in the outer mitochondrial membrane (OMM) are canonical mediators of apoptosis, but whether the same pore structure can drive distinct cell death pathways remains unclear. Here, we identify the OMM protein MIRO1 as a context-specific modulator of BAX activity. Mechanistically, MIRO1 binds BAX via MIRO1's N-terminal domain to promote macropore formation and the release of mitochondrial DNA (mtDNA) into the cytoplasm, triggering the STING-pIRF3 signaling axis. In glioma cells, this pathway sustains GPX4 expression via pIRF3-mediated transcriptional activation and confers ferroptosis resistance while bypassing inflammation. By contrast, in Parkinsonian neurons, the MIRO1-BAX complex promotes mitochondrial-stress-induced apoptosis. Using structure-guided drug discovery, we developed first-in-class small molecules that allosterically disrupt the MIRO1-BAX complex by engaging MIRO1's distal GTPase pocket. These compounds sensitize glioma cells to ferroptosis and protect neurons from apoptosis. Our findings reveal a disease-specific mitochondrial switch for life-death decisions and illuminate the molecular logic by which cells exploit and interpret OMM permeabilization.
    DOI:  https://doi.org/10.64898/2026.06.29.733391
  16. Mol Neurodegener. 2026 Jul 07.
    The human LRRK2-R1441G mutation drives age-dependent oxidative stress and mitochondrial dysfunction in dopaminergic neurons.
    Yuanxin Chen, Lianteng Zhi, Shiquan Cui, Huaixin Wang, Chenbo Zeng, Hui Zhang.
       BACKGROUND: Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of Parkinson's disease (PD), particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons.
    METHODS: We employed a BAC transgenic mouse model overexpressing human LRRK2-R1441G (BAC-hR1441G) and crossed it with TH-mito-roGFP mice to enable mitochondria-targeted redox imaging specifically in DA neurons. Acute midbrain slices from 3-, 6-, and 10-month-old mice were imaged using two-photon microscopy to assess mitochondrial oxidative stress. In parallel, mitochondrial respiratory function, membrane potential flickering events, and expression of uncoupling proteins (UCP4/UCP5) were analyzed. Spatial transcriptomic profiling was performed using the GeoMx® Digital Spatial Profiler to uncover associated molecular alterations.
    RESULTS: We observed a progressive increase in mitochondrial oxidative stress in SNc DA neurons of BAC-hR1441G mice at 3, 6, and 10 months of age. This was accompanied by reduced respiratory complex activity, attenuated mitochondrial membrane potential flickering, and diminished expression of UCP4 and UCP5. Spatial transcriptomic analysis revealed dysregulation of genes linked to mitochondrial uncoupling, calcium signaling, and redox regulation in BAC-hR1441G SNc DA neurons.
    CONCLUSIONS: These findings reveal an age-dependent progression of mitochondrial dysfunction in BAC-hR1441G SNc DA neurons. Dysregulation of calcium channels and uncoupling proteins emerges as a key mechanism contributing to bioenergetic failure, suggesting potential therapeutic targets to mitigate PD progression.
    Keywords:  LRRK2; Mitochondrial dysfunction; Mitochondrial membrane potential (MMP); Oxidative stress; Parkinson’s disease; Uncoupling protein (UCP)
    DOI:  https://doi.org/10.1186/s13024-026-00969-7
  17. Mol Ther Adv. 2026 Sep 10. 34(3): 201788
    Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
    Liqun Xu, Yilang Wu, Wanfei Wu, Xiao Li, Ronghao Deng, Haibao Zhu, Aihua Mao, Pingnan Sun, Xin Zhang, Wencan Xu, Chi-Ju Wei.
      Fusogenic plasma membrane vesicles (PMVs) were engineered as carriers for mitochondrial delivery into senescent SH-SY5Y cells, a human neuroblastoma cell line widely used as an in vitro model for neurodegenerative diseases. Mitochondrial transfer was achieved via cell fusion mediated by the fusogenic vesicular stomatitis virus glycoprotein G. After mitochondrial transplantation, senescent SH-SY5Y cells exhibited marked phenotypic reversal, accompanied by restoration of glucose metabolism, ATP production, lactate levels, and mitochondrial respiratory activity to near-normal levels. In addition, mitochondrial transplantation regulated the senescence-associated secretory phenotype and associated inflammatory signaling pathways, while significantly enhancing antiapoptotic activity. Single-nucleotide polymorphism tracing of mitochondrial DNA confirmed the stable persistence of transplanted mitochondria within recipient cells, which was associated with recovery of normal mitochondrial morphology, function, and biogenesis. Notably, autophagic activity decreased after mitochondrial transplantation. Finally, alpha-synuclein expression was reduced, whereas dopamine production and the activities of enzymes involved in dopamine synthesis were increased after mitochondrial transplantation. The results demonstrated that mitochondrial transplantation can effectively reverse the senescence phenotype of SH-SY5Y cells, suggesting that mitochondrial transplantation may represent a promising therapeutic strategy for neurodegenerative disorders such as Parkinson disease.
    Keywords:  PMVs; Parkinson disease; SH-SY5Y cells; SNP analysis; autophagy; cellular senescence; mitochondria transplantation; plasma membrane vesicles; single-nucleotide polymorphism analysis
    DOI:  https://doi.org/10.1016/j.omta.2026.201788
  18. Front Aging. 2026 ;7 1830839
    Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
    Nengneng Shi, Xiaojing Li.
      Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.
    Keywords:  age-related disease; aging; inflammation; mitochondria; mitochondrial transcription factor A; oxidative stress
    DOI:  https://doi.org/10.3389/fragi.2026.1830839
  19. Aging (Albany NY). 2026 Jul 06. 18(1): 787-812
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy
    DOI:  https://doi.org/10.18632/aging.206395
  20. Biogerontology. 2026 Jul 07. pii: 124. [Epub ahead of print]27(4):
    Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.
    Antero Salminen, Kai Kaarniranta, Anu Kauppinen.
      About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.
    Keywords:  Ageing; Bacterial origin; CGAS-STING; DNA/RNA sensors; Endosymbiosis; Evolution
    DOI:  https://doi.org/10.1007/s10522-026-10470-9
  21. Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]
    Mitochondria produce lactate to vent redox pressure.
    Serwah A Danquah, Lucas B Sullivan.
      Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
    DOI:  https://doi.org/10.1016/j.tem.2026.06.005
  22. Cell Rep. 2026 Jul 04. pii: S2211-1247(26)00681-9. [Epub ahead of print]45(7): 117603
    A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
    Chunyan Wu, Tongtong Wang, Songlin Gong, Jing Zhang, Charlotte G Mann, Min Li, Ziyu Liu, Yizhi Sun, Shenwei Shi, Zhenghong Liu, Katrien De Bock, Miroslav Balaz, John Speakman, Christian Wolfrum.
      Brown adipose tissue (BAT) regulates whole-body energy balance through uncoupling protein 1 (UCP1)-dependent thermogenesis and secretion of metabolic factors. Recent studies suggest UCP1-independent mechanisms contribute to energy balance, with UCP1 being conditionally dispensable. However, how adaptation to UCP1 deficiency is regulated remains unclear. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift toward an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). The Ucp1/Gfral knockout increased food intake to compensate for decreased energy expenditure in AT. Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed. These findings identify a regulatory brown adipocyte subpopulation emerging in response to UCP1 deficiency, representing a compensatory mechanism for maintaining energy homeostasis in mammals.
    Keywords:  CP: metabolism; GDF15; GFRAL; Ucp1 knockout mice; adipose tissue; cold exposure; energy expenditure; single-nucleus RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117603
  23. EMBO Rep. 2026 Jul 10.
    Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD.
    Tran Diem Nghi, Truong Thi My Nhung, Seunghyun Kim, Jonghyeok Yun, Nguyen Tran Nam Tien, Ara Lee, Minkyo Jung, Eun Jin Jang, Bon Seong Goo, Jin Yeong Yoo, Sung Ryong Shin, Ji Young Mun, Kyeng Min Park, Nguyen Phuoc Long, Cana Park, Sang Ki Park.
      Embryonic neural stem and progenitor cells occupy a specialized niche along the lateral ventricles, where receptors on their apical membrane sense extracellular cues essential for preserving progenitor identity. How such surface signals are coupled to mitochondrial metabolism remains unclear. Here, we identify EPHA2 as a receptor enriched in cortical progenitors and show that disruption of its non-canonical, ligand-independent signaling compromises progenitor maintenance in vivo. EPHA2 perturbation reduces mitochondrial respiration, Complex I activity, and mitochondrial NAD+ regeneration, and is accompanied by lower mitochondrial abundance of the Complex I assembly factor ECSIT. Restoring mitochondrial NAD+ regeneration with MTS-LbNOX, or restoring mitochondrial ECSIT with ECSIT WT-but not a mitochondrial targeting-deficient mutant-attenuates the progenitor defects caused by EPHA2 perturbation. Maternal supplementation with NAD+ or its precursor NMN similarly mitigates these developmental defects. We further identify a PP2A-sensitive ECSIT phospho-state, including T179, that is consistent with regulated mitochondrial ECSIT accumulation downstream of EPHA2. Together, these findings support a model in which EPHA2 helps maintain embryonic cortical progenitors by sustaining ECSIT-dependent Complex I-linked mitochondrial redox homeostasis.
    DOI:  https://doi.org/10.1038/s44319-026-00858-6
  24. Genome Med. 2026 Jul 04.
    RankVar: machine learning-based variant ranking and reinterpretation for rare genetic diseases.
    Yuan Zhang, Mian Umair Ahsan, Peng Wang, Xiaoqi Lin, Ian M Campbell, Cong Liu, Wendy K Chung, Chunhua Weng, Kai Wang.
       BACKGROUND: Prior biological knowledge and phenotype information can help identify disease genes from whole genome/exome sequencing studies, but how best to incorporate external knowledge with variant data remains challenging. We developed a machine learning algorithm called RankVar to prioritize causative variants for rare diseases, based on clinical notes and genome/exome sequencing profiles.
    METHODS: RankVar uses a random forest classifier trained on ~ 1 million variants from the 1000 Genomes Project with spiked-in pathogenic variants. For testing, we compiled sequencing data and phenotype information from several independent datasets: 260 subjects from the Children's Hospital of Philadelphia (CHOP) with positive genetic diagnosis of various Mendelian diseases, 135 subjects from Birth Defects Biorepository (BDB), as well as 356 and 97 subjects with candidate causal variants for autism spectrum disorders from the Simons Simplex Collection (SSC) and the Simons Foundation Powering Autism Research for Knowledge (SPARK), respectively.
    RESULTS: RankVar achieves a top 10 variant accuracy of 90.0%, 81.5%, 46.1%, and 76.3% for CHOP, BDB, SSC, and SPARK, respectively, with improved performance over existing approaches. Notably, RankVar successfully identified X-linked and Y-linked disease-causal variants, such as KDM6A (p.N915Kfs5*) and SRY (p.W98X), as the top candidate variants. Moreover, we evaluated RankVar for genomic reinterpretation of 130 unsolved CHOP cases with hearing loss and successfully identified 61 candidate causal variants after manual review.
    CONCLUSIONS: In summary, RankVar performed favorably relative to existing methods in our evaluation, accommodated different genetic models and X/Y chromosome variants, and may provide a useful framework for prioritizing variants in monogenic or oligogenic diseases. We anticipate that RankVar may aid in primary genetic diagnosis, genome reinterpretation of previously unsolved cases, and the discovery of novel disease genes.
    Keywords:  Machine learning; Rare genetic disease; Variant prioritization
    DOI:  https://doi.org/10.1186/s13073-026-01701-2
  25. FEBS J. 2026 Jul 08.
    TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.
    Dóra Varga, Zsolt Ráduly, Beáta Boros-Oláh, Éva Nagy, Zsolt Karányi, László Halász, Bálint László Bálint, György Vámosi, Emese Tóth, Péter Bai, Serena Santangelo, Patrizia Bossolasco, Antonia Ratti, Vincent Géli, Yves Pommier, Lóránt Székvölgyi.
      Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); DRIP‐seq; R‐loop; TOP1MT; mitochondrion; rs2293925; topoisomerase
    DOI:  https://doi.org/10.1111/febs.70649
  26. Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):
    SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
    Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.
      Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation
    DOI:  https://doi.org/10.1007/s12035-026-06050-0
  27. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123
    Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
    Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.
      Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
    Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance
    DOI:  https://doi.org/10.1073/pnas.2529208123
  28. bioRxiv. 2026 Jul 01. pii: 2026.06.26.734825. [Epub ahead of print]
    Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.
    C J Mabry, A K Coleman, M H Smith, S L Hahn, T M Newbolt, M J Chapman, L W Stranahan, C G Weindel, K L Patrick, R O Watson.
      Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo , loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8 + T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity.
    HIGHLIGHTS: Trim14 raises the apoptotic threshold in Mtb-infected macrophages.Trim14 controls phosphorylation and mitochondrial targeting of Stat3.Reduced mitochondrial Stat3 promotes mPTP opening and apoptotic commitment. Trim14 deficiency enhances apoptosis, CD8 + T cell immunity, and Mtb resistance.
    DOI:  https://doi.org/10.64898/2026.06.26.734825
  29. ACS Appl Mater Interfaces. 2026 Jul 06.
    Droplet Microfluidics-Enabled Mitochondrial Transfer from Young to Senescent MSCs to Ameliorate Cellular Senescence.
    Zhen Liu, Meijun Wang, Jiayu Sun, Wayne Y W Lee, Ho Yin Tsang, Kwan Ting Chow, Dong Sun.
      Mesenchymal stem cells (MSCs) are widely used for tissue repair and regeneration, but prolonged in vitro expansion induces senescence and limits their therapeutic efficacy. Given the key role of mitochondria in cellular senescence and metabolic regulation, mitochondrial transfer may offer a promising strategy for ameliorating senescence-associated phenotypes. However, conventional mitochondrial transfer methods, such as coculture and microinjection, are limited by poor quantitative control, low throughput, and potential cell damage. Here, an inertial-focusing-assisted droplet microfluidic platform was developed for high-throughput, high-efficiency, and quantitative control of mitochondrial transfer at the single-cell level. The platform achieved 29.2% single-cell droplets and 1.3% multicell droplets, with a transfer efficiency of up to 56% at a droplet generation rate exceeding 4000 Hz. Using this platform, the transfer of 19 mitochondria from young adipose-derived MSCs (ADSCs) to senescent ADSCs enhanced proliferation capacity and metabolic activities, reduced senescence-associated markers, and transformed the senescent phenotype into a young MSC-like phenotype. The developed technique provides a cell therapy strategy for mitochondrial-related diseases.
    Keywords:  cell therapy; cellular senescence; droplet microfluidics; mesenchymal stem cells; mitochondrial transfer; single-cell level
    DOI:  https://doi.org/10.1021/acsami.6c05873
  30. Res Sq. 2026 Jul 01. pii: rs.3.rs-10121216. [Epub ahead of print]
    R1398 is the GTP-𝛾-phosphate sensor that drives the ROC G-domain switching mechanism unique to Parkinson's disease-associated LRRK2.
    Quyen Hoang, Yangshin Park, Chunxiang Wu, Rajnesh Yadav, Kayla Tennessen, Neo Hoang, Cardea Hoang, Xylena Reed, Xiaorong Huang, Mark Cookson, R Nichols, Jingling Liao.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Strategies that directly inhibit the LRRK2 kinase active site have not demonstrated disease-modifying efficacy in recent clinical testing. A naturally occurring protective variant, R1398H, provides an alternative route for understanding how reduced disease risk may be achieved by tuning the regulatory GTPase domain rather than the kinase domain itself. Here, we combine structural, computational, biochemical, and cell-based analyses to define how R1398H alters the Ras of complex proteins (ROC) G domain of LRRK2. Purified ROC carrying R1398H is folded but resolves as a stable homodimer corresponding to the GDP-bound off state previously defined for wild-type ROC. A 2.0 Å crystal structure shows unambiguous density for H1398 and reveals close superposition with the GDP-bound wild-type ROC dimer. Molecular dynamics modeling predicts that R1398 engages the 𝛾-phosphate of GTP to stabilize switch-region interactions required for activation, whereas histidine at this position weakens 𝛾-phosphate sensing. Consistent with this model, R1398H reduces GTP hydrolysis, selectively weakens GTP-state stabilization while preserving GDP binding, and decreases Rab29-dependent trans-Golgi recruitment of full-length LRRK2. These findings identify R1398 as a 𝛾-phosphate sensor that couples nucleotide chemistry to ROC conformational switching and suggest a genetics-anchored strategy for stabilizing a protective off-state conformation of LRRK2.
    DOI:  https://doi.org/10.21203/rs.3.rs-10121216/v1
  31. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615
    ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
    Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.
      Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.
    Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117615
  32. Neurosci Bull. 2026 Jul 07.
    Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
    Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.
      Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.
    Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING
    DOI:  https://doi.org/10.1007/s12264-026-01657-8
  33. Stem Cell Rev Rep. 2026 Jul 09.
    Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
    Hao-Cheng Liu, Si-Yuan Chen, Nan-Nan Yu, Mei-Hua Jin, Hu-Nan Sun, Ying-Hao Han.
      Stem cell fate decisions-whether to self-renew, differentiate, or senesce-are inextricably linked to the metabolic identity and quality-control status of mitochondria. The ubiquitin-proteasome system and selective autophagy pathways assemble into an integrated surveillance network at the mitochondrial outer membrane that gauges organelle health, sculpts morphology, and transduces metabolic information into lineage-determining transcriptional programmes. This Review examines how the ubiquitination machinery-spanning the canonical PINK1-Parkin axis and non-Parkin E3 ligases including MARCH5, MUL1, and the emerging Cullin-RING component RBX2-orchestrates outer-membrane protein degradation, mitochondria-derived vesicle biogenesis, and the balance between fusion and fission. We discuss how these post-translational events govern stem cell identity across haematopoietic, muscle, neural, mesenchymal, and pluripotent compartments. Recent 2024-2025 advances include an Nicotinamide Adenine Dinucleotide (NAD+)-dependent metabolic checkpoint governing haematopoietic stem cell activation and aging, the crystallographic resolution of USP30 inhibitor binding, molecular glue activators that allosterically enhance Parkin RING-domain activity, ClpP-based mitochondria-targeted PROTAC platforms, and HIF-1α/BNIP3-mediated pharmacological rejuvenation of aged mesenchymal stem cells. We further discuss the WAC-PINK1-Parkin axis in mesenchymal stem cell aging, the bidirectional interplay between reactive oxygen species and E3 ligase activity, and the ACC1-FIS1 ubiquitination axis. Finally, we consider the cell-type-specific calibration of mitochondrial ubiquitination as a unifying principle for precision therapeutics and the inverted quality-control logic exploited by cancer stem cells. We propose that the cell-type-specific calibration of mitochondrial ubiquitination-whereby identical molecular events carry divergent functional consequences across stem cell compartments-offers a unifying framework for precision therapeutics.
    Keywords:  Mitochondrial dynamics; Mitochondrial ubiquitination; Mitophagy; PINK1-Parkin; Stem cell fate
    DOI:  https://doi.org/10.1007/s12015-026-11189-3
  34. Aging Cell. 2026 Jul;25(7): e70624
    Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
    Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.
      Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.
    Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control
    DOI:  https://doi.org/10.1111/acel.70624
  35. J Neuroinflammation. 2026 Jul 07.
    Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
    Pilar González-García, Ignacio Serrano-Martínez, Eliana Barriocanal-Casado, Alejandro Cuenca-Martagón, Pablo Vargas-Rodríguez, Norma Adán, Irene Forte-Lago, Juan Carlos Morales, Patricia Gomez-Suaga, Júlia Bonet-Freixinet, Silvia Ginés, Luis C López, Elena González-Rey.
       BACKGROUND: Huntington's disease (HD) is an inherited, fatal neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene, leading to progressive motor, cognitive and psychiatric impairment. Despite its monogenic origin, HD pathogenesis is multifactorial, with convergent contributions from mitochondrial dysfunction, oxidative stress, synaptic failure, and chronic neuroinflammation, which drive neuronal vulnerability and degeneration, particularly within the striatum. Current clinical management remains exclusively symptomatic and fails to halt disease progression, highlighting a critical unmet need for strategies targeting fundamental pathogenic mechanisms. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory properties and has recently been implicated in the regulation of mitochondrial function. Notably, cortistatin deficiency is associated with exacerbated systemic and central inflammation, suggesting that impaired cortistatin signaling may contribute to neurodegeneration. However, its role in HD pathophysiology remains unexplored.
    METHODS: We performed a comprehensive reanalysis of publicly available transcriptomic datasets from HD patients to assess cortistatin expression, followed by validation in experimental HD models. Wild-type and cortistatin-deficient mice treated with 3-nitropropionic acid served as pharmacological HD models, enabling evaluation of cortistatin-dependent disease severity. Behavioral assessments, glial and oxidative markers, and immune factors were evaluated to determine neurological dysfunction and inflammatory responses. Complementary in vitro studies were conducted in striatal neurons expressing mutant huntingtin to examine mitochondrial integrity, inflammatory signaling, metabolic function, and mitochondria-endoplasmic reticulum interactions.
    RESULTS: Cortistatin expression was significantly reduced in postmortem HD human brains and across experimental HD models. Cortistatin deficiency exacerbated motor deficits, neuropathological alterations, inflammatory activation, and neuronal vulnerability in HD context. At the cellular level, reduced cortistatin expression was accompanied by amplified inflammatory signaling, disrupted mitochondrial integrity, impaired mitochondria-endoplasmic reticulum interactions, and increased oxidative stress. Conversely, exogenous cortistatin administration attenuated inflammatory mediator production, preserved mitochondrial structure, and improved redox balance in mutant huntingtin-expressing striatal neurons.
    CONCLUSIONS: Our findings identify cortistatin deficiency as a previously unrecognized contributor to HD pathogenesis and establish cortistatin as a key modulator of neuroinflammation and mitochondrial homeostasis. These results support cortistatin-based strategies as a promising disease-modifying therapeutic avenue for HD and related neurodegenerative disorders characterized by inflammatory activation and mitochondrial impairment.
    Keywords:  Cortistatin; Huntingtin; Huntington’s disease; Mitochondria; Neurodegenerative diseases.; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1186/s12974-026-03947-4
  36. Front Aging Neurosci. 2026 ;18 1865383
    Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
    Lingzhe Wang, Bin Xu.
      Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of nigral dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited. Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network. This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.
    Keywords:  PINK1; Parkin; Parkinson’s disease; functional uncoupling; lysosomal dysfunction; mitochondrial quality control; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2026.1865383
  37. Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.
    Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle
    DOI:  https://doi.org/10.7554/eLife.107953
  38. EMBO Rep. 2026 Jul 07.
    De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
    Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.
      Postnatal maturation of the mammalian heart requires a vast increase in respiratory enzymes. The mitochondria-specific lipid cardiolipin (CL) is essential for respiratory chain integrity but has no defined function in heart maturation. Here, we determined how the two steps of CL biogenesis, de novo synthesis and acyl chain remodeling, affect the maturation of cardiac mitochondria in mice. Cardiomyocyte-restricted deletion of the CL synthase Crls1 in late gestation does not affect CL levels at birth but blocks the increase in the tissue concentration of CL observed during normal postnatal maturation. Deletion of Crls1 prevents the postnatal rise in cristae density and in the intramitochondrial concentration of respiratory proteins. This inhibits cardiac development, precipitates heart failure, and causes death by the age of 2 weeks. In contrast, ablation of CL remodeling by cardiomyocyte-restricted deletion of Tafazzin does not disrupt mitochondrial maturation or cardiac development, although it has a similar effect on the CL concentration and profoundly alters the CL species composition. Our data show that CL synthesis, but not CL remodeling, controls expression of the respiratory chain by a mechanism independent of the CL concentration.
    DOI:  https://doi.org/10.1038/s44319-026-00864-8
  39. Biochemistry (Mosc). 2026 Jun;91(6): 893-909
    Interplay between Neuronal Metabolism and Signaling in Model Systems with Impaired α-Ketoglutarate Dehydrogenase Complex Activity.
    Márton Kokas, Attila Ambrus, László Tretter, Tímea Komlódi.
      The α-ketoglutarate dehydrogenase complex (KGDHC) serves as a master regulator of cell's molecular machinery. Beyond its classical role as a rate-limiting enzyme in the tricarboxylic acid (TCA) cycle, KGDHC has emerged as a critical redox sensor that can act as both a source and a target of reactive oxygen species (ROS), thereby regulating cellular redox homeostasis. This review summarizes evidence from genetically modified animal models and cell culture studies demonstrating that compromised KGDHC activity affects neuronal metabolism, redox homeostasis, and cellular signaling. KGDHC dysfunction causes mitochondrial failure, resulting in reduced ATP synthesis and activation of AMP-activated protein kinase (AMPK). Although inhibition of KGDHC reduces mitochondrial ROS formation, it also disrupts physiological ROS-dependent signaling mechanisms. In KGDHC-deficient mice, impaired ROS signaling and energy deficit decrease brain adaptability, increase susceptibility to neurotoxins, and disrupt crucial pathways by downregulating PGC-1α and Nrf2. These alterations result in suppression of antioxidant defences and lead to neuronal death in the hippocampus and memory impairment. Moreover, KGDHC dysfunction induces mitochondrial fragmentation and is strongly linked to excitotoxicity, further accelerating neuronal dysfunction. As observed in heterozygous models, even partial KGDHC deficiency can exacerbate persisting cellular and mitochondrial defects, leading to the development of more severe pathological conditions.
    Keywords:  cognitive decline; neuronal signaling; reactive oxygen species; succinylation; α-ketoglutarate dehydrogenase complex
    DOI:  https://doi.org/10.1134/S0006297926600663
  40. Mitochondrion. 2026 Jul 10. pii: S1567-7249(26)00082-6. [Epub ahead of print] 102192
    Mitochondrial translocation of DNMT3L suppresses oxidative phosphorylation and restrains megakaryopoiesis.
    Shuoh-Wen Chen, Hsiao-Wen Chen, Chao-Hsuan Chu, Pu-Sheng Hsu, Yi-Shan Yu, Shau-Ping Lin, Yu-Xuan Wu, Eric Chang-Yi Lin, Ting-An Lin, Min-Hui Chen, Hsin-Yu Chang, He-Yi Yang, Hsin-Chen Lee, Yuan-I Chang.
      DNMT3L, a catalytically inactive member of the DNA methyltransferase family, is identified here as a negative regulator of megakaryopoiesis. In K562 cells undergoing PMA-induced megakaryocytic differentiation, DNMT3L protein levels declined progressively, and shRNA-mediated depletion enhanced differentiation, whereas overexpression attenuated it. Consistent with these findings, Dnmt3l-knockout mice exhibited elevated peripheral blood platelet counts and expanded bone marrow megakaryocytes. Mechanistically, megakaryocytic differentiation triggered rapid mitochondrial translocation of DNMT3L within 6 h; mitochondrial DNMT3L suppressed oxidative phosphorylation (OXPHOS) capacity and ATP production and downregulated mitochondrial-encoded genes spanning Complex I, III, IV, and ATP synthase, without altering mitochondrial DNA copy number. This metabolic suppression was mediated through compartment-specific remodeling of DNMT3L-containing protein complexes: upon differentiation, DNMT3L selectively dissociated from DNMT1 and DNMT3B in mitochondria, relieving the repressive constraint on OXPHOS, whereas in the nucleus DNMT3L remained associated with DNMT3A, which concomitantly accumulated during differentiation. These findings reveal a previously unrecognized mechanism by which a catalytically inactive epigenetic co-regulator spatially redistributes to coordinate mitochondrial metabolic output with nuclear epigenetic control, thereby facilitating terminal megakaryocytic maturation.
    Keywords:  DNMT3L; Megakaryopoiesis; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.mito.2026.102192
  41. Nat Commun. 2026 Jul 06.
    A human-specific microRNA controls the timing of excitatory synaptogenesis.
    Michael Soutschek, Alessandra Lo Bianco, Simon Galkin, Tatjana Wüst, Koen Wentinck, David Colameo, Tomas Germade, Fridolin Gross, Lukas von Ziegler, Johannes Bohacek, Betina Elfving, Pierre-Luc Germain, Jochen Winterer, Tatjana Kleele, Gerhard Schratt.
      Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human induced pluripotent stem-cell derived neurons. We found that inhibition of a human-specific microRNA, miR-1229-3p, alters the trajectory of human neuronal maturation and enhances excitatory synaptic transmission. Transcriptome analysis following miR-1229 knockdown revealed a downregulation of mitochondrial DNA (mtDNA) encoded genes. We further show that miR-1229 regulates mitochondrial morphology, mtDNA abundance as well as mitophagy, and that stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Accordingly, miR-1229 directly targets an entire network of genes involved in mitochondrial function and ER-associated protein homeostasis. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.
    DOI:  https://doi.org/10.1038/s41467-026-74753-y
  42. Curr Opin Chem Biol. 2026 Jul 09. pii: S1367-5931(26)00073-6. [Epub ahead of print]94 102724
    Resolving cellular signaling in space and time: From organelle proteomics to spatial phosphoproteomics.
    Alejandro Matía, Ruth Hüttenhain.
      Cellular signaling is inherently organized in space and time, requiring coordinated control of protein localization, molecular interactions, and enzymatic activity across subcellular compartments. Recent advances in chemical biology, protein engineering, and quantitative proteomics have made it possible to interrogate these dimensions in an integrated manner. Here, we highlight emerging strategies to resolve signaling organization across three interconnected dimensions: organelle-resolved proteome mapping to define spatial context, proximity labeling to capture local protein interaction networks, and spatially resolved phosphoproteomics to quantify signaling outputs. Developments in proximity labeling, including split, conditionally activated and light-gated enzymes, enable temporally controlled, context-dependent profiling of transient protein assemblies in living cells. Advances in high-throughput and low-input phosphoproteomics, together with improved computational frameworks for kinase activity inference and subcellular enrichment strategies, are enabling spatially resolved measurement of signaling activity. Together, these approaches are shifting the field from static localization maps toward dynamic models of signaling networks.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102724
  43. Nanoscale. 2026 Jul 08.
    Restoring the powerhouse: mitochondrial transplantation in regenerative medicine and cancer therapy.
    Ngoc-Tri Tran, Hsiu-Ching Liu, Der-Yang Cho, Ming-You Shie, Shang-Hsiu Hu.
      Mitochondrial dysfunction acts as a central contributor to diverse pathologies, ranging from neurodegenerative disorders to cancer, yet traditional pharmacotherapy often fails to restore organelle bioenergetics. Building on the discovery of natural intercellular mitochondrial transfer, Mitochondrial Transplantation (MtT) has emerged as a groundbreaking strategy to replace damaged organelles with healthy exogenous mitochondria. The present review synthesizes the recent progress in MtT, highlighting the intervention's dual therapeutic role: restoring metabolic homeostasis in regenerative medicine and reversing metabolic reprogramming to sensitize tumors in oncology. The text critically assesses current isolation techniques and innovative delivery strategies designed to overcome stability and uptake challenges. By evaluating biological mechanisms and translational barriers of "mitotherapy", the article provides a comprehensive theoretical foundation for advancing precision organelle-centered medicine.
    DOI:  https://doi.org/10.1039/d6nr00488a
  44. Bioessays. 2026 Jul;48(7): e70159
    Decoding the Hot-Mitochondrion Paradox.
    Peyman Fahimi, Michael Lynch, Chérif F Matta.
      In a 2018 paper and a subsequent article published in 2023, researchers reported that mitochondria maintain temperatures 10°C-15°C higher than the surrounding cytoplasm-a finding that deviates by five to six orders of magnitude from theoretical predictions based on Fourier's law of heat conduction. In 2022, we proposed a solution to this apparent paradox. In the present perspective, we build upon that framework and introduce new ideas to further unravel how a biological membrane-whether of an organelle or a whole cell-can become significantly warmer than its environment. We propose that ion-translocating proteins embedded in the inner mitochondrial membrane (IMM) can be modeled as ratchet engines, introducing a novel, previously overlooked mode of heat transfer. This mechanism, coupled with localized heat release during the cyclical dehydration-translocation-hydration of ions through membrane proteins, may generate transient but substantial temperature spikes. The cumulative thermal occupancy of these microscopic events across the three-dimensional surface of the IMM can account for the elevated temperatures detected by molecular probes.
    DOI:  https://doi.org/10.1002/bies.70159
  45. NPJ Parkinsons Dis. 2026 Jul 08.
    Interaction of G2019S LRRK2 and metabolic syndrome in a two-hit mouse model of Parkinson's disease: LRRK2-driven systemic depletion of pyrimidine nucleosides.
    Yue Ma, Madalynn L Erb, Kayla A Sipple, Alina V Offerman, Junwei Niu, Zachary B Madaj, Zhen Fu, Kin H Lau, Darren J Moore.
      G2019S LRRK2 is the most common cause of familial Parkinson's disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.
    DOI:  https://doi.org/10.1038/s41531-026-01465-x
  46. Nat Rev Neurosci. 2026 Jul 06.
    Using human 3D organoid models to gain mechanistic insight in motor neuron diseases.
    Benedetta Frizzi, Adriana Margarida Barbosa Correia, Irene Faravelli, Ludo Van Den Bosch, Stefania Corti.
      Motor neuron diseases (MNDs) are caused by the progressive loss of motor neurons and eventually lead to paralysis and death. Once viewed as primarily neurocentric, MNDs are now recognized to be driven by intertwined cell-autonomous and non-cell-autonomous mechanisms. Dissecting these interactions is essential for developing effective therapies. Here, we describe induced pluripotent stem cell-derived 3D models that can be used to capture distinct aspects of MND pathology. We show that spinal cord organoids can be used to investigate cell-autonomous mechanisms and motor neuron-glia interactions (with axially elongated spinal cord organoids being particularly useful to study developmental vulnerability) as well as in 3D muscle and combined neuromuscular models to dissect muscle pathology and neuromuscular junction dismantling. In parallel, we discuss advances in bioengineering, machine learning and human trunk-like models, which together can begin to reproduce the coordinated co-development and spatial organization of the multiple tissues affected in MNDs. We discuss how these systems have advanced our understanding of disease mechanisms and highlight opportunities for drug repurposing. Finally, we propose a mechanism-informed and phenotype-informed framework to guide 3D model selection for future research and to prioritize promising avenues for therapeutic development.
    DOI:  https://doi.org/10.1038/s41583-026-01057-x
  47. J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70335
    Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.
    Natasha Jaiswal, Matthew Gavin, Louise Lantier, Olivia Yu Yu Ong, David H Wasserman, Paul M Titchenell.
       BACKGROUND: The serine/threonine kinase AKT is a key regulator of glucose and energy metabolism. Prevailing dogma suggests that AKT is an obligate intermediate for glucose uptake in all metabolic tissues and that impaired AKT signalling is a major molecular driver of insulin resistance in obesity. However, whether AKT is universally required for insulin-stimulated glucose uptake across tissues in vivo has remained unresolved.
    METHOD: Several mouse models of adipose-specific AKT2 deletion (F-AKT2KO) and skeletal muscle-specific AKT1, AKT2 and combined AKT1/AKT2 knockout mice (M-AKT1KO, M-AKT2KO and M-AKTDKO) were generated. Skeletal muscle and adipose tissues were analysed following in vivo administration of insulin (2 U/kg), using Western blotting, phosphoproteomics, PI(3,4,5)P3 ELISA and mitochondrial respiration assays. Glucose metabolism was assessed using [3H]-2-deoxyglucose uptake, hyperinsulinemic-euglycemic clamps, glucose and insulin tolerance tests. Global phosphoproteomics was performed in insulin-stimulated skeletal muscle lacking AKT isoforms.
    RESULTS: Loss of AKT2 in adipose tissue impaired insulin signalling, including reduced pAS160Thr649, and markedly decreased insulin-stimulated glucose uptake (~2-3 fold reduction in F-AKT2KO vs F-Control, p < 0.001, n = 7-11), resulting in systemic insulin resistance. In contrast, M-AKTDKO mice exhibited a robust increase in insulin-stimulated glucose uptake (~3-4 fold increase) despite complete loss of AKT signalling, including pAS160Thr649. Phosphoproteomic analysis of M-AKTDKO (n = 3-4) identified ~7088 phosphosites, with 795 uniquely upregulated in insulin-stimulated M-AKTDKO muscle (fold change > 2, p < 0.05), enriched in PI3K and AMPK pathways. Consistently, ~8-fold (p < 0.05) increase in PIP3 levels was observed in M-AKTDKO muscle in response to insulin. Additionally, AKT deficiency was associated with reduced complex I-dependent mitochondrial respiration (~37% decrease in state 3 respiration), consistent with altered energetic status and AMPK activation. Genetic epistasis experiments demonstrated that both AKT and AMPK activity are required for insulin-stimulated glucose uptake, systemic glucose homeostasis and whole body insulin sensitivity.
    CONCLUSION: These findings challenge the long-standing assumption that AKT is universally required for insulin-stimulated glucose uptake in vivo. The study demonstrates that while AKT is essential in adipose tissue, it is dispensable for insulin-stimulated glucose uptake in skeletal muscle. AKT exerts negative feedback on PI3K signalling in both tissues; however, only skeletal muscle engages AMPK in the abscence of AKT to preserve glucose uptake. These findings redefine tissue-specific insulin signalling mechanisms and identify AMPK as a critical downstream target of PI3K that coordinates with AKT to regulate glucose uptake.
    Keywords:  AKT signalling; AMPK signalling; GLUT4 translocation; PI3K‐PIP3 pathway; insulin signalling
    DOI:  https://doi.org/10.1002/jcsm.70335
  48. Front Immunol. 2026 ;17 1761658
    The role of mitochondrial proteases in inflammation and immunity.
    Anna Rebeka Oliveira Ferreira, Emily A Day.
      The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.
    Keywords:  MAVS; cGAS-STING; immune cells; inflammatory disease; innate immunity; macrophages; mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1761658
  49. Hum Mutat. 2026 ;2026 6864813
    Long-Chain Fatty Acid Oxidation Disorder Genes: A Comprehensive Genetic Database of LC-FAOD Variants, Genotypes, and Phenotypes.
    Heather Richbourg, Vanessa Rangel Miller, Omid Khazaie Japalaghi, Moeenaldeen AlSayed, Peter R Baker, Sean Daugherty, Tali Ekstein, Sarah C Grünert, Mark J Kiel, Aneal Khan, Hironori Kobayashi, Lawrence Korngut, Stephanie A Monteleone, Ida Vanessa D Schwartz, Nicole Miller, Jerry Vockley.
      Long-chain fatty acid oxidation disorders (LC-FAODs) are characterized by the inability to metabolize long-chain fatty acids. Serious clinical manifestations occur, including cardiomyopathy, hypoglycemia, rhabdomyolysis, and liver failure. Confirming a diagnosis with genetic testing is complicated by the rarity of the disorders, genetic and phenotypic heterogeneity, and the high frequency of variants of uncertain significance. A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20. The database integrates data from a systematic literature review and a sponsored gene panel program with associated clinical and biochemical data. The database was reviewed and curated by an expert panel and stored in MongoDB and MySQL. As of March 2025 (literature review cutoff), the database reports 6947 variants from 4188 individuals with ≥ 1 variant in an LC-FAOD gene. ACADVL variants are the most common (40%), followed by HADHA (25%), CPT2 (21%), CPT1A and HADHB (5% each), and SLC25A20 (4%). Associated phenotypes are reported for 1496 individuals, newborn screening results for 2589, and enzyme activity assays for 499 individuals. Severe outcomes (cardiomyopathy < 1 year or death at any age) are reported for 219 individuals with ≥ 2 P/LP LC-FAOD gene variants, and the most common genotype among them is homozygosity for the LCHAD variant, HADHA p.Glu510Gln (n = 48/219). The LC-FAOD gene database is a comprehensive archive of variants, genotypes, and phenotypes associated with this important group of FAODs. It is open to the greater scientific and LC-FAOD communities through a public website.
    Keywords:  cardiomyopathy; hypoglycemia; locus-specific database; long-chain fatty acid oxidation disorders (LC-FAODs); rhabdomyolysis
    DOI:  https://doi.org/10.1155/humu/6864813
  50. Nat Cell Biol. 2026 Jul 06.
    Addendum: In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      
    DOI:  https://doi.org/10.1038/s41556-026-02020-9
  51. Mol Genet Genomic Med. 2026 Jul;14(7): e70221
    COQ2-Associated Primary Coenzyme Q10 Deficiency Presenting With Proteinuria: A Case Report and Literature Review.
    Yuqi Yue, Fei Zhao, Qiuxia Chen.
       BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiency (PCOQ10D) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in genes involved in the CoQ10 biosynthetic pathway, including PDSS2, COQ2, COQ6, and COQ8B/ADCK4. Among these, pathogenic variants in the COQ2 gene impair oxidative phosphorylation and mitochondrial biogenesis in podocytes, often leading to encephalopathy and nephropathy.
    METHODS: Clinical data were collected from a pediatric patient with proteinuria caused by COQ2 gene variants, who was admitted to the Children's Hospital Affiliated to Nanjing Medical University in June 2025. Relevant examinations were completed, and whole-exome sequencing (WES) was performed to screen for potential genetic variants in the patient's genomic DNA. Pathogenicity assessment of the identified variants was conducted in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines and online bioinformatics tools. Additionally, a systematic literature review on COQ2-associated nephropathy was carried out in this study.
    RESULTS: The patient initially presented with global developmental delay accompanied by neurological lesions and developed proteinuria at 6 months of age. Genetic testing revealed two pathogenic variants: c.368G>A, p.(Arg123His) and c.908A>G, p.(Tyr303Cys). After oral administration of high-dose CoQ10 (85 mg/kg/d) combined with enalapril maleate (0.80 mL/kg/d), the patient achieved complete remission of proteinuria and maintained stable renal function.
    CONCLUSIONS: PCOQ10D exhibits marked phenotypic heterogeneity, characterized by variations in age of onset, organ involvement, and clinical severity, as well as significant interindividual differences in treatment responses to CoQ10 supplementation. This case expands the phenotypic spectrum of the disease. Moreover, the therapeutic outcomes suggest that all diagnosed patients require long-term supplementation with adequate doses of CoQ10, which is of great significance for delaying disease progression.
    Keywords:  COQ2 gene; primary coenzyme Q10 deficiency‐1; proteinuria
    DOI:  https://doi.org/10.1002/mgg3.70221
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