bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–08–30
67 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
  2. Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
  3. 2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.
  4. Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
  5. COX14 Variants Are Associated With Mitochondrial Complex IV Deficiency Nuclear Type 10 (MC4DN10).
  6. Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.
  7. Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
  8. Vitelliform retinal lesions: Uncommon adult-onset presentation of the common mitochondrial MELAS variant.
  9. A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
  10. Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
  11. Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
  12. Adaptive and degenerative mitochondrial remodeling define distinct redox states in age-related macular degeneration.
  13. Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
  14. Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
  15. Understanding cardiovascular aging as a disorder of mitochondrial network.
  16. Delay Differential Equation Approach to Oligomerization Reveals the Delay Dynamics Underlying Oscillations in Mitochondrial Fission.
  17. Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
  18. The molecular basis of mitochondrial crista formation by the MIC10 complex.
  19. Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.
  20. Functional Reconstitution of Mitochondrial Respiratory Supercomplexes.
  21. The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.
  22. Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
  23. Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1.
  24. Mitochondria and exosome intercellular co-transfer via annular gap junction vesicles in the human glioblastoma stem cell niche.
  25. Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.
  26. Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.
  27. Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
  28. Mitochondrial DNA A3243G variant-associated MELAS: Recent advances in clinical trials, therapeutic interventions, and disease-modifying strategies.
  29. ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?
  30. Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.
  31. Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.
  32. Mitochondrial Homeostasis Mediates the Sustained Neuroprotection of CNTF-Chitosan Hydrogel Against NMDA-Induced Retinal Ganglion Cell Excitotoxicity.
  33. Protocol for assessing molecular signatures and metabolic function of primary murine cortical astrocytes.
  34. Ancient Mitochondrial Genetic Variant: Comment.
  35. Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
  36. Adipose Stem Cell Mitochondrial Transplantation in ART: From Biological Rationale to Clinical Milestone.
  37. Structural basis of Saccharomyces cerevisiae Mba1 in mitochondrial co-translational membrane insertion.
  38. A Function-Centric Framework for Mitochondrial Quality Control.
  39. NMNAT2 Functional Landscape and Localization in Programmed Axon Degeneration.
  40. The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.
  41. Mitochondrial regulation of cellular senescence heterogeneity.
  42. Patient's own mitochondria injected into eyes in attempt to restore vision.
  43. Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
  44. Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.
  45. Partial reduction of the mitochondrial lipoyltransferase LipT2 promotes longevity and redox remodeling in Drosophila.
  46. Nicotinamide Mononucleotide Adenylyltransferase 1 and NAD+ Homeostasis in Neuroprotection and Aging.
  47. Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
  48. Neuromuscular Dysfunction and Charcot-Marie-Tooth Disease Reversal in Mfn2 T105M Knock-In Rats.
  49. Mitochondrial NAD+ determines the metabolic capacity for liver regeneration.
  50. Mitochondrial ribosome content as a proxy for respiration.
  51. Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
  52. Mitochondrial RNA-Type I Interferon Axis in Sjögren's Disease: Molecular Mechanisms and Translational Implications.
  53. SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.
  54. Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
  55. A young male with kidney damage from genetic mitochondrial disease: case report and literature review.
  56. Irritable Bowel Disease: Think Malonic and Methylmalonic Aciduria (CMAMMA)!
  57. Adipocyte-specific MICU1 deficiency impairs memory and compromises hippocampal integrity in adult male mice.
  58. Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.
  59. Inner Ear Organoids: Recent Progress and Challenges.
  60. Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.
  61. Propionic Acid Remodels Mitochondrial Metabolism in SH-SY5Y Cells.
  62. Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.
  63. Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.
  64. An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo.
  65. Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.
  66. The clinical and molecular spectrum of AGO2-associated Lessel-Kreienkamp neurodevelopmental syndrome.
  67. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review.
  1. J Inherit Metab Dis. 2026 Sep;49(5): e70236
    From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
    Simon Wetzel, Sebastian Porsdam Mann, Florian A Rosenberger.
      Proteomics by mass spectrometry has rapidly matured from a niche method into a standard tool. The recent 10-year trajectory of single-cell proteomics has opened a new biological dimension for studying disease. Mitochondrial diseases, with their pronounced cell-to-cell heterogeneity, are particularly, well-suited to these methods. Here, we discuss how this approach can serve as an orthogonal functional layer for rare disease diagnostics. We trace the evolution of rare disease diagnostics from biochemical enzyme assays through genomics, transcriptomics, proteomics and metabolomics, highlighting incremental gains in diagnostic yield from individual omics layers and their integration. We discuss the limitations of bulk approaches in capturing the functional consequences of genetic perturbations, the new opportunities opened up by single-cell measurements and how spatial single-cell proteomics can further enrich the biological signal of affected cells in diagnostic tissues. We observe that the persisting diagnostic gap reflects not only technological limitations but, increasingly, challenges in data sharing and infrastructure as well as interpretive frameworks for functional molecular evidence. In this context, we consider opportunities for artificial intelligence and the ethical dimensions of single-cell proteomics in rare disease diagnostics. Finally, we propose a single-cell deep visual proteomics (scDVP) framework for clinical diagnostics of rare diseases with cell-to-cell variability, arguing that mitochondrial diseases are an ideal proof-of-concept.
    Keywords:  diagnostics; mitochondria; omics ethics; rare diseases; single‐cell proteomics; spatial proteomics
    DOI:  https://doi.org/10.1002/jimd.70236
  2. Sci Adv. 2026 Aug 28. 12(35): eaeg8792
    Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
    Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.aeg8792
  3. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261473291
    2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.
    Amel Karaa, Maria Isabel G Lopez Sanchez, Clare Stuart, Luca Bolliger, Kate Murray, Maria E O'Hanlon, Brian Tseng, Philip Yeske, Sean Murray.
      Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.
    Keywords:  clinical trial; drug development; mitochondrial disease; rare disease
    DOI:  https://doi.org/10.1177/26330040261473291
  4. Brain Sci. 2026 Aug 20. pii: 890. [Epub ahead of print]16(8):
    Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
    Kate Erin Harris, Gerassimos Lascaratos, Kai-Yin Chau.
       BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.
    METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.
    RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.
    CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.
    Keywords:  ATP hydrolysis; ATP synthase; ATP synthesis; Complex V; bioenergetics; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/brainsci16080890
  5. Am J Med Genet A. 2026 Aug 26.
    COX14 Variants Are Associated With Mitochondrial Complex IV Deficiency Nuclear Type 10 (MC4DN10).
    Elias K Awad, Emily Waskow, Hari Tunuguntla, Joseph Spinner, Hanna J Tadros, Lisa T Emrick, Daniel G Calame, Fernando Scaglia.
      COX14 encodes a transmembrane protein essential for cytochrome c oxidase (COX) complex assembly. A homozygous missense variant in COX14 was reported in three siblings from a single consanguineous family with severe, fatal infantile mitochondrial complex IV deficiency nuclear type 10 (MC4DN10; MIM# 619053). No additional cases have been identified since, and the ClinGen Mitochondrial Disease Gene Curation Expert Panel classified the COX14-MC4DN10 gene-disease association as having limited evidence. We report a 9-year-old male with biallelic COX14 variants (c.82delT, p.Tyr28Thrfs*83, and c.3G>A, p.Met1?) representing the second unrelated family with MC4DN10. In contrast to the fatal neonatal course previously described, this individual demonstrates an attenuated encephalomyopathic phenotype with prolonged survival. Initial presentation at 6 months included hypotonia, feeding difficulties, and developmental delay. Previously unreported features included growth hormone deficiency, ascending aortic dilation, and distinct neuroradiological findings. At age 8 years, he developed neurological regression and ataxia with brain MRI findings consistent with Leigh syndrome. Muscle biopsy confirmed reduced COX enzymatic activity (33% of mean). Identification of a second unrelated family with biallelic COX14 variants and biochemically confirmed complex IV deficiency strengthens the gene-disease association for MC4DN10. This individual presents an attenuated encephalomyopathic phenotype with novel endocrine and cardiovascular manifestations, underscoring the importance of genomic evaluation in suspected mitochondrial disorders even in the absence of classic biochemical markers such as lactic acidosis.
    Keywords:   COX14 ; Leigh syndrome; MC4DN10; ascending aortic dilation; cytochrome c oxidase deficiency; encephalomyopathy; growth hormone deficiency; mitochondrial complex IV deficiency nuclear type 10
    DOI:  https://doi.org/10.1002/ajmg.a.70260
  6. J Genet Genomics. 2026 Aug 22. pii: S1673-8527(26)00272-9. [Epub ahead of print]
    Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.
    Yanchun Ji, Feilong Meng, Yinglong Gao, Zhipeng Nie, Yunfan He, Juanjuan Zhang, Ya Li, Minglian Zhang, Jianyong Wang, Yongming Zhang, Shihui Wei, Jun Qin Mo, Min-Xin Guan.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.
    Keywords:  Chinese; Inheritance pattern; Leber hereditary optic neuropathy (LHON); Mitochondrial DNA mutation; Mitochondrial haplogroup; Nuclear modifier gene
    DOI:  https://doi.org/10.1016/j.jgg.2026.08.007
  7. Mol Metab. 2026 Aug 25. pii: S2212-8778(26)00117-1. [Epub ahead of print] 102433
    Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
    Essam A Assali, Mahmoud Taha, Ahmad Salhab, Johnny Amer, Karthickeyan Chella Krishnan, Marko Kostic, Michaela Veliova, Alexandra J Brownstein, Orian S Shirihai, Rifaat Safadi, Israel Sekler.
      Mitochondrial calcium signaling, particularly its glucagon-mediated oscillatory dynamics, plays a pivotal role in regulating hepatic metabolism and is known to be disrupted in steatotic liver disease. We recently identified the mitochondrial Na+/Ca2+ exchanger NCLX as a key mediator of glucagon-induced mitochondrial calcium oscillations, essential for proper gluconeogenic function. Here, using hepatocyte-specific NCLX knockout (cKO) mice, we demonstrate that NCLX is critical for intrahepatic lipolysis and fatty acid oxidation (FAO); its loss impairs glucagon-stimulated lipid droplet catabolism and blunts FAO. Mechanistically, we find that NCLX deficiency disrupts allosteric activation of lipolytic enzymes and increases CPT1 sensitivity to malonyl-CoA-mediated inhibition, resulting in defective lipolysis and FAO. We further show that glucagon regulates hepatic NCLX via cAMP/PKA-dependent phosphorylation at NCLX Ser258. Notably, PDE2A acts as a negative regulator of this pathway by degrading mitochondrial cAMP. Hepatic mitochondrial PDE2A abundance and cAMP-degrading activity are elevated in HFD, and in vivo BAY 60-7550 treatment suppresses mitochondrial cAMP degradation and augments PKA signaling in steatosic livers. Pharmacologic inhibition of PDE2A with BAY 60-7550 enhances NCLX phosphorylation, restores mitochondrial calcium efflux and oscillations, and stimulates FAO in an NCLX-dependent manner. Importantly, we uncover that cAMP/PKA-dependent phosphorylation of NCLX at Ser258 is suppressed in human steatotic livers, and that pharmacologic inhibition of PDE2A ameliorates hepatic FAO and steatosis in both dietary and genetic MASLD models. Collectively, our findings establish the glucagon-PKA-PDE2A-NCLX signaling axis as a key metabolic rheostat integrating mitochondrial calcium dynamics with lipid homeostasis, providing a promising therapeutic target for MASLD.
    Keywords:  Glucagon signaling; Hepatic steatosis; MASLD (Metabolic dysfunction-associated steatotic liver disease); NCLX; PDE2A (Phosphodiesterase 2A); fatty acid oxidation; lipolysis; mitochondrial bioenergetics; mitochondrial calcium signaling
    DOI:  https://doi.org/10.1016/j.molmet.2026.102433
  8. Mol Genet Metab. 2026 Aug 19. pii: S1096-7192(26)00528-7. [Epub ahead of print]149(1-2): 110245
    Vitelliform retinal lesions: Uncommon adult-onset presentation of the common mitochondrial MELAS variant.
    Jai Kumar Rajavoor Muniswamy, Michael Stewart, Eric Eggenberger, Karthik Muthusamy.
      
    Keywords:  MT-TL1 (m.3243A>G); Mitochondrial disease; Retinal dystrophy; Vitelliform macular dystrophy
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110245
  9. Autophagy. 2026 Aug 28.
    A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
    Ian Collinson, Robin A Corey, Adam G Grieve.
      The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) - followed by PARL-mediated cleavage and degradation. This happens in healthy mitochondria with a high membrane potential (ΔΨ) across the inner-membrane - required for passage of proteins into or across the inner-membrane. The second being surface stabilization, Parkin activation and initiation of mitophagy upon membrane depolarization. But what if PINK1 acts in active mitochondria as well? Our recent work identifies a third fate - matrix entry! The findings expand the biology of PINK1 beyond mitochondrial surveillance for quality control alone. They suggest an additional mitophagy-independent regulatory role within the matrix, which turns out to be governed by the unusual properties of its TMD for the conferral of a decisive conformational switch.
    Keywords:  Mitochondria; PARL; PINK1; Parkinson’s disease; transmembrane
    DOI:  https://doi.org/10.1080/15548627.2026.2726091
  10. Curr Issues Mol Biol. 2026 Aug 04. pii: 792. [Epub ahead of print]48(8):
    Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
    Alexander V Panov, Semen V Nesterov, Lev S Yaguzhinsky.
      Traditional bioenergetic paradigms historically relied on classical equilibrium thermodynamics to calculate mitochondrial kinetics, often overlooking the non-equilibrium processes dictated by complex structural architecture. Recent discoveries fundamentally challenge these outdated views by demonstrating that the inner mitochondrial membrane is strictly segregated into distinct functional domains, where individual cristae operate as autonomous, ultra-confined nanocompartments, where the transport of metabolites and protons is tightly controlled by ultrastructure-assisted electric and entropic effects. Compartmentalization prevents proton dissipation, allows for the rapid generation of a localized proton motive force optimized for efficient ATP synthesis and provides robust functional redundancy against localized membrane damage. Furthermore, recognizing cristae as isolated microspaces resolves the long-standing paradox of mitochondrial nicotinamide adenine dinucleotide transhydrogenase (TH). We describe a multi-stage transport pipeline-the TH-isocitrate dehydrogenase axis-wherein matrix-generated reducing equivalents are exported into the cytoplasm via an irreversible isocitrate/α-ketoglutarate loop. This universal pipeline continuously supplies uncommitted NADPH for biosynthesis, systemic antioxidant defense and detoxification. We also highlight the role of compartmentalization in ATP transport and utilization processes. Consequently, disruptions to cristae compartmentalization emerge as primary pathogenic drivers in ischemic, neurodegenerative, and cardiovascular diseases.
    Keywords:  NADPH transport; NADPH-isocitrate dehydrogenases; cellular bioenergetics; microcompartmentalization; mitochondrial cristae; nonequilibrium thermodynamics; proton motive force; transhydrogenase
    DOI:  https://doi.org/10.3390/cimb48080792
  11. Nat Commun. 2026 Jul 28. pii: 9165. [Epub ahead of print]17(1):
    Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
    Chuyu Chen, Qianzi He, Giulia Tombesi, Eve Napier, Matthew Jaconelli, Oscar Andrés Moreno-Ramos, Hannah Serio, Yahaira Naaldijk, Vanessa Promes, Amanda Schneeweis, Kaitlyn Quinn, Christopher Nasios, Elisa Greggio, Yevgenia Kozorovitskiy, Daniel Arango, Amir R Khan, Dario R Alessi, Daniel A Dombeck, Sabine Hilfiker, Rajeshwar Awatramani, Loukia Parisiadou.
      Parkinson's disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. Here, we used intersectional genetic mouse models to determine how the PD-linked kinase LRRK2 affects vulnerable dopamine subtypes. Immunofluorescence and proximity-labeling proteomics revealed enriched LRRK2 expression in vulnerable dopamine neuron subclusters. High-resolution imaging showed that pathogenic LRRK2 disrupts presynaptic release-site organization in vulnerable dopamine axons, leading to reduced spontaneous and evoked striatal dopamine release in vivo. Proteomic analyses further showed that mutant LRRK2 increases phosphorylation of RAB3 proteins, impairing their interaction with the active-zone effectors RIM1 and RIM2. Together, these findings highlight a subtype-specific, cell-autonomous mechanism by which pathogenic LRRK2 impairs PD-vulnerable nigrostriatal synapses and provide a framework for therapeutic strategies targeting early synaptic deficits in PD.
    DOI:  https://doi.org/10.1038/s41467-026-75194-3
  12. Redox Biol. 2026 Aug 22. pii: S2213-2317(26)00364-2. [Epub ahead of print]96 104365
    Adaptive and degenerative mitochondrial remodeling define distinct redox states in age-related macular degeneration.
    Cecilia Giulivi, Carol Villafuerte-Trisolini, Zoe Lee Greenblatt, Jennifer Dang, Atena Tork, Rida Mullah, Sophie Le, Angela Min, Maya Nair, Aldo Vorkapich, Huy-An Tran, Elizabeth Doyle, Alestor Law, Owen O'Keefe, Annabelle Wu, Bradley Shibata, Ana Ripolles-Garcia, Sara M Thomasy, R Alan Harris, Rui Chen, Yin Allison Liu, Glenn Yiu.
      Age-related macular degeneration (AMD) is associated with mitochondrial dysfunction and oxidative stress, yet the relationship between mitochondrial remodeling, redox homeostasis, and disease progression remains poorly understood. Nonhuman primates (NHPs) develop spontaneous AMD-related phenotypes, including punctate deposits and soft drusen, providing a unique animal model to investigate mitochondrial pathology in the aging retinal pigment epithelium (RPE). We integrated quantitative mitochondrial ultrastructural profiling with flavoprotein fluorescence imaging, plasma metabolomics, and whole-exome sequencing to characterize mitochondrial and redox alterations in aged rhesus macaques with AMD-related lesions. Flavoprotein fluorescence imaging demonstrated increased metabolic heterogeneity in eyes with soft drusen, consistent with altered mitochondrial redox states and oxidative stress. Morphometric analysis identified distinct mitochondrial remodeling patterns across phenotypes. Normal aging was characterized by concentric cristae and type I paracrystalline inclusions. Eyes with punctate deposits exhibited increased mitochondrial fusion-associated morphology, hyperbranching, and type I paracrystalline inclusions, consistent with a stress-responsive mitochondrial remodeling pattern. In contrast, eyes with soft drusen exhibited reduced fusion-associated morphology, reduced structural complexity, and ultrastructural features consistent with mitochondrial deterioration. These ultrastructural patterns were accompanied by distinct plasma metabolomic signatures. Punctate deposits were associated with altered glycolytic, tricarboxylic acid cycle, and redox-buffering metabolites, consistent with differences in stress-responsive metabolism, whereas soft drusen exhibited metabolomic signatures consistent with altered redox homeostasis. Whole-exome sequencing identified a mitochondrial DNA variant, MT:9582G > A, in cytochrome c oxidase subunit III (COX3) associated with the drusen phenotype. Collectively, these findings identify distinct mitochondrial remodeling patterns associated with AMD-related phenotypes in aged rhesus macaques. The convergence of ultrastructural, imaging, metabolomic, and genetic analyses suggests that punctate deposits and soft drusen are associated with different mitochondrial and redox-related responses to chronic retinal stress. These findings provide a framework for future studies investigating mitochondrial biology and redox-driven mechanisms in AMD.
    Keywords:  Age-related macular degeneration; Mitochondria; Nonhuman primates; Redox homeostasis; Retinal pigment epithelium; Rhesus macaques
    DOI:  https://doi.org/10.1016/j.redox.2026.104365
  13. Mitochondrion. 2026 Aug 22. pii: S1567-7249(26)00095-4. [Epub ahead of print]91 102205
    Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
    Yang Yang, Nirajan Neupane, Jouni Kvist, Jonna Saarimäki-Vire, Matthias Schewe, Kalle Luopajärvi, Pooja Manjunath, Svetlana Konovalova, Rubén Torregrosa-Muñumer, Veijo Kinnunen, Pekka Katajisto, Timo Otonkoski, Eija Pirinen, Jayasimman Rajendran, Henna Tyynismaa.
      Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.
    Keywords:  Adipose tissue; Body weight homeostasis; Grpel2; Mitochondrial protein import; Nucleotide exchange factor; mtHSP70
    DOI:  https://doi.org/10.1016/j.mito.2026.102205
  14. Genetics. 2026 Aug 26. pii: iyag203. [Epub ahead of print]
    Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
    Mahima Ghosh, Patricia Melloy.
      
    Keywords:   AAC2 ; HSP31 ; MFB1 ; budding yeast; cytotoxicity; mitochondrial protein import; proteostasis
    DOI:  https://doi.org/10.1093/genetics/iyag203
  15. J Cardiovasc Aging. 2026 ;pii: 12. [Epub ahead of print]6(2):
    Understanding cardiovascular aging as a disorder of mitochondrial network.
    Taslima Akter Shila, Dhrubo Ahmad, Jianli Zhao, Huilan Tan, Bo Wang, John Zhang, Yajing Wang.
      Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of "mitochondrial age", a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.
    Keywords:  Cardiovascular aging; endothelial dysfunction; epidemiology; heart failure with preserved ejection fraction; hypertension; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.20517/jca.2026.07
  16. Bull Math Biol. 2026 Aug 22. pii: 165. [Epub ahead of print]88(9):
    Delay Differential Equation Approach to Oligomerization Reveals the Delay Dynamics Underlying Oscillations in Mitochondrial Fission.
    Kitrick Fynaardt, Anna K Leinheiser, Colleen C Mitchell, Chad E Grueter.
      Disruptions in the balance of mitochondrial fission and fusion are implicated in a host of diseases including cardiovascular, metabolic, and neurodegenerative, as well as cancer. Leinheiser et al. proposed a mechanistic model for mitochondrial fission which relies on the oligomerization of Dynamin-related protein 1 (Drp1). In this work, we propose an alternative state-dependent delay-differential equation (sdDDE) framework for mitochondrial fission, which reveals that the intrinsic delay dynamics in Drp1 oligomerization can drive oscillations in the rate of mitochondrial fission. To develop this sdDDE model, we generate a simplified model which disallows oligomer disassembly on the mitochondrial membrane. Following homogenization, the simplified model approaches a steady state dominated by oligomers too small to reach the threshold for fission. Therefore, the fission rate approaches zero when initial conditions reside within the basin of attraction of this fission-free equilibrium. We therefore reincorporate oligomer disassembly on the mitochondrial membrane. However, the attracting, fission-free equilibrium persists. To eliminate this fission-free equilibrium, we incorporate an atomization term into the oligomerization mechanism, highlighting the importance of oligomer disassembly in sustaining mitochondrial fission. Using homogenization techniques, we derive an advection PDE with nonlocal interactions and obtain a reduced sdDDE system governing oligomer partial moments. Analysis of this reduced system reveals an analogous Hopf bifurcation to the Leinheiser et al. fission model, demonstrating that intrinsic delays in Drp1 oligomerization are sufficient to generate oscillatory mitochondrial fission dynamics.
    Keywords:  DDE; Delay-differential equation; Delay-differential equation of threshold type; Homogenization; Hopf bifurcation; Mitochondrial dynamics; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11538-026-01743-y
  17. Int J Mol Sci. 2026 Aug 17. pii: 7334. [Epub ahead of print]27(16):
    Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
    Victoriano Pérez-Vázquez, Juan Manuel Guzmán-Flores, Katya Vargas-Ortiz, Carmen Palacios-Reyes, Joel Ramírez-Emiliano.
      Obesity and type 2 diabetes (T2D) are multifactorial metabolic disorders characterized by progressive dysfunction of multiple organs and biological systems. Although mitochondrial dysfunction is a hallmark of disease progression, the mechanisms linking metabolic stress to coordinated tissue dysfunction remain incompletely understood. Comparative proteomic studies have consistently identified coordinated remodeling of oxidative phosphorylation, fatty acid oxidation, tricarboxylic acid cycle activity, redox regulation, mitochondrial proteostasis, and adaptive signaling across metabolically affected organs, revealing conserved organizational principles underlying mitochondrial adaptation. However, these findings have largely been interpreted within reductionist, pathway-centered frameworks. Here, we integrate evidence from comparative proteomics, mitochondrial biology, bioenergetics, redox biology, signaling, and systems biology to propose the concept of mitochondrial-centered biological networks (MCBNs), in which mitochondria function as dynamic regulatory hubs coordinating interconnected processes that collectively determine metabolic adaptation and tissue resilience. Building on this framework, we introduce the Mitochondrial Homeostasis Hypothesis, which proposes that preservation or restoration of mitochondrial homeostasis depends on coordinated regulation of MCBNs and constitutes a fundamental systems-level mechanism underlying resistance to obesity, T2D, and hypercaloric diet-induced metabolic dysfunction. Curcumin represents a well-studied network-modulating intervention that coordinately influences mitochondrial bioenergetics, metabolic flexibility, redox homeostasis, proteostasis, inflammatory signaling, and adaptive stress responses, supporting the concept that mitochondrial homeostasis is preserved through coordinated network regulation rather than isolated modulation of individual molecular pathways. Finally, we discuss how emerging technologies, including functional proteomics, redox proteomics, spatial and single-cell proteomics, acetylomics, integrated multi-omics, and artificial intelligence-assisted network analysis, provide unprecedented opportunities to quantitatively characterize MCBNs, validate the proposed hypothesis, identify network-based biomarkers, and accelerate the development of network-guided precision mitochondrial medicine.
    Keywords:  comparative proteomics; curcumin; mitochondrial homeostasis; mitochondrial-centered biological networks; network medicine; obesity; precision mitochondrial medicine; systems biology; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27167334
  18. Sci Adv. 2026 Aug 28. 12(35): eaee8657
    The molecular basis of mitochondrial crista formation by the MIC10 complex.
    Chelsea M Brown, Tsjerk A Wassenaar, Zachary Freyberg, Siewert J Marrink.
      Mitochondrial cristae are essential for respiration, yet the molecular basis of how the high curvature of these membrane folds is maintained remains unclear. Using structure prediction tools and multiscale simulations, we examined the role of the MIC10 subcomplex of the mitochondrial contact site and cristae organizing system (MICOS). We found that the MIC10 proteins Mic10, Mic26, and Mic27 strongly recruit cardiolipin at conserved positive loop motifs, driving oligomerization of these subunits and resulting in the stabilization of curvature in model membranes. Reconstruction of the full MIC10 complex in a realistic crista junction setup shows its capability to maintain membrane bending, while intrinsically disordered regions may form a permeability barrier between cristae and the intermembrane space. These findings provide a mechanistic model for cristae curvature formation and suggest how MICOS components cooperate with cardiolipins to maintain mitochondrial architecture.
    DOI:  https://doi.org/10.1126/sciadv.aee8657
  19. Neurol Genet. 2026 Aug;12(4): e200411
    Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.
    Róisín M Boggan, Theodora-Dafni Michalettou, Yi Shiau Ng, Imogen G Franklin, Lucas T Cortés, Charlotte L Alston, Emma L Blakely, Boriana Büchner, Enrico Bugiardini, Kevin Colclough, Catherine Feeney, Michael G Hanna, Andrew T Hattersley, Thomas Klopstock, Cornelia Kornblum, Michelangelo Mancuso, Kashyap A Patel, Robert D S Pitceathly, Chiara Pizzamiglio, Holger Prokisch, Jochen Schäfer, Andrew M Schaefer, Maggie H Shepherd, Annemarie Thaele, Rhys H Thomas, Doug M Turnbull, Cathy E Woodward, Robert McFarland, Robert W Taylor, Heather J Cordell, Sarah J Pickett.
       Background and Objectives: Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD).
    Methods: We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region.
    Results: We identified significant genetic linkage to encephalopathy (chromosome 7q22; LOD = 3.72), and regions suggestive of genetic linkage on chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like episodes. No linkage was identified for diabetes or hearing impairment. Association analysis within the chromosome 7 region identified variant rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10-5), yet no variants reached the proportional significance threshold (5.3 × 10-6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10-3) and IMMP2L (p = 6.4 × 10-3) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds.
    Discussion: The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.
    DOI:  https://doi.org/10.1212/NXG.0000000000200411
  20. J Vis Exp. 2026 Aug 21.
    Functional Reconstitution of Mitochondrial Respiratory Supercomplexes.
    Abhilash Padavannil, Peiyi Liu, James A Letts.
      Mitochondria are central hubs in bioenergetic metabolism and are the primary source of ATP. The inner mitochondrial membrane houses the oxidative phosphorylation system, which includes electron transport chain complexes (CI, CII, CIII2, and CIV) and the ATP synthase (CV). In mammals, CI, CIII2, and CIV form higher-order structures called supercomplexes (SCs) such as SC I+III2+IV, SC I+III2, and SC III2+IV. Although the physiological factors favoring SC formation remain unclear, it has been proposed that SC formation may enhance electron-transfer rates between complexes, reduce reactive oxygen species production, or prevent nonspecific protein aggregation within the densely packed mitochondrial inner membrane. Structural and functional studies of respiratory SCs have relied heavily on detergent-extracted complexes. While these studies have improved our understanding of the electron transport chain, the lack of a sealed membrane bilayer limits their ability to probe the functional benefits of supercomplex assembly. Recent advances, however, have shown that membrane proteins can be structurally characterized in reconstituted, native-like membrane environments, offering a more physiological context for these investigations. Here, we present a simple, quick, and reproducible protocol for reconstituting respiratory SCs into liposomes. This method allows for testing the effects of varying lipid compositions, protein concentration, and membrane potential on the function of respiratory SCs, providing a valuable tool for future mechanistic studies.
    DOI:  https://doi.org/10.3791/72243
  21. Biochem Soc Trans. 2026 Sep 23. 54(9): 1155-1167
    The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.
    Lilia Colina-Tenorio, Martina Bohuslavová, Alexander W Bruce, Hassan Hashimi.
      Cristae are mitochondrial subcompartments that give the organelle its distinctive appearance. More significantly, mitochondria are the proverbial powerhouses as cristae house the molecular machinery underlying cellular respiration, a process that converts carbon sources into ATP by chemiosmosis. The form of cristae is invariably connected to their bioenergetic function. Here, we review our current understanding of the molecules underpinning crista formation. Not surprisingly, respiratory chain multiprotein complexes are involved in crista formation, with F1FO-ATP synthase dimers being eminent membrane sculptors. But crista formation also requires factors that are not directly part of the respiratory chain. The most ancient is the MICOS complex, which delineates the subcompartment and acts as a hub for crista biogenesis. The mitochondrial inner membrane (IM), from which cristae emerge, is remodelled by different dynamin-related proteins in animals and fungi. Cardiolipin is an integral component of the membranous fabric of the IM. To begin to grasp general design principles underlying crista formation, we synthesize findings from canonical animal and yeast experimental models with those from diverse protists and other eukaryotes. However, how these molecules are orchestrated during crista formation remains a hidden piece in our understanding of how cells differentiate in specialized forms. We highlight the few knowns about crista formation in a handful of organisms to guide research into the many unknowns about how complex subcompartments represented by mitochondrial cristae are formed.
    Keywords:  ATP synthase; MICOS; cristae; dynamin-related protein; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1042/BST20260167
  22. J Clin Invest. 2026 Sep 01. pii: e204023. [Epub ahead of print]
    Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
    David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara R Price, Sandra Hj Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.
      Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
    Keywords:  Calcium signaling; Cell biology; Cellular immune response; Hepatology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI204023
  23. Biomolecules. 2026 Aug 12. pii: 1177. [Epub ahead of print]16(8):
    Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1.
    Kalisse I Horne, Joshua Chang Mell, Chiaki Noguchi, Sri Havya Jana, Shriya Pinisetty, Rhea Masand, Christian Sell, Eishi Noguchi.
      Timeless and its fission yeast ortholog Swi1 are evolutionarily conserved components of the replication fork protection complex that ensures faithful DNA replication and genome stability. While their nuclear roles are well-characterized, their roles in mitochondrial genome maintenance remain unknown. Here, we demonstrate a previously unrecognized connection between Timeless/Swi1 and mitochondrial homeostasis. In fission yeast, swi1 deletion increased association of the DNA repair protein Rad52 with mitochondrial DNA sequences across the mitochondrial genome, suggesting altered mitochondrial genome maintenance. Unexpectedly, swi1∆ cells showed an increased mtDNA copy number and improved growth under respiratory conditions, suggesting activation of compensatory mechanisms that promote mitochondrial genome maintenance. The loss of Swi1 also partially rescued the growth defect under respiratory conditions and mtDNA loss associated with depletion of mitochondrial DNA polymerase γ, linking Swi1 to pathways regulating mitochondrial replication under stress. Consistent with these phenotypes, transcriptomic and pathway enrichment analyses revealed transcriptional changes indicative of reduced glycolysis and enhanced oxidative phosphorylation, suggesting a shift toward respiratory metabolism. In human cells, Timeless depletion elicited distinct mitochondrial responses depending on the cell type. While Timeless-depleted TE-11 and Saos-2 cells elicited mitochondrial phenotypes comparable to those observed in fission yeast, Timeless depletion in U-2 OS cells led to reduced mtDNA copy number, elevated mitochondrial reactive oxygen species, and decreased mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Despite these phenotypic differences, both fission yeast and human cells exhibited elevated levels of orthologs of the mitochondrial transcription factor A (TFAM) and the oxidative stress regulator NRF2, suggesting the conserved activation of compensatory mitochondrial and antioxidant pathways. Together, these findings identify an evolutionarily conserved connection between Timeless/Swi1 and mitochondrial homeostasis and reveal distinct adaptive responses to mitochondrial stress.
    Keywords:  DNA polymerase γ; Schizosaccharomyces pombe; Swi1; Timeless; fission yeast; mitochondria; mitochondrial genome; mtDNA; oxidative stress; stress response
    DOI:  https://doi.org/10.3390/biom16081177
  24. Hum Cell. 2026 Aug 24. pii: 130. [Epub ahead of print]39(9):
    Mitochondria and exosome intercellular co-transfer via annular gap junction vesicles in the human glioblastoma stem cell niche.
    Gabriel Arismendi-Morillo.
      
    Keywords:  Annular gap junction vesicles; Exosomes; Glioblastoma; Mitochondrial transfer
    DOI:  https://doi.org/10.1007/s13577-026-01437-6
  25. Cureus. 2026 Aug;18(8): e114956
    Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.
    Ngo Cheung.
      This study is a secondary computational reanalysis of the publicly available GSE85718 microarray dataset generated during the long-term nicotinamide mononucleotide (NMN) study. NMN has been reported to improve several age-sensitive physiological traits in mice, including energy metabolism, insulin sensitivity, plasma lipid profiles, and skeletal-muscle mitochondrial function. However, the transcriptional mechanisms behind these effects remain less clear than the broader nicotinamide adenine dinucleotide (NAD+) and sirtuin-centered model often used to explain NMN biology. The present analysis used a per-tissue age-by-treatment interaction model to test whether NMN modifies the rate of age-associated transcriptional change rather than simply shifting expression at one age. The model was expression ~ age × treatment, with the age-by-treatment term used as the central test. A gene was considered an NMN-rescue candidate only when it changed with age in control mice and showed an opposite-signed interaction term, consistent with NMN shifting old-age expression toward the young-control state. No individual gene reached genome-wide false discovery rate (FDR) <0.05 for age, NMN at six months, or the interaction term in skeletal muscle, liver, or white adipose tissue (WAT). Therefore, all gene-level results should be treated as hypothesis-generating. Using relaxed nominal criteria, 421 rescue candidates were identified in skeletal muscle, 355 in liver, and 397 in WAT. Only 35 genes were rescued in at least two tissues, 26 of which were direction-consistent, and none were rescued in all three tissues. Ras-related protein Rab-11A (RAB11A) emerged as the strongest cross-tissue candidate, with rescue in skeletal muscle and WAT, high confidence in at least one tissue, consistent directionality, and involvement in 39 gene set enrichment analysis (GSEA) leading-edge terms, largely related to trafficking and cellular transport. Carnitine palmitoyltransferase 2 (CPT2) was the only mitochondrial gene among the robust cross-tissue candidates and was consistently rescued in skeletal muscle and WAT, supporting a focused fatty-acid oxidation and substrate-handling hypothesis rather than broad mitochondrial activation. At the pathway level, liver showed the clearest signal: NMN was associated with suppression of fatty-acyl-coenzyme A (CoA) and long-chain fatty-acyl-CoA metabolic programs. These findings do not establish that NMN prevents transcriptional aging or that RAB11A or CPT2 mediates the physiological effects of NMN. Instead, they identify tissue-specific, testable candidates from a secondary reanalysis of an existing animal dataset. In particular, they support moving beyond a generic "NAD+ improves mitochondria" model toward testable mechanisms involving cellular logistics, membrane recycling, and substrate utilization.
    Keywords:  age-by-treatment interaction; aging; cpt2; liver; nad+ metabolism; nmn; rab11a; skeletal muscle; transcriptional drift; white adipose tissue
    DOI:  https://doi.org/10.7759/cureus.114956
  26. PLoS Biol. 2026 Aug 28. 24(8): e3003649
    Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.
    Jie Zhang, Qian Shan, Xin Wang, Meijiao Li, Yang Yang, Mei Duan, Ruofeng Tang, Junxiang Zhou, Fengyang Wang, Yuehui Shi, Kai Jiang, Chonglin Yang.
      Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003649
  27. Sci Adv. 2026 Aug 28. 12(35): eadu0632
    Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
    Fangbing Chen, Yanhui Liang, Wei Zheng, Aobo Yao, Ning Wang, Huangyao Chen, Zhenpeng Zhuang, Meng Lian, Yu Zhao, Zhen Ouyang, Zhaohai Zhou, Weikai Ge, Qishuai Liu, Yinghua Ye, Liangxue Lai, Kepin Wang.
      The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.
    DOI:  https://doi.org/10.1126/sciadv.adu0632
  28. Intractable Rare Dis Res. 2026 Aug 31. 15(3): 219-231
    Mitochondrial DNA A3243G variant-associated MELAS: Recent advances in clinical trials, therapeutic interventions, and disease-modifying strategies.
    Kuan-Yu Chu.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, most often caused by the m.3243A>G mitochondrial DNA variant, represents one of the most clinically significant inherited mitochondrial disorders. This variant disrupts mitochondrial tRNALeu(UUR) function, leading to impaired mitochondrial protein synthesis and progressive multisystem dysfunction. This narrative review synthesizes recent clinical trials, therapeutic advances, and emerging disease-modifying strategies for m.3243A>G-associated MELAS, with emphasis on evidence published between 2024 and 2026, drawing on PubMed/MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov, and the EU Clinical Trials Register. Key advances include: i) regulatory approval of high-dose taurine supplementation (9-12 g/day), which achieved complete prevention of stroke-like episodes in 60% of participants in a phase III trial; ii) phase IIb data (company-reported) indicating that sonlicromanol (KH176) showed signals of improvement in cognition, mood, and fatigue, supporting progression to a phase III registrational trial (KHENERFIN, NCT06451757); iii) ongoing trials of zagociguat and TTI-0102 targeting vascular dysfunction and oxidative stress; iv) KL1333, a novel NAD+ modulator, in phase II evaluation (FALCON trial); and v) promising preclinical gene-based approaches-including mitochondria-targeted TALENs, DdCBE base editors, and mitoARCUS nucleases-demonstrating heteroplasmy shifting in patient-derived cells and animal models, though direct clinical applicability to m.3243A>G MELAS requires further investigation. The therapeutic landscape for MELAS is evolving from symptomatic care toward mechanism-based disease modification, led by taurine as the first regulatory-approved disease-modifying therapy and complemented by late-stage small molecules and mitochondrial genome-editing technologies.
    Keywords:  NAD; cysteamine; genetic therapy; oxidative stress; taurine
    DOI:  https://doi.org/10.5582/irdr.2026.01026
  29. Biomolecules. 2026 Aug 01. pii: 1126. [Epub ahead of print]16(8):
    ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?
    Hiroshi Mitsumoto, Hélène Blasco, Philippe Corcia, Vincenzo Silani.
      Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.
    Keywords:  ALS; MND; amyotrophic lateral sclerosis; bioenergetics; frontotemporal systemic disease; hypothalamus; metabolic disease; mitochondria; mitochondrial associated membrane (MAM); motor neuron disease; multisystem involvement
    DOI:  https://doi.org/10.3390/biom16081126
  30. Genes (Basel). 2026 Jul 23. pii: 850. [Epub ahead of print]17(8):
    Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.
    Albert Z Lim, Aye-Myat Moe, Renae J Stefanetti, Yi Shiau Ng.
      Primary mitochondrial diseases (PMDs) are one of the most common genetic disorders with an estimated prevalence of 1 in 4300. This review article summarises the latest updates in the field of mitochondrial medicine over the last decade. The availability of exome and genome sequencing in clinical practice has empowered clinicians to unravel the phenotypic heterogeneity of PMD and to end the diagnostic odyssey experienced by many patients and families. In unresolved cases, the detection of variant(s) of unknown significance by next-generation sequencing creates diagnostic and clinical uncertainties, and integrating a multi-omics approach can improve diagnostic yield. Alongside breakthroughs in genomic technologies, there is growing interest in using fluid biomarkers to guide diagnosis, monitor disease progression, and potentially serve as clinical trial endpoints. However, the clinical application of these fluid biomarkers in unselected patient cohorts with different disease onset and phenotypes would require more robust evidence. Natural history studies derived from national and international collaborations have provided insights into genotype-phenotype relationships and prognostic factors across several genotypes, including m.3243A>G, MT-ATP6, POLG, and TK2. Advances in therapeutic discoveries and clinical trials are challenging the obsolete dogma that PMDs are untreatable and bringing hope to patients; four compounds have been licensed, and many trials are in progress. Many barriers and challenges to translating laboratory discoveries into clinical therapy in PMD remain, including preclinical models for efficacy and safety testing, sample size, trial design, and the selection of outcome measures and trial endpoints.
    Keywords:  fluid biomarkers; outcome measures; phenotypes; trial endpoints; whole-genome sequencing
    DOI:  https://doi.org/10.3390/genes17080850
  31. Antioxidants (Basel). 2026 Aug 21. pii: 1043. [Epub ahead of print]15(8):
    Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.
    Masahiro Kawasumi, Mika Teranishi.
      Parkinson's disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, which lack muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial homeostasis and motor function under conditions where muscle regeneration does not occur. Silencing of pdr-1 attenuated age-related mitochondrial fragmentation in body-wall muscle cells but was associated with later impairments in locomotor activity and loss of nuclear GFP signals, suggesting progressive muscle cell damage. By day 2 of adulthood, mitochondrial reactive oxygen species (mtROS) levels were elevated in muscle cells subjected to pdr-1 RNAi, and in the pdr-1(gk448) mutant this mtROS elevation was accompanied by a reduction in mitochondrial membrane potential (ΔΨm). In vivo imaging further revealed elevated mitochondrial Ca2+ levels ([Ca2+]mito) in PDR-1-deficient muscle cells. Moreover, the mtROS increase associated with PDR-1 deficiency was suppressed in mcu-1 mutants. These findings support a model in which MCU-1-dependent elevation of [Ca2+]mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle.
    Keywords:  Caenorhabditis elegans; Parkinson’s disease; body-wall muscle cells; mitochondrial calcium influx; mitochondrial membrane potential; mitochondrial quality control; mitochondrial reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox15081043
  32. Int J Mol Sci. 2026 Aug 12. pii: 7200. [Epub ahead of print]27(16):
    Mitochondrial Homeostasis Mediates the Sustained Neuroprotection of CNTF-Chitosan Hydrogel Against NMDA-Induced Retinal Ganglion Cell Excitotoxicity.
    Huiting Jiang, Xunhui Guo, Yuanyuan Bai, Xinyue Ma, Hongmei Duan, Xiaoguang Li, Zhaoyang Yang.
      N-methyl-D-aspartate (NMDA) excitotoxicity drives mitochondrial dysfunction and retinal ganglion cell (RGC) loss in blinding retinal disorders. Ciliary neurotrophic factor (CNTF) is neuroprotective, but its short half-life limits long-term therapy. Here, we investigated whether mitochondrial homeostasis mediates the sustained protection of a CNTF-loaded chitosan hydrogel. In vitro, free CNTF and the hydrogel equally protected RGCs against NMDA, effects completely abolished by the mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). In vivo, free CNTF provided only transient rescue, whereas the hydrogel sustained RGC survival, mitochondrial integrity, and visual function for 28 days, with persistent upregulation of mitochondrial biogenesis genes. Adeno-associated virus-mediated DRP1 overexpression-induced mitochondrial fission fully reversed the hydrogel's benefits, mirroring CCCP inhibition. Collectively, intact mitochondrial homeostasis is essential for the long-term neuroprotection of the CNTF-chitosan hydrogel, which extends CNTF retention without altering its mitochondrial-dependent mechanism. This hydrogel represents a promising long-acting treatment for retinal excitotoxicity.
    Keywords:  NMDA excitotoxicity; chitosan hydrogel; ciliary neurotrophic factor; mitochondrial dynamics; mitochondrial homeostasis; retinal ganglion cells
    DOI:  https://doi.org/10.3390/ijms27167200
  33. STAR Protoc. 2026 Aug 22. pii: S2666-1667(26)00446-6. [Epub ahead of print]7(3): 104793
    Protocol for assessing molecular signatures and metabolic function of primary murine cortical astrocytes.
    Nicole Blakeley, Baptiste Lacoste.
      Astrocytes are the most numerous brain cells and are central to the regulation of brain metabolism. Here, we present a protocol for identifying molecular signatures and assessing the metabolic function of primary murine cortical astrocytes. We describe steps for extracting, isolating and culturing astrocytes, characterizing these cells with immunocytochemistry, and extracting their metabolites. We then detail procedures for assessing mitochondrial function with challenges, RNA extraction for bulk sequencing, and DNA extraction for sequencing and epigenetics.
    Keywords:  Cell Biology; Cell culture; Cell isolation; Cell-based Assays; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2026.104793
  34. Anesthesiology. 2026 Aug 26.
    Ancient Mitochondrial Genetic Variant: Comment.
    Venezuelan Anesthesia Perioperative Risk Society author group
      
    DOI:  https://doi.org/10.1097/ALN.0000000000006263
  35. Curr Opin Pharmacol. 2026 Aug 27. pii: S1471-4892(26)00058-5. [Epub ahead of print]90 102662
    Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
    Lamiaa M ElAbbasy.
      Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
    DOI:  https://doi.org/10.1016/j.coph.2026.102662
  36. Cells. 2026 Aug 10. pii: 1438. [Epub ahead of print]15(16):
    Adipose Stem Cell Mitochondrial Transplantation in ART: From Biological Rationale to Clinical Milestone.
    Helaruwan Pasan Kumara Wijethunga Arachchilage, Sanath Udayanga Kankanam Gamage, Atsushi Morimoto, Yoshiharu Morimoto.
      Oocyte quality is the primary determinant of success in assisted reproductive technologies (ART), and mitochondrial dysfunction is increasingly recognized as a central mediator of poor oocyte competence across advanced maternal age, recurrent implantation failure, polycystic ovary syndrome, endometriosis, and obesity. Chemical interventions improve the mitochondrial microenvironment but cannot restore depleted mitochondrial mass, while heterologous mitochondrial replacement remains constrained by ethical, legal, and biological limitations. This review examines the biological basis for mitochondrial intervention in oocytes, evaluates chemical and cellular therapeutic approaches, and assesses the evidence for autologous Adipose Stem Cell-derived Mitochondria ENergy Transfer (ASCENT). Mitochondria govern oocyte ATP production, calcium-mediated meiotic integrity, and redox homeostasis, and their disruption contributes to aneuploidy, fertilization failure, and embryonic arrest. Among cellular interventions, autologous adipose-derived stem cell mitochondrial transplantation offers minimally invasive tissue accessibility, morphological compatibility with oocyte mitochondria, robust membrane potential, and a preclinically validated Mito-ICSI delivery platform. Notably, ASCENT is currently the only autologous approach for which safety across three consecutive offspring generations has been reported in a mammalian model, with primary maternal origin of offspring mtDNA confirmed. Together, preclinical efficacy, transgenerational safety, and human proof-of-concept support progression toward a rigorously designed clinical trial, while ASC-derived mitochondria hold broader relevance in regenerative medicine.
    Keywords:  Adipose Stem Cell Energy Transfer (ASCENT); Mito-ICSI; adipose-derived stem cells; autologous therapy; mitochondrial dysfunction; mitochondrial transplantation
    DOI:  https://doi.org/10.3390/cells15161438
  37. J Struct Biol. 2026 Aug 27. pii: S1047-8477(26)00075-4. [Epub ahead of print] 108359
    Structural basis of Saccharomyces cerevisiae Mba1 in mitochondrial co-translational membrane insertion.
    Jing Yang, Maosen Ruan, Dongshuai Bai, Yong Liu, Yizhuo Wang, Hengfang Tang, Yunyan Li, Junfeng Wang.
      Co-translational membrane insertion is essential for the efficient integration of mitochondrially encoded proteins into the inner mitochondrial membrane (IMM) and is critical for respiratory chain biogenesis. Mba1 is a mitochondrial ribosome-associated protein implicated in coupling mitochondrial translation with inner-membrane protein biogenesis, but its structural basis of function remains poorly understood. Here, we determined the solution structure of mature Saccharomyces cerevisiae Mba1 (mMba1) using multidimensional nuclear magnetic resonance (NMR) spectroscopy. The structure reveals a compact α + β fold with a central hydrophobic cavity and distinct charged surface regions. Ribosome titration, paramagnetic relaxation enhancement, and Cox2-derived peptide titration identified several regions of mMba1 that are affected by these different interaction conditions. Mapping these regions onto the structure reveals spatially distinct surfaces that may contribute to ribosome association, membrane proximity, and interactions with hydrophobic peptide segments. These findings provide a structural framework for interpreting previous functional studies of Mba1 and support a working model in which Mba1 may function as a peripheral adaptor at the mitoribosome-inner membrane interface. Further structural and biochemical studies will be required to establish the molecular mechanisms underlying these interactions.
    Keywords:  Co-translational insertion; Mba1; Membrane association; NMR; Ribosome
    DOI:  https://doi.org/10.1016/j.jsb.2026.108359
  38. Biomolecules. 2026 Jul 30. pii: 1116. [Epub ahead of print]16(8):
    A Function-Centric Framework for Mitochondrial Quality Control.
    Fulya Ozcan, Filip Vujovic, Ramin M Farahani.
      Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules-including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles-into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.
    Keywords:  cell cycle; electron transport chain; mitochondria; quality control; signalling pathways
    DOI:  https://doi.org/10.3390/biom16081116
  39. Neuroscientist. 2026 Aug 25. 10738584261476959
    NMNAT2 Functional Landscape and Localization in Programmed Axon Degeneration.
    Alan Nicol, Eleanor Hopkins, Flora Hui, Andrea Brancale, Pete A Williams.
      Why is NMNAT2 (and the NAD-NMNAT2-SARM1 axis) important? Axon loss is a common and early driver of disability across neurodegenerative diseases, peripheral neuropathies, traumatic injury, and neurotoxic chemotherapy. A major conceptual advance from the Wallerian degeneration research field is that axons can execute an intrinsic self-destruction program (programmed axon degeneration) that is actively suppressed in healthy axons. NMNAT2 acts as the central endogenous axon maintenance factor in this system: it is highly labile; it must be continuously delivered from the soma into axons; and when its levels fall, axon degeneration is triggered through activation of SARM1, an NAD-consuming enzyme. This makes NMNAT2 a mechanistically grounded therapeutic node: stabilizing it, improving axonal delivery, or blocking downstream SARM1 can strongly preserve axons in diverse injury and disease contexts. NMNAT2 is a short-lived axonal NAD biosynthetic enzyme that maintains a low NMN:NAD ratio to restrain the executioner SARM1, thereby preserving axon integrity. This review integrates NMNAT2's localization-dependent pools, turnover mechanisms, upstream stressors, downstream SARM1 signaling, and engineered and disease-associated variants. A localization-aware representation of NMNAT2's functions, trafficking, proteostatic regulation, upstream stressors, and genetic variants should enable targeted experimental design and therapeutic hypothesis generation aimed at stabilizing axons. Here the functional landscape and localization of NMNAT2 in neurodegeneration is examined, ending with gaps identified in the literature and strategies to address these.
    Keywords:  NAD; NMNAT2; SARM1; Wallerian degeneration; programmed axon degeneration
    DOI:  https://doi.org/10.1177/10738584261476959
  40. Antioxidants (Basel). 2026 Jul 30. pii: 948. [Epub ahead of print]15(8):
    The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.
    Giustino Varrassi, Y Van Tran, Giacomo Farì, Miguel Narvaez Encinas, Alberto Corriero, Filomena Puntillo, Phong Van Pham, Matteo Luigi Giuseppe Leoni.
      Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.
    Keywords:  biomarkers; glaucoma; mitochondria; neurodegenerative diseases; neuroinflammation; optic nerve diseases; oxidative stress; precision medicine; retina; retinal ganglion cells
    DOI:  https://doi.org/10.3390/antiox15080948
  41. Front Cell Dev Biol. 2026 ;14 1866640
    Mitochondrial regulation of cellular senescence heterogeneity.
    Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo.
      Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere-mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.
    Keywords:  cellular senescence; metabolic reprogramming; mitochondrial dysfunction; mitophagy; reactive oxygen species (ROS); senescence heterogeneity; senescence-associated secretory phenotype (SASP); senolytics
    DOI:  https://doi.org/10.3389/fcell.2026.1866640
  42. Nature. 2026 Aug 24.
    Patient's own mitochondria injected into eyes in attempt to restore vision.
    Miryam Naddaf.
      
    Keywords:  Diseases; Sensory systems; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-026-02616-z
  43. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2534325123
    Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
    Alejandro Arco-Hierves, Konstantina Pamboukas, Linda Bilonda Mutala, Lukasz S Borowski, Celine Mayet, Paul Mazet, Sacha E Silva-Saffar, Dory Vergallo, Anna Paszek, Marta M Dilling, Laurie Askenatzis, Juliette Pascaud, Philippe Labrot, Charlene Lasgi, Johannes N Spelbrink, Albertas Navickas, Thibaut Naninck, Nabila Seddiki, Arnaud Tete, Roman J Szczesny, Gaetane Nocturne, Xavier Mariette, Rami Bechara.
      Chronic interferon (IFN) activation is a hallmark of autoimmune diseases such as systemic lupus erythematosus and Sjögren's disease (SjD), where epithelial cells are key contributors. Although viral and retroelement triggers have been proposed as triggers, direct evidence in patient tissues is limited, and endogenous mechanisms of epithelial IFN dysregulation remain unclear. Mitochondrial double-stranded RNA (mt-dsRNA) is a potent type I IFN (IFN-I) inducer, but its regulation in epithelial cells is poorly understood. We identify a mechanism in which the RNA methyltransferase METTL3 stabilizes REXO2 mRNA in primary salivary gland epithelial cells through N6-methyladenosine (m6A) modification. REXO2 encodes a mitochondrial exonuclease that controls mt-dsRNA. METTL3 inhibition reduces REXO2, causing mt-dsRNA accumulation and IFN-I signaling amplification and inflammation. Single-cell and bulk transcriptomic analyses, together with immunofluorescence of salivary gland tissues from SjD patients and controls, reveal reduced REXO2 expression and elevated IFN-I signatures in SjD. Rexo2 is likewise downregulated in epithelial cells of a spontaneous SjD mouse model. REXO2 loss amplifies IFN-I responses and inflammation across several epithelial contexts, while methyl donors restore REXO2 and dampen IFN activation, highlighting a targetable regulatory checkpoint in IFN-driven autoimmune diseases, alongside potential parallel stress pathways.
    Keywords:  RNA methylation; Sjögren’s disease; autoimmunity; interferon; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2534325123
  44. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261476231
    Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.
    Leigh Syndrome Roadmap Project Natural History Study Consortium
       Background: Leigh Syndrome Spectrum (LSS) is the most common pediatric mitochondrial disease syndromic presentation. However, its natural history has not been well-characterized, particularly across diverse populations.
    Objectives: Information obtained through robust, prospective natural history studies (NHSs) in LSS will be foundational to accurately counsel newly diagnosed families, develop effective therapeutics, and identify outcome measures for future clinical trials.
    Design: We describe an ongoing multi-site, international, patient advocacy group funded, observational NHS in LSS. We employed a multi-site international federated design with local regulatory review coupled with central regulatory and coordinator support. To date, NHS outcome measures have been collected on LSS participants across 5 sites every 3 to 6 months for up to 3.8 years.
    Methods: Objective and subjective outcome measures were carefully selected by the international LSS outcome measure working group. Study data across sites were anonymized and combined for cleaning and analysis at the Data Coordinating Center (Children's Hospital of Philadelphia). Descriptive statistics of the study cohort and inter-measure correlations were analyzed across NHS assessments.
    Results: Preliminary analysis of the first 74 participants was completed to characterize demographics, symptomatology, and clinical history. The average age at enrollment was 10.7 years, ranging from 0 to 50 years. The most common gene disorders were MT-ATP6 (22%, n=16), MT-ND5 (8%, n=6) and SURF1 (8%, n=6). No statistically significant between-group differences were detected by sex or genetic etiology. High inter-measure correlation between all the outcome measures and "gold standard" outcomes provides justification for future use of these assessments in both NHSs and clinical trials.
    Conclusion: We have demonstrated the feasibility of prospectively collecting robust international-site LSS NHS data through multi-site collaboration. These LSS community data will be critical for informing therapeutic development, outcome measure selection and clinical trial design, and providing baseline comparator evidence for development of future therapeutic interventions.
    Keywords:  Leigh syndrome spectrum; mitochondrial disease; natural history; neurodegenerative disease
    DOI:  https://doi.org/10.1177/26330040261476231
  45. Biogerontology. 2026 Aug 25. pii: 147. [Epub ahead of print]27(5):
    Partial reduction of the mitochondrial lipoyltransferase LipT2 promotes longevity and redox remodeling in Drosophila.
    Yoshihito Kishita, Manabu Tsuda, Yukiko Sato-Miyata, Satomi Takeo, Toshiro Aigaki.
      Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes, and mutations in the lipoyltransferase LIPT2 cause severe metabolic and neurological defects in humans. In Drosophila, two independent lipT2 loss-of-function alleles cause severe physiological abnormalities in homozygotes. Here, we show that heterozygotes for these same alleles exhibit significantly extended lifespan and delayed age-dependent decline in locomotor performance. Metabolic analysis revealed no major alterations in central carbon metabolites or cellular energy status, indicating that overall metabolic homeostasis is largely preserved. In contrast, LipT2 heterozygosity was associated with reduced DCF fluorescence and selective changes in redox-related metabolites, including glutathione and urate. LipT2 heterozygotes also exhibited enhanced resistance to paraquat-induced oxidative stress without induction of canonical antioxidant genes. These findings indicate that partial reduction of LipT2 activity is associated with selective remodeling of cellular redox homeostasis while preserving metabolic homeostasis, providing a physiological state associated with longevity and enhanced stress resistance. Thus, the effects of LipT2 deficiency are strongly dependent on gene dosage, with moderate reduction being associated with longevity and maintenance of physiological function rather than overt metabolic dysfunction.
    Keywords:   Drosophila melanogaster ; Gene dosage; LipT2; Longevity; Oxidative stress resistance; Redox homeostasis
    DOI:  https://doi.org/10.1007/s10522-026-10494-1
  46. Metabolites. 2026 Aug 21. pii: 597. [Epub ahead of print]16(8):
    Nicotinamide Mononucleotide Adenylyltransferase 1 and NAD+ Homeostasis in Neuroprotection and Aging.
    You Sun, Bowei Li, Zhengjiang Qian.
      Nicotinamide adenine dinucleotide (NAD+) is a fundamental metabolic cofactor and signaling molecule that supports redox reactions, DNA repair, chromatin regulation, stress adaptation, inflammation, and neuronal maintenance. Age-associated NAD+ decline has been implicated in brain aging and neurodegenerative disorders, but the causal node and limiting compartment differ across tissues and disease states. Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) catalyzes the final step in NAD+ biosynthesis and represents the major nuclear isoform of the mammalian NMNAT family. Direct human genetic evidence establishes NMNAT-1 as a causal gene in inherited retinal degeneration, whereas evidence linking endogenous NMNAT-1 to broader brain aging or sporadic neurodegeneration is mainly convergent preclinical, preliminary, or indirect. Beyond NAD+ synthesis, biochemical and Drosophila studies suggest possible chaperone-like and proteostasis-supporting functions, but a separable NAD+-independent function of endogenous mammalian NMNAT-1 has not yet been established in vivo. Here, we review the molecular structure, localization, and regulation of NMNAT-1, emphasizing calibrated distinctions among catalytic nuclear NAD+ supply, engineered axonal protection, pathway-adjacent NAD+ interventions, and putative non-catalytic protection. We further discuss how NMNAT-1 dysfunction may contribute to aging-associated genomic instability, neuroinflammation, synaptic impairment, retinal degeneration, selected neurodegenerative models, and glioma biology. Finally, we evaluate therapeutic strategies targeting NMNAT-1 and NAD+ pathways, noting that no human trial has yet established efficacy for an NMNAT-1-directed neurological therapy. A compartment-aware and evidence-stratified view is therefore essential for translating NMNAT-1 biology into interventions for age-related neural disease.
    Keywords:  NAD+; NMNAT-1; PARP1; SARM1; aging; axon degeneration; neuroprotection; proteostasis; retinal degeneration; sirtuins
    DOI:  https://doi.org/10.3390/metabo16080597
  47. Cell Rep. 2026 Aug 27. pii: S2211-1247(26)00951-4. [Epub ahead of print]45(9): 117873
    Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
    Soumya Maity, Manigandan Venkatesan, Adhishree Chidambaram, Sukanthathulse Uthayabalan, Louis Tung Faat Lai, Nicholas D Clark, Abhinaya Lakkureddi, Karthik Ramachandran, Kristen Bentz, Ravi Ramalingam, Sanjana Sen, Moeez Akram, Susan T Weintraub, Brij B Singh, David Gius, Joseph A Baur, Arianne L Theiss, Jeffrey Caplan, Doreen Matthies, Peter B Stathopulos, Muniswamy Madesh.
      Mitochondrial magnesium (mMg2+) is essential for cellular metabolism and bioenergetics, yet the mechanisms governing its transport remain poorly understood. Although MRS2 constitutes the pore of the mMg2+ channel, the molecular machinery regulating its function is unknown. Here, unbiased proteomics identified the prohibitin (PHB) complex as a prominent MRS2-interacting partner. Integrated biochemical and functional analyses demonstrate that the conserved coiled-coil domain mediates MRS2 homo-oligomerization, whereas the C-terminal region of MRS2 interacts with PHB1 to promote channel activity. Quantitative calibration of mitochondria-targeted MagFRET sensors revealed maximal mMg2+ uptake (∼15 mM), which was markedly reduced in Phb1-deficient hepatocytes. Complementary loss- and gain-of-function studies establish PHB1 as a positive regulator of MRS2-mediated mMg2+ uptake without affecting MCU-dependent Ca2+ transport. In vivo, hepatic Phb1 deletion attenuated mMg2+ uptake and enhanced cellular bioenergetics. These findings identify PHB1 as an activator of the MRS2, advancing our understanding of mMg2+ uptake machinery and its role in metabolic regulation.
    Keywords:  CP: molecular biology; MCU; MRS2; PHB; bioenergetics; calcium; channel; endoplasmic reticulum; magnesium; metabolism; mitochondria; prohibitin; structure
    DOI:  https://doi.org/10.1016/j.celrep.2026.117873
  48. Int J Mol Sci. 2026 Aug 18. pii: 7376. [Epub ahead of print]27(16):
    Neuromuscular Dysfunction and Charcot-Marie-Tooth Disease Reversal in Mfn2 T105M Knock-In Rats.
    Jochen Weigele, Antonietta Franco, Gerald W Dorn.
      Charcot-Marie-Tooth (CMT) disease type 2A is a rare heritable disorder caused by pathogenic variants of mitofusin (MFN) 2 that suppress mitochondrial fusion and motility in peripheral nerves, culminating in denervation myoatrophy. The rarity of this condition and the limited choice of animal models preclude pre-clinical evaluation of many tests that could be translated to human trials. Here, we introduced the CMT2A pathogenic variant MFN2 T105M into the rat genome for phenotype characterization and evaluation of disease response to a third-generation mitofusin activator, 8015-P2. CMT2A rats exhibited peripheral motor and sensory neuron dysfunction. Functional, histological, neuroelectrophysiological and magnetic resonance imaging testing readily distinguished between wild-type (WT) and mutant rats via axonopathy and myoatrophy. Compound 8015-P2 reversed CMT2A-linked neuromuscular degeneration in a dose- and time-dependent manner; at 10 mg/kg/d, normalization occurred at 4 weeks. The minimal effective 8015-P2 dose was 2 mg/kg/day. Rapidity of phenotype reversal and primary muscle abnormalities are consistent with extra-neuronal effects of the causal MFN2 DNA variant. These data demonstrate unprecedented utility of the Mfn2 T105M rat as a model of CMT2A, expand the menu of clinically applicable tests that may have use in future human trials, and establish a strong foundation for exploration of extra-neuronal consequences of pathogenic mitofusin variants in non-mouse models.
    Keywords:  electromyography; magnetic resonance imaging; mitochondria; mitofusin activator; myopathy; neuropathy
    DOI:  https://doi.org/10.3390/ijms27167376
  49. J Hepatol. 2026 Aug 25. pii: S0168-8278(26)02843-6. [Epub ahead of print]
    Mitochondrial NAD+ determines the metabolic capacity for liver regeneration.
    Panu K Luukkonen.
      
    DOI:  https://doi.org/10.1016/j.jhep.2026.08.003
  50. Biol Lett. 2026 Aug 26. pii: 20260144. [Epub ahead of print]22(8):
    Mitochondrial ribosome content as a proxy for respiration.
    Francis Mairet.
      Quantifying cellular activities remains a major challenge across fields ranging from microbial ecology to biotechnology and biomedical sciences. Building on the well-established linear relationship between growth rate and ribosome content-the so-called microbial growth law-this study proposes using organelle ribosome content to infer metabolic activity. In exponentially growing yeast (Saccharomyces cerevisiae), including under overflow metabolism conditions, a strong linear correlation was observed between mitochondrial ribosome content and oxygen uptake rate, underscoring the potential of this approach. Additionally, under fully respiratory conditions, cytoplasmic and mitochondrial ribosome fractions were linearly correlated, whereas overflow conditions fell below this linear relationship, providing a means to identify such metabolic states. Although these findings require broader validation across additional species, organelle ribosome quantification may provide a promising proxy for deciphering cellular metabolism.
    Keywords:  cellular resource allocation; microbial growth laws; overflow metabolism; oxygen uptake rates
    DOI:  https://doi.org/10.1098/rsbl.2026.0144
  51. Biochem Biophys Res Commun. 2026 Aug 21. pii: S0006-291X(26)01232-5. [Epub ahead of print]834 154468
    Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
    Ryo Takahashi, Mizuho Okamoto, Tsukika Tanaka, Tsubasa Asukabe, Yui Tomiyama, Rena Okuizumi, Michio Sato, Akio Fujisawa, Yorihiro Yamamoto, Misato Kashiba.
      Aging and age related pathological conditions are long-term processes in which cellular states gradually change over extended periods. However, many experimental studies of oxidative stress in cultured cells rely on short-term exposure to exogenous oxidative agents, which may not adequately reflect chronic oxidative conditions. To address this limitation, we established a cellular model of long-term oxidative stress by reducing endogenous antioxidant capacity through inhibition of coenzyme Q10 (CoQ10) biosynthesis rather than applying acute oxidative insults. Using HepG2 cells treated with 4-nitrobenzoic acid, we compared mitochondrial responses to acute and chronic CoQ10 depletion. CoQ10 levels were reduced under both acute and chronic conditions and were restored by co- treatment with 4-hydroxybenzoic acid. Acute CoQ10 depletion resulted in a reduced number of mitochondria and mitochondrial enlargement, accompanied by an increase in mitochondrial DNA copy number (mtDNAcn). In contrast, long-term culture under continuous CoQ10 depletion restored mitochondrial number, size, and mtDNAcn to levels comparable to those of control cells, despite persistently reduced CoQ10 content. However, cell proliferation remained impaired, and mitochondrial ultrastructural properties differed from those of control cells, indicating incomplete recovery under chronic conditions. Furthermore, 4-hydroxybenzoic acid reversed the mitochondrial alterations observed under acute conditions. Together, these findings demonstrate that mitochondrial responses to CoQ10 deficiency are strongly time dependent and involve reversible yet incomplete adaptive remodeling, highlighting the importance of modeling chronic oxidative stress when interpreting mitochondrial phenotypes.
    Keywords:  Cell growth; CoQ10; Coenzyme Q10; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154468
  52. Int J Mol Sci. 2026 Aug 15. pii: 7295. [Epub ahead of print]27(16):
    Mitochondrial RNA-Type I Interferon Axis in Sjögren's Disease: Molecular Mechanisms and Translational Implications.
    You-Jung Ha, Yeon Bi Han, Keun-Suh Kim, Woo-Jin Jeong, Joon Young Hyon, Yoosik Kim, Yun Jong Lee.
      Sjögren's disease (SjD) is a systemic autoimmune disease characterized by exocrine dysfunction, lymphocytic infiltration of the exocrine glands, and prominent activation of the interferon (IFN) pathway. Although IFN signatures are recognized as a central feature of SjD, endogenous triggers that sustain chronic IFN-driven inflammation remain incompletely understood. Mitochondrial RNAs (mtRNAs), particularly double-stranded species, have recently emerged as immunostimulatory molecules capable of linking mitochondrial stress to innate immune activation. In this review, we discuss the biological basis of mtRNA biogenesis and processing, the formation and mislocalization of mitochondrial double-stranded RNAs, and their recognition by innate immune sensors relevant to induction of type I IFN. We also describe how epithelial stress, mitochondrial dysfunction, and mtRNA accumulation amplify IFN-rich inflammatory circuits and glandular injury in SjD. Experimental studies in salivary gland epithelial models and SjD-relevant tissues support a mechanistic role for the mtRNA-type I IFN axis, while emerging clinical data suggest that extracellular mtRNA levels in saliva and plasma may have potential as biomarkers of disease activity and patient stratification. Although current evidence remains limited, the mtRNA-type I IFN axis provides a biologically plausible link between epithelial stress and immune dysregulation, and may have translational implications in SjD.
    Keywords:  Sjögren’s disease; biomarkers; innate immunity; interferon signature; mitochondrial double-stranded RNA; salivary gland epithelial cells
    DOI:  https://doi.org/10.3390/ijms27167295
  53. Sci Adv. 2026 Aug 28. 12(35): eadw3811
    SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.
    Francesco Padovani, Ivana Čavka, Ana Rita Rodrigues Neves, Cristina Piñeiro López, Nada Al-Refaie, Leonardo Bolcato, Dimitra Chatzitheodoridou, Yagya Chadha, Pablo Lagos, Timon Stegmaier, Xiaofeng A Su, Jette Lengefeld, Daphne S Cabianca, Simone Köhler, Kurt M Schmoller.
      The analysis of spot-like structures is a widespread task in microscopy image analysis. Existing solutions are typically specific to single applications and do not use multidimensional information, often leaving manual annotation as the only option. Here, we present SpotMAX, a generalist AI-assisted framework for automated spot detection and quantification. SpotMAX detects spots in three-dimensional (3D) data and leverages the full scope of multidimensional datasets with an easy-to-use graphical user interface and a framework for cell segmentation and tracking. Tested on a large 3D dataset, SpotMAX outperforms or is on par with state-of-the-art tools and expert human annotators. We applied SpotMAX across diverse experimental questions, ranging from meiotic crossover events in Caenorhabditis elegans to mitochondrial DNA dynamics in Saccharomyces cerevisiae and telomere length in mouse stem cells, leading to new biological insights. With its flexibility in integrating other AI models into a holistic analysis workflow, we anticipate that SpotMAX will become the standard for spot analysis in microscopy data.
    DOI:  https://doi.org/10.1126/sciadv.adw3811
  54. Curr Protoc. 2026 Sep;6(9): e70451
    Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
    Xavier R Chapa-Dubocq, Sukanya G Gakare, Walia Zahra, Meagan Donovan, Keishla M Rodriguez-Graciani, Tanner Hoole, Scott Edwards, Patricia E Molina, Michael C Salling, Janos Paloczi, Liz Simon.
      Mitochondria are essential for maintaining the high energetic demands of the heart and brain, generating ATP required for contractile function, neuronal signaling, and ionic homeostasis. In both tissues, metabolic flexibility is critical for maintaining bioenergetic efficiency, redox balance, and cellular viability. Despite their importance, existing experimental approaches to assess mitochondrial bioenergetic function present notable limitations. Isolated mitochondria and permeabilized cell assays provide precise control over substrates and respiratory states but disrupt organelle integrity and remove native cellular and extracellular context. Conversely, measurements in isolated or cultured cells preserve intact mitochondria but introduce phenotypic and metabolic artifacts. These constraints highlight the need for an intermediate platform that preserves native tissue architecture and cellular diversity while enabling quantitative assessment of mitochondrial bioenergetics. Building on prior demonstrations of respiration measurements in intact cardiac and neural tissue, we describe a tissue punch-based approach that enables region-specific analysis of mitochondrial function in small ex vivo tissue slices of intact heart and brain. This method preserves cytoarchitecture, and intercellular interactions while remaining compatible with high-resolution Seahorse respirometry analysis. Tissue punches allow multiple technical replicates from individual organs, reduce variability associated with isolation procedures, and enable assessment of regional metabolic heterogeneity, such as atrial versus ventricular myocardium or discrete brain regions. Here we present detailed and reproducible workflow protocols for brain and cardiac tissue punch preparation and extracellular flux analysis, including guidance on sample acquisition, punch sizing, normalization strategies, and data interpretation, with considerations for adapting the protocols across multiple pre-clinical models. © 2026 Wiley Periodicals LLC. Support Protocol: Preparation, Reagent Setup, and Instrumentation Basic Protocol 1: Cardiac tissue preparation Basic Protocol 2: Brain tissue preparation: rodents Basic Protocol 3: Brain tissue preparation: nonhuman primates Basic Protocol 4: Placement of tissue punches on Seahorse organoid plate Basic Protocol 5: Mitochondrial respiration measurements Basic Protocol 6: Tissue disruption for total protein quantification.
    Keywords:  Seahorse XF analysis; animal models; bioenergetics; brain slices; heart slices; mitochondrial metabolism; tissue‐based respirometry
    DOI:  https://doi.org/10.1002/cpz1.70451
  55. BMC Nephrol. 2026 Aug 04. pii: 504. [Epub ahead of print]27(1):
    A young male with kidney damage from genetic mitochondrial disease: case report and literature review.
    Miao Jia, Qian Wu, Jun Zou, Donghua Jin.
       BACKGROUND: The most familiar ear and kidney syndrome is Alport syndrome for a nephrologist. Mutations in the mitochondrial gene MT-TL1, which encodes UUR, can also cause renal dysfunction and hearing loss. In this study, we reported a young Chinese male presented with proteinuria and renal dysfunction with a morphological presentation of focal segmental glomerulosclerosis (FSGS) with m.3243 A > G mutation in the mitochondria in the mitochondrial gene MT-TL1. We conducted a systematic literature review to summarize previously reported cases.
    CASE PRESENTATION: A 17-year-old male was admitted to our hospital due to foamy urine that had persisted for three months after an upper respiratory tract infection. He also complained of weakness in both lower extremities, particularly the calves. He had progressive hearing loss and body hair growth in the last two years.His urinalysis revealed 2 + proteinuria and 24-hour urine protein of 0.85 g.His blood tests revealed increased serum creatinine of 2.1 mg/dl, blood urea nitrogen of 36.1 mg/dl, and uric acid of 12.5 mg/dl. His fasting blood glucose was within the normal range of 99 mg/dl. Renal biopsy pathology revealed changes consistent with FSGS.High-power microscopy demonstrated swollen podocytes and an increased number of dysmorphic mitochondria within renal tubular epithelial cells. Consequently, whole-exome sequencing was performed, confirming that both the patient and her mother harbor the m.3243 A > G mutation in the mitochondrial MT-TL1gene.We provide patients with treatments to improve mitochondrial energy synthesis, reduce creatinine production, promote creatinine excretion, and lower uric acid levels.After a 23-month follow-up, renal function remained stable.
    CONCLUSION: The UUR gene is an important tRNA gene in mtDNA. Its mutation can lead to mitochondrial dysfunction and cause a variety of diseases.The family history of patients with concurrent ear and renal diseases should be assessed in detail.
    Keywords:  Mitochondria-related nephropathy; Mitochondrial genes; Podocytopathy
    DOI:  https://doi.org/10.1186/s12882-026-05238-9
  56. JIMD Rep. 2026 Sep;67(5): e70119
    Irritable Bowel Disease: Think Malonic and Methylmalonic Aciduria (CMAMMA)!
    Khaled Alatibi, Martin J Hug, Sara Tucci.
      Combined malonic and methylmalonic aciduria (CMAMMA; OMIM 614265) is a rare disorder of mitochondrial fatty acid synthesis caused by pathogenic variants in the ACSF3 gene, which encodes malonyl-CoA synthetase. The clinical presentation is highly heterogeneous and may include seizures, memory impairment, psychiatric manifestations, and cognitive decline. We describe an adult patient with long-standing unexplained fatigue and irritable bowel syndrome who remained undiagnosed for 15 years. Subsequent blood and urine analyses revealed elevated methylmalonic acid levels, and molecular genetic testing identified the biallelic ACSF3 variant c.1672C>T (p.Arg558Trp), confirming the diagnosis of CMAMMA. Functional studies in patient-derived fibroblasts demonstrated altered global protein malonylation together with markedly reduced lipoylation of pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase, consistent with impaired mitochondrial energy metabolism. Introduction of a diet enriched in carbohydrates and restricted in protein, based on recommendations for methylmalonic aciduria, resulted in a pronounced worsening of gastrointestinal symptoms, which improved after discontinuation of the dietary intervention. This case highlights that CMAMMA may remain unrecognized for many years and should also be considered in adults presenting with unexplained gastrointestinal symptoms. Furthermore, the findings suggest that impaired glucose oxidation plays a central role in disease pathophysiology and that high dietary carbohydrate intake may exacerbate clinical manifestations.
    Keywords:  ACSF3; CMAMMA; case report; fatigue; irritable bowel syndrome; juvenile onset; lipoylation degree; pyruvate oxidation
    DOI:  https://doi.org/10.1002/jmd2.70119
  57. Biomed J. 2026 Aug 22. pii: S2319-4170(26)00090-9. [Epub ahead of print] 101034
    Adipocyte-specific MICU1 deficiency impairs memory and compromises hippocampal integrity in adult male mice.
    Wei-Hsuan Wang, Pei-Jane Tsai, Ching-Han Lin, Hao-Yeh Tsai, Yau-Sheng Tsai, Pei-Chun Chen.
      Peripheral metabolic stress is increasingly implicated in cognitive decline, but whether adipocyte-specific perturbation of mitochondrial calcium regulation is associated with hippocampal vulnerability remains unclear. Here, we used adipocyte-specific mitochondrial calcium uptake 1 knockout mice (aMICU1 KO) to examine whether adipocyte MICU1 deficiency is accompanied by memory-related behavioral changes and hippocampal pathology. aMICU1 KO mice showed no significant changes in body weight or adipose tissue mass but exhibited impaired spontaneous alternation in the Y-maze and reduced novel object recognition, whereas locomotor activity, anxiety-like behavior, impulsivity, and rotarod performance were not significantly altered. Histological and molecular analyses revealed reduced Nissl-positive cell counts in the dentate gyrus and CA regions, increased TUNEL staining, elevated cleaved caspase-3, and reduced BrdU+ and BrdU+/DCX+ cell populations. Hippocampal MICU1 expression was unchanged, supporting a non-cell-autonomous association rather than direct brain MICU1 loss. Adipose tissue and plasma analyses identified increased GDF15 as a prominent stress-associated circulating factor; however, hippocampal GFRAL/RET expression and downstream AKT/ERK phosphorylation were not robustly activated. Thus, GDF15 should be interpreted as a systemic stress-associated marker rather than a proven causal mediator. Together, these findings identify adipocyte MICU1 deficiency as a peripheral perturbation associated with hippocampal vulnerability and memory impairment, and they provide a foundation for future studies testing the adipocyte mitochondrial mechanisms and peripheral mediators that link adipose dysfunction to brain pathology.
    Keywords:  GDF15; MICU1; adipocyte mitochondrial dysfunction; adipose–brain communication; cognitive impairment; hippocampal degeneration; peripheral mitochondrial stress
    DOI:  https://doi.org/10.1016/j.bj.2026.101034
  58. Children (Basel). 2026 Jul 23. pii: 977. [Epub ahead of print]13(8):
    Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.
    Cheng-Yu Lee, Dau-Ming Niu, Chia-Feng Yang, Yann-Jang Chen.
      Background/Objectives: Whole exome sequencing (WES) has emerged as a clinically valuable second-tier test following abnormal biochemical newborn screening (NBS). However, population-specific data on diagnostic yield, secondary findings (SFs), and exome-wide carrier burden remain scarce in East Asian neonates, particularly since the release of the ACMG SF v3.3 gene list. We aimed to characterize these metrics in a Taiwanese neonatal cohort. Methods: We retrospectively analyzed 118 consecutive neonates referred to Taipei Veterans General Hospital between August 2021 and August 2022 following abnormal biochemical NBS. WES was performed on the Illumina NovaSeq 6000 platform; variants were classified per the 2015 ACMG/AMP framework and re-evaluated under ACMG SF v3.3. Referral categories comprised lysosomal storage diseases (n = 61), amino acid disorders (n = 38), fatty acid oxidation disorders (n = 13), and organic acid disorders (n = 6). Results: Fifty neonates (42.4%) received confirmed molecular diagnoses and 45 (38.1%) were carriers (combined molecular resolution 80.5%). Five participants (4.2%) harbored pathogenic/likely pathogenic variants in ACMG SF v3.3 genes (TTN, LDLR, PTEN, RYR1, TP53). Incidental findings occurred in 51.7%, and at least one recessive-carrier variant was detected in 99.2% (mean 4.15 per individual; median 4). The Taiwanese-specific c.639+919G>A cardiac Fabry variant accounted for 24/25 confirmed male Fabry cases, and the p.Gly576Ser pseudodeficiency allele confounded all suspected Pompe cases. Conclusions: Second-tier WES substantially improves diagnostic precision, discriminating confirmed diagnoses from carrier, pseudodeficiency, and biochemical false-positive states. The high carrier burden and incidental-finding rate underscore the importance of comprehensive pre- and post-test genetic counseling in East Asian neonatal genomic programs.
    Keywords:  East Asian; Taiwan; carrier burden; inborn errors of metabolism; newborn screening; secondary findings; whole exome sequencing
    DOI:  https://doi.org/10.3390/children13080977
  59. Stem Cell Rev Rep. 2026 Aug 22.
    Inner Ear Organoids: Recent Progress and Challenges.
    Yingxinyu Li, Cairong He, Jiayan Liu, Haiqin Zhang, Hongxia Zhang, Zheyu He, Mengyang He, Meiling Chen, Feiyan Zhou, Jie Ding.
      Hearing loss is a prevalent sensory disorder primarily caused by the irreversible loss of cochlear hair cells and the limited regenerative capacity of the mammalian inner ear. The structural complexity and inaccessibility of inner ear tissues have long hindered mechanistic studies and therapeutic development. In recent years, inner ear organoids have emerged as a robust in vitro platform that recapitulates key aspects of inner ear development, cellular composition, and functional organization. Derived from pluripotent stem cells or tissue-specific progenitors, inner ear organoids exhibit intrinsic self-organizing capabilities under the spatiotemporal regulation of developmental signaling pathways, including TGF-β, BMP, FGF, and Wnt. These systems enable the generation of hair cell-like cells, supporting cells, and neuronal components, thereby providing a powerful tool for investigating developmental processes and disease mechanisms. Notably, patient-specific induced pluripotent stem cell-derived organoids facilitate modeling of hereditary hearing disorders and enable personalized therapeutic screening. Beyond basic research, inner ear organoids hold significant promise for drug discovery, ototoxicity assessment, and gene therapy validation. However, current models still face several limitations, including incomplete cellular heterogeneity, insufficient functional maturation, lack of vascularization and immune components, and variability across culture systems. Emerging bioengineering approaches, such as organ-on-a-chip platforms, synthetic biomaterials, and 3D bioprinting, are expected to enhance the physiological relevance and translational potential of these models. In this review, we summarize recent advances in the generation of inner ear organoids, discuss their applications in basic and translational research, and highlight current challenges and future directions toward clinical translation.
    Keywords:  Hair cells; Hearing loss; Inner ear organoid; Three-dimensional cell culture
    DOI:  https://doi.org/10.1007/s12015-026-11219-0
  60. Brain Sci. 2026 Aug 04. pii: 828. [Epub ahead of print]16(8):
    Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.
    Shaoshuai Lu, Ziyang Chen, Yanyan Wang, Hongsheng Bian, Shuang Yu, Lili Huang.
      O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.
    Keywords:  O-GlcNAcylation; OGA inhibitors; brain energy metabolism; neurodegenerative diseases; precision therapy; proteostasis; synaptic plasticity
    DOI:  https://doi.org/10.3390/brainsci16080828
  61. Biology (Basel). 2026 Aug 18. pii: 1424. [Epub ahead of print]15(16):
    Propionic Acid Remodels Mitochondrial Metabolism in SH-SY5Y Cells.
    Caitlyn Mahony, Erin Buchanan, Colleen O'Ryan.
      Mitochondrial mechanisms are increasingly implicated in complex neurological conditions, including Autism Spectrum Disorder (ASD). Propionic acid (PPA) is widely used to study mitochondrial dysfunction in preclinical models of ASD. However, the molecular mechanisms that drive PPA-induced neurotoxicity are unresolved. Here, we examined mitochondrial remodeling under PPA-induced stress in neuroblastoma SH-SY5Y cells. PPA systemically altered the transcriptional regulation of mitochondrial dynamics and disrupted canonical proteins involved in mitochondrial fusion (L-OPA1, MFN2), fission (DRP1) and quality control (LC3-II). Confocal microscopy revealed an upregulation of both fission and fusion events and impairments to mitochondrial integrity, connectivity and turnover. Live-cell respirometry demonstrated consequent deficits in both oxidative and glycolytic energy production, while respiratory chain electron flow assays illustrated a shift in TCA cycle flux driven by a remodeling of mitochondrial substrate utilization. This work describes a molecular signature of metabolic stress in the SH-SY5Y system, providing novel insights into the mechanisms and manifestations of PPA-induced neurotoxicity.
    Keywords:  autism spectrum disorder; confocal microscopy; inherited metabolic diseases; mitochondrial dysfunction; propionic acidemia; respirometry
    DOI:  https://doi.org/10.3390/biology15161424
  62. Nat Genet. 2026 Aug 25.
    Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.
    Shenzhi Chen, Vincent Loubiere, Ethan W Hollingsworth, Ken Murakami, Nikolaus Mandlburger, Sandra H Jacinto, Atrin Dizehchi, Jacob Schreiber, Evgeny Z Kvon, Alexander Stark.
      Enhancers control tissue-specific gene expression across animals1. Although deep learning2,3 has enabled enhancer prediction and design in mammalian cell lines and non-mammalian model organisms4-10 (reviewed in a previous publication11), it remains unclear whether such approaches can operate within the regulatory complexity of mammalian genomes and tissues in vivo. Here we present a general strategy for designing tissue-specific enhancers that function reliably in mice. We use deep learning to train compact convolutional neural networks on curated chromatin accessibility data and fine-tune them by transfer learning on validated human and mouse enhancers. Guided by these models, we design 15 synthetic enhancers for the heart, limb and central nervous system in mouse embryos, all of which are active in their intended target tissue. These results demonstrate that mammalian enhancer function can be reliably inferred from DNA sequence alone, enabling the predictive de novo design of tissue-specific synthetic enhancers from modest training sets. This work establishes a generalizable framework for programmable control of mammalian gene expression in vivo, opening new avenues in functional genomics, synthetic biology and gene therapy.
    DOI:  https://doi.org/10.1038/s41588-026-02729-1
  63. J Neuromuscul Dis. 2026 Aug 25. 22143602261477464
    Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.
    Kento Kodama, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Makoto Samukawa, Motomasa Suzuki, Shunsuke Ogaya, Yuka Kawata, Naoki Gamo, Shin Hisahara, Chikashi Yano, Risa Nagatomo, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Yusuke Sakiyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima.
      BackgroundDistal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan.MethodsWe conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed.ResultsBiallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset.ConclusionOur findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.
    Keywords:  CMT; IPN; SIGMAR1; dHMN; pyramidal tract
    DOI:  https://doi.org/10.1177/22143602261477464
  64. Nat Chem Biol. 2026 Aug 28.
    An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo.
    Peiwen Shi, Bruno Melillo, Matthew W McHenry, Christina M Camara, Ka Yang, Evert Njomen, Marina Godes, Maria F Pazyra-Murphy, Mary Rose Branch, Bethany Tesar, Rosalind A Segal, Lee L Rubin, Michael D Cameron, Gregory H Bird, Thomas E Wales, Steven P Gygi, Benjamin F Cravatt, Loren D Walensky.
      No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.
    DOI:  https://doi.org/10.1038/s41589-026-02297-9
  65. Am J Hum Genet. 2026 Aug 25. pii: S0002-9297(26)00303-4. [Epub ahead of print]
    Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.
    Undiagnosed Diseases Network
      Identifying pathogenic non-coding variants that contribute to Mendelian conditions remains challenging, as the functional impact of these variants on gene function is often unknown. We present IsoRanker, a long-read transcriptome sequencing-based framework that prioritizes functionally relevant variants by detecting genes and isoforms with outlier expression, allelic imbalance, and/or nonsense-mediated decay (NMD). We generated paired cycloheximide-treated and untreated fibroblast transcriptomes from 31 individuals (3 individuals with known transcript-altering rare variants and 28 individuals with unsolved conditions) and linked transcripts to phased long-read genomes. IsoRanker successfully recovered known transcript alterations in this cohort, and exploratory subsampling analyses suggested that their prioritization was largely preserved down to cohorts of 11 individuals and ∼5 million full-length transcripts per individual. Performance was dependent upon de novo isoform caller choice, particularly for NMD-sensitive and previously unannotated isoforms. Among 28 previously unsolved cases, IsoRanker deprioritized 8 out of 10 fibroblast-expressed candidate splice-site variants while nominating 4 new leads. In one individual, IsoRanker prioritized HARS1, revealing bi-allelic non-coding variants that together produced a partial HARS1 loss of function and informed targeted therapy in this individual. These findings support long-read, NMD-aware transcriptomics with IsoRanker as an effective approach for generating isoform-level functional evidence, improving classification of non-coding variants and supporting the diagnosis of individuals with rare genetic conditions.
    Keywords:  HARS1; IsoRanker; Mendelian; RNA; functional genomics; long-read transcript; rare disease; splicing; transcriptomics; variant interpretation
    DOI:  https://doi.org/10.1016/j.ajhg.2026.08.002
  66. Genome Med. 2026 Aug 22. pii: 125. [Epub ahead of print]18(1):
    The clinical and molecular spectrum of AGO2-associated Lessel-Kreienkamp neurodevelopmental syndrome.
    Debora Tibbe, Christina Kiel, Olena Ielesicheva, Kerstin Robles de Maruri, Helia Mahboobi, Joschka Züghart, Hans-Hinrich Hönck, Christoph Meier, Fabiola Biasella, Marcela Legüe, María Francisca Lopez Avaria, Edward Blair, Tracy Lester, Benito Banos-Pinero, Jose S Pulido, Adele Schneider, Rebecca Procopio, Chloe Quelin, Bailey J Leal, Julian A Martinez-Agosto, Stephanie A Bottomley, Ágnes Till, Kinga Hadzsiev, Renata Szalai, Kathryn Nicole Weaver, Joel Fluss, Henri Margot, Berta Almoguera, Isabel Lorda-Sánchez, Lucía López-López, J Austin Hamm, Himanshu Goel, Yasemin Alanay, Ozlem Akgun Doğan, Gulşah Şebnem Ozkose-Iyigel, Genevieve Baujat, Marion Lesieur-Sebellin, Sophie Rondeau, Katherine Schon, Joseph Christopher, Bertrand Isidor, Benjamin Cogne, Neena S Agrawal, Ryan Dahlhauser, Yutaka Furuta, Rachel Rabin, John Pappas, Chirag Patel, Irma Järvelä, Merja Rauhala, Isabelle Schrauwen, Suzanne M Leal, Siddharth Banka, Riya Tharakan, Céline Pebrel-Richard, Fanny Laffargue, Nelly Durand, Tristan Celse, Maja Hempel, Ilia Valentin, Andrea Gregorova, Lenka Noskova, Sara Baumgartner, Christa Überbacher, Kai Muru, Ülle Murumets, Stella Lilles, Katharina Steindl, Anita Rauch, Federica Ruscitti, Alain Verloes, Jonathan Levy, Joohyun Park, Tobias B Haack, Ingrid Bader, Sophie Julia, Guillaume Banneau, Alison M Muir, Davor Lessel, Hans-Jürgen Kreienkamp.
       BACKGROUND: Pathogenic variants in AGO2, encoding a central component of the RNA-induced silencing complex (RISC), cause the neurodevelopmental disorder Lessel-Kreienkamp syndrome (LESKRES). The variant spectrum and associated molecular mechanisms underlying phenotypic variability and disease severity remain incompletely understood.
    METHODS: We investigated 45 newly identified individuals carrying 33 distinct AGO2 variants, 30 of which were previously unreported. Phenotypic data from these and previously reported cases (n = 70) were integrated to delineate the LESKRES-associated clinical spectrum and genotype-phenotype correlations. Functional studies included shRNA-based silencing, co-immunoprecipitation, subcellular localization, and sequencing of AGO2-bound miRNAs.
    RESULTS: All individuals presented with a neurodevelopmental disorder of variable severity. Delayed speech and language development (97%), intellectual disability (97%), and motor delay (93%) were the most consistent features, frequently accompanied by muscular hypotonia, autistic traits, attention deficit hyperactivity disorder, visual impairment and structural brain anomalies. Systemic manifestations, including skeletal, craniofacial, cardiac, and male urogenital anomalies were common, underscoring AGO2's multisystemic role. Moreover, we report occurrence of gonadal mosaicism and reveal the presence of interfamilial and variant-specific clinical heterogeneity. Variants clustered in defined regions of AGO2, including the L1 loop, helix-7, and multiple loops of the PIWI domain, highlight structural hotspots critical for RISC activity. Not all pathogenic variants impaired shRNA-mediated silencing; this was restricted to p.(Arg714Trp) and p.(Asn729His). Biochemical analyses revealed that p.(Asp619Asn) impaired GW182 binding and P-body assembly. Variants p.(Arg506Gln), p.(Glu531Gln) p.(Gly604Arg) and p.(Asp619Asn), reduced C-terminal phosphorylation, implicating defective AGO2 recycling. AGO2-miRNA co-immunoprecipitation and sequencing demonstrated variant-specific perturbations in miRNA association, strand selectivity, and isomiR generation. Variants near the hinge of the helix-7 region, especially p.(Phe182del), induced extensive changes in miRNA association and 3'-end modification, suggesting impaired anchoring within the miRNA-binding pocket.
    CONCLUSIONS: Our findings substantially broaden the clinical and molecular landscape of LESKRES, establishing AGO2 as a pivotal regulator of neurodevelopment whose structural integrity is essential for precise miRNA-mediated gene regulation. Pathogenic variants disrupt distinct interconnected processes: P-body association, phosphorylation-dependent turnover, and miRNA interactions, culminating in dysregulated post-transcriptional gene silencing. These mechanistic insights link specific structural perturbations in AGO2 to graded clinical outcomes and underscore the critical role of AGO2 conformational dynamics in human neurodevelopment.
    Keywords:  GW182; IsomiR; P-bodies; RISC; RNA interference
    DOI:  https://doi.org/10.1186/s13073-026-01745-4
  67. Nutrients. 2026 Aug 19. pii: 2702. [Epub ahead of print]18(16):
    Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review.
    Sergio Abanades, Irene Fernández, Nuria Capdevila, Francisco Cardona.
      Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation. This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework. Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.
    Keywords:  ME/CFS; NAD+; fatigue; fibromyalgia; glutathione; micronutrition; mitochondrial dysfunction; myalgic encephalomyelitis/chronic fatigue syndrome; precision nutrition
    DOI:  https://doi.org/10.3390/nu18162702
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