bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–11–15
seventy papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.
  2. Mitochondrial Diseases in the Era of Precision Medicine: Advances in Molecular Pathogenesis, Diagnosis, and Therapeutic Intervention.
  3. Mitochondrial base editing for disease modeling and therapeutic correction.
  4. Genome Editing of Mitochondrial Dysfunction in Neurological Disease: Progress and Translational Barriers.
  5. Mitochondrial translation deficiency limits the cardiac benefit of ketogenic diet in early-onset cardiomyopathy.
  6. Measurement of Skeletal Muscle Mitochondrial DNA Synthesis Using Stable Isotope Labeling.
  7. Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.
  8. Mitochondria-Targeted Chlorambucil Derivative Drives Mitochondrial Nucleic-Acid Output and Innate Immune Signaling.
  9. Rare genetic variants in leber hereditary optic neuropathy: molecular mechanisms, diagnosis, and emerging therapies.
  10. Adolescent Hypertrophic Cardiomyopathy Can Be the First Clue to Multisystem Mitochondrial Disease.
  11. Mitochondrial dysfunction in Parkinson's disease and aging.
  12. Nanoscale remodeling of mitochondrial architecture during mtRNA surveillance failure.
  13. Toward Understanding the Molecular Basis and Precise Diagnosis of Mitochondrial Diabetes: A Comprehensive Review.
  14. Mitochondrial protein import stress augments α-synuclein aggregation and neural damage.
  15. Engineering ATP import in yeast uncovers a synthetic route to extend cellular lifespan.
  16. ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12.
  17. MitoFLUX-EM reveals damaged mitochondria are captured by pre-existing mitolysosomes during PINK1-dependent mitophagy in the heart.
  18. Mitochondrial-Wide Association Studies: Integrating Population-Based Data and Mitochondrial Genetics.
  19. Mitochondria-RNA Binding Protein Crosstalk in Neurodegeneration: Mechanisms Linking Mitochondrial Stress, RNA Dysregulation and Neuronal Vulnerability.
  20. Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies.
  21. SUMO-2/3 modification of PINK1 restrains basal mitophagy through MAPL-dependent regulation of mitochondrial surveillance.
  22. Mitoribosome dysfunction in sensorineural hearing loss: genetic mechanisms and clinical implication.
  23. Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant.
  24. Brown adipose tissue sustains thermogenesis through metabolic flexibility in glucose utilization.
  25. Mitochondrial cristae remodeling in ischemic stroke: mechanisms and therapeutic perspectives.
  26. Mitochondria on the move: Mitochondrial release and transfer in nervous system health and disease.
  27. MitoTALENs reduce mutant mitochondrial DNA carryover following pronuclear transfer.
  28. Do Golgi-mitochondria membrane contact sites regulate lipid flux and local apoptotic fate decisions?
  29. Leveraging Deep Learning to Reveal Fine-Scale In Vivo Mitochondrial Dynamics and Axonal Transport.
  30. Integrated Multi-Omics Convergence Scoring Reveals Modular Network Architecture with Age-Associated Mitochondrial Signatures in Sarcopenia.
  31. Lipid droplets buffer hydrogen sulfide-induced redox imbalance.
  32. Mitochondrial Quality Control and Apoptotic Thresholds in Major Depressive Disorder: A Structured Narrative Review.
  33. Mitochondrial protein import defects enhance tumour immunogenicity.
  34. Neuronal and mitochondrial phenotypes in iPSC-derived bipolar disorder models with and without a family history of mitochondrial disease.
  35. Poly(N-isopropylacrylamide)-Grafted Hyaluronic Acid Semi-Gels for Localized Mitochondrial Transplantation in Spinal Cord Injuries.
  36. Mitochondrial Complex III Deficiency with Nutritional Vitamin B12 Deficiency.
  37. FMNL1 polymerized actin filaments complete mitochondrial division downstream of Golgi-derived vesicles.
  38. Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies.
  39. Structural insights into the evolution of mitochondrial protein import from the trypanosome ATOM complex.
  40. Generation of Human Cardiomyocytes With Adult-Like Metabolism by a Chemically Defined Medium for Mitochondrial Disease Modeling.
  41. LSP Methylation in Skeletal Muscle and Cross-Tissue Candidate NUMT Signals Reveal Complementary Features of Mitonuclear Aging in Mice.
  42. Single-cell variant landscape of the human mitochondrial genome reveals cell type-specific functions and disease mechanisms.
  43. Mitochondria‑associated small RNAs in breast cancer: An asymmetric evidence landscape from metabolic rewiring to immune selection (Review).
  44. Mechanisms of Mitochondrial DNA Leakage as Primary Upstream Catalysts for NLRP3 Inflammasome Activation in Neurodegenerative Pathology: A Systematic Review.
  45. Mapping of Ligandable tyrosine and lysine residues in proteins implicated in mitochondrial DNA depletion and therapeutic relevance.
  46. PINK1‑regulated mitophagy dysfunction in the pathogenesis of Parkinson's disease (Review).
  47. Cytosolic DNA sensing through the cGAS-STING pathway contributes to neuroinflammation and dopaminergic neuron loss in Parkinson's disease.
  48. Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells.
  49. Mitochondrial LONP1: Linking structure and function to context‑dependent roles in disease (Review).
  50. Imaging of Organelle and Actin Cytoskeletal Morphology During Aging.
  51. Mitofusin-2 deficiency impairs neutrophil maturation and reduces non-glucose substrate utilization.
  52. A Reliable Ratiometric Fluorescent Probe for the Quantification of Mitochondrial Peroxynitrite in Cells and Tissues.
  53. Mitochondrial Morphology and TOMM20/TIMM44 Abundance During Prolonged HEK293 Cell Culture Under Different Glucose and Medium-Replacement Conditions.
  54. DNMT1-II: Emerging extranuclear functions and their significance in health and disease.
  55. Restoring Bioenergetics in the Traumatized Eye: The Emergence of Mitochondrial Implantation as a Treatment for Acute Ocular Injury.
  56. Mitochondrial dysfunction in asthma: damage signals sustain airway inflammation and remodeling.
  57. An integrative single-cell epigenomic atlas annotates the regulatory genome of the adult mouse brain.
  58. Mitochondrial Regulation of Brown Adipose Tissue During Hypoxia in Rodents.
  59. TSPO: a conserved mitochondrial conduit linking cellular homeostasis to disease.
  60. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  61. Early Metabolic Rewiring and Mitochondrial Remodeling in Response to Mitochondrial Impairment in a Rotenone Model of Parkinson's Disease.
  62. A Homozygous Missense Variant in DCLK2 as a Potential Modifier of Disease Severity in PDHA1-Associated Primary Pyruvate Dehydrogenase Complex Deficiency.
  63. Expanding the cardiac phenotype of homozygous PPA2 variants: insights from a large Finnish family.
  64. Bioinformatic analysis of ACAD9 genetic variability.
  65. Miro1 and mitochondrial dysfunction in Huntington's disease: Emerging mechanistic links and therapeutic perspectives.
  66. Mitochondria-localized circRNA BRAKE restrains adipogenesis under nutrient overload by disrupting ATP synthase assembly in mice.
  67. The hidden burden of structural variants in neurodegenerative and neuromuscular disorders.
  68. B30Research advances on mitochondrial non-coding RNAs in cardiovascular diseases: Mechanisms, applications, and challenges.
  69. Mitochondrial DNA Abnormalities in Idiopathic Inflammatory Myopathies: Innate Immune Signaling and Therapeutic Prospects.
  70. Mitochondria and blood-brain barrier dysfunction: a promising target for cerebrovascular disorders.
  1. FEBS Lett. 2026 Nov 09.
    Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.
    Boseon Kim, Thi Thanh Mai Tran, Nakyung Kang, Min-Woo Lee, Mihye Lee.
      Mitochondria are essential organelles that regulate cellular metabolism, signaling, and stress responses. Their function depends on coordinated protein synthesis from the mitochondrial and nuclear genomes, together with mechanisms that preserve mitochondrial proteostasis. Translation of both nuclear- and mitochondrial-encoded transcripts is dynamically regulated in response to developmental, metabolic, and environmental cues, allowing mitochondria to remodel their proteome and adapt to changing physiological demands. Disruption of these processes impairs respiratory complex assembly, mitochondrial function, and protein homeostasis, contributing to a wide range of metabolic, cardiovascular, muscular, neurodegenerative, and immune disorders. In this review, we summarize the evolutionary specialization of the mitochondrial translational machinery and the molecular mechanisms that regulate mitochondrial protein synthesis. We discuss recent advances in cytosolic translational control of nuclear-encoded mitochondrial proteins, mito-nuclear coordination, tissue-specific regulation of mitochondrial proteostasis, and their implications for human disease. Finally, we highlight emerging challenges and future directions in the translational regulation of mitochondrial protein synthesis and its relevance to mitochondrial biology and disease.
    Keywords:  RNA localization; metabolism; mitochondrial dysfunction; mitochondrial protein; mito‐nuclear coordination; translational control
    DOI:  https://doi.org/10.1002/1873-3468.70502
  2. Yale J Biol Med. 2026 Sep;99(3): 576-599
    Mitochondrial Diseases in the Era of Precision Medicine: Advances in Molecular Pathogenesis, Diagnosis, and Therapeutic Intervention.
    Abdul Aziz Mohamed Yusoff, Siti Muslihah Ab Radzak, Siti Zulaikha Nashwa Mohd Khair.
      Pathogenic mutations in mitochondrial DNA or nuclear genes encoding mitochondrial proteins essential for mitochondrial function give rise to mitochondrial diseases, a highly heterogeneous group of inherited multisystemic disorders. These genetic defects impair the respiratory chain and disrupt oxidative phosphorylation, resulting in critical adenosine triphosphate depletion and tissue-specific energy failure, predominantly affecting high-energy organs such as the brain, heart, and skeletal muscle. Disease pathogenesis is shaped by heteroplasmy thresholds and is further exacerbated by elevated reactive oxygen species, aberrant calcium signaling, and defective mitophagy. Although next-generation sequencing and biochemical profiling have significantly transformed diagnostic frameworks, these progressive metabolic disorders have historically been managed primarily with supportive or palliative care. Driven by precision medicine, the therapeutic paradigm has recently shifted toward genetic and organelle-targeted interventions. Advanced mitochondrial genome-editing platforms, including zinc-finger nucleases, transcription activator-like effector nucleases, and DddA-derived cytosine base editors, enable precise elimination or correction of mutant mitochondrial DNA variants, thereby modulating heteroplasmy. Concurrently, metabolic regulatory agents, mitochondria-targeted peptides, and organelle transfer techniques, encompassing germline mitochondrial replacement therapy to prevent maternal transmission and mitochondrial transplantation for tissue regeneration, are being actively investigated. Despite promising preclinical outcomes, clinical translation remains constrained by challenges in safe delivery, off-target effects, and ethical concerns associated with germline modification. This review bridges the gap between fundamental molecular pathology and cutting-edge therapeutic strategies, highlighting multidisciplinary approaches poised to transform mitochondrial disease management from symptomatic care toward prevention and disease-modifying intervention.
    Keywords:  Gene therapy; Genome editing; Mitochondrial DNA mutations; Mitochondrial diseases; Mitochondrial dysfunction; Mitochondrial replacement therapy; Therapeutic innovation; precision medicine
    DOI:  https://doi.org/10.59249/VSCB1173
  3. Genome Biol. 2026 Aug 13. pii: 351. [Epub ahead of print]27(1):
    Mitochondrial base editing for disease modeling and therapeutic correction.
    Seongho Hong, Sanghun Kim, Je Kyung Seong, Youngho Kim, Hyunji Lee.
      Recent development of mitochondrial DNA (mtDNA) editors has made it possible to generate experimental models carrying patient-relevant mtDNA mutations, characterize disease-associated phenotypes in cells and animals, and directly correct pathogenic variants in vivo. Here, we summarize the current landscape of mtDNA base editors and discuss key considerations for their application to mitochondrial disease model generation, including target selection, cross-species conservation, editing window constraints, strand bias, sequence-context dependence, and the balance between editing efficiency and safety. We further review strategies for validating mtDNA-edited models at functional, molecular, and organismal levels, and highlight recent studies demonstrating therapeutic rescue in animal models.
    DOI:  https://doi.org/10.1186/s13059-026-04244-2
  4. Yale J Biol Med. 2026 Sep;99(3): 521-539
    Genome Editing of Mitochondrial Dysfunction in Neurological Disease: Progress and Translational Barriers.
    Reva Sharma, Nirupama Niranjan, Anika Long, Rishika Sharma, Fuad Safieh, Pranesh Kumar, Pranaav Sund, Zahra Sellami.
      Mitochondrial dysfunction is increasingly recognized as a shared mechanism across neurological disease. Specifically, impaired oxidative phosphorylation, oxidative stress, and mitochondrial DNA damage are factors in primary mitochondrial disorders and major neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, and amyotrophic lateral sclerosis. This review surveys the mechanisms driving mitochondrial dysfunction and evaluates the current landscape of gene-editing technologies developed to address them. We examine mitochondria-targeted editors and nuclear-targeted editors, examining the editing capability, delivery constraints, and off-target risk of each. Heteroplasmy-shifting nucleases currently offer the strongest in vivo evidence for mtDNA-directed therapy, while base editors extend correction to homoplasmic mutations at the cost of a narrower editing scope and off-target editing. Nuclear editing platforms avoid the mitochondrial gRNA import barrier entirely, allowing current technologies to achieve the most progress toward functional, behavioral rescue in animal models. Across all platforms, delivery efficiency, off-target specificity, and translation from rodent to primate models remain unresolved barriers to clinical application. Gene editing for mitochondrial dysfunction is highly creditable as a precision therapy for genetically defined disease subsets, including primary mitochondrial disease and other neurodegenerative disorders with a known nuclear driver, rather than as a universal strategy for sporadic neurodegeneration, where mitochondrial dysfunction arises from multifactorial and poorly localized causes.
    Keywords:  Adeno-Associated Virus; Base Editing; CRISPR-Cas9; Gene Editing; Mitochondrial DNA; Mitochondrial Dysfunction; Neurodegenerative Disease; Nuclear DNA; Oxidative Phosphorylation; Reactive Oxygen Species
    DOI:  https://doi.org/10.59249/AFKC3347
  5. J Bioenerg Biomembr. 2026 Nov 07. pii: 62. [Epub ahead of print]58(1):
    Mitochondrial translation deficiency limits the cardiac benefit of ketogenic diet in early-onset cardiomyopathy.
    Ozlem Kartal, Sukru Anil Dogan.
      Mitochondrial cardiomyopathy is a devastating disorder with no effective treatment. Ketogenic diet (KD) has shown therapeutic benefit in some mitochondrial disease models but failed or caused harm in others, suggesting its efficacy depends on the underlying genetic defect. KD has ameliorated cardiomyopathy in models where the electron transport chain retains structural integrity, yet it has not been tested in a model with a primary defect in mitochondrial translation. We therefore examined KD in heart- and skeletal muscle-specific Dars2 knockout mice (hmKO), a model of fatal early-onset mitochondrial cardiomyopathy caused by loss of mitochondrial aspartyl-tRNA synthetase, which is essential for translation of all 13 mitochondrial DNA-encoded oxidative phosphorylation subunits. Male hmKO mice and wild type littermates received either a ketogenic or normal chow diet from weaning until the humane endpoint. KD induced a partial shift toward cardiac fatty acid metabolism and activated mitochondrial biogenesis signaling. However, these adaptations did not improve survival, cardiac hypertrophy, skeletal muscle atrophy, motor performance, respiratory chain complex abundance, enzyme activities, or cardiac ATP levels. KD reduced antioxidant gene expression, without increasing protein carbonylation, and amplified the mitokine response, with increased GDF15 and FGF21 in the heart and serum. These findings show that substrate availability alone cannot restore cardiac bioenergetics when mitochondrial translation capacity is severely impaired. Instead, mitochondrial translation machinery defines a critical boundary for metabolic interventions in mitochondrial cardiomyopathy. Our results argue that the therapeutic potential of KD in mitochondrial disease is mechanism-dependent and should not be generalized across genetically and bioenergetically distinct forms of mitochondrial cardiomyopathy.
    Keywords:  Aminoacyl-tRNA synthetase; DARS2; Ketogenic diet; Mitochondrial cardiomyopathy; Mitochondrial translation; Stress responses
    DOI:  https://doi.org/10.1007/s10863-026-10143-9
  6. Methods Mol Biol. 2027 ;3105 333-345
    Measurement of Skeletal Muscle Mitochondrial DNA Synthesis Using Stable Isotope Labeling.
    Robert V Musci, Morgan Johnson, Noelle Morrow, Clover D Crenshaw, Morgan K Daniel, Frederick F Peelor, Benjamin F Miller, Johanna Pham, Andrea L Hevener, Jonathan Wanagat.
      Stable isotope labeling with deuterium oxide provides a robust approach for quantifying mitochondrial DNA synthesis and turnover in vivo. This chapter describes a protocol for measuring mitochondrial DNA fractional synthesis rate and half-life in frozen samples of rodent skeletal muscle. The method combines long-term deuterium oxide labeling with isolation of mitochondria from frozen tissue, enzymatic removal of contaminating nuclear DNA using DNase, purification of mitochondrial DNA, and measurement of deuterium incorporation into deoxyribose by gas chromatography-mass spectrometry. This approach enables quantitative assessment of mitochondrial DNA turnover under physiological and experimental conditions while minimizing confounding from nuclear DNA contamination.
    Keywords:  Deuterium oxide; Fractional synthesis; Half life; Mitochondrial DNA; Skeletal muscle; Stable isotope
    DOI:  https://doi.org/10.1007/978-1-0716-5703-4_18
  7. Mol Metab. 2026 Nov 11. pii: S2212-8778(26)00156-0. [Epub ahead of print] 102472
    Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.
    Inaya Laubach, Guido Primiano, Nneka Southwell, Nicola Rizzardi, Belem Yoval-Sánchez, Christian Bergamini, Serenella Servidei, Alexander Galkin, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.
      Mitochondrial diseases are a heterogeneous group of genetic disorders caused by impaired oxidative phosphorylation (OxPhos). When skeletal muscle is predominantly affected, they are defined as primary mitochondrial myopathies. Although the genetic causes of mitochondrial myopathies and the resulting bioenergetic impairments are well established, the metabolic drivers behind progressive muscle dysfunction remain poorly defined. This gap in knowledge may contribute to the lack of effective treatments for these disorders. OxPhos defective muscle initiates a metabolic response coordinated by systemic signals which results in muscle and adipose tissue wasting. Here, we show ectopic muscle lipid accumulation in a COX10 KO mouse model of mitochondrial myopathy due to inability to oxidize fatty acids in muscle. In both the mouse model and in mitochondrial patients, we find an increase in ceramides, which is mechanistically linked to chronic ER stress, phosphorylation of eIF2α, and activation of ATF4 signaling. We propose that Ph-eIF2α-mediated attenuation of global protein synthesis and ATF4-initiated atrophy pathways contribute to muscle wasting and weakness. Importantly, inhibition of de novo synthesis of ceramides with myriocin reduces ER stress and ATF4 signaling and improves muscle proteostasis, body weight, and motor functions in the COX10 KO mouse. Together, these findings highlight the role of lipid metabolism as a contributor to mitochondrial myopathy and identify lipid-mediated stress pathways that can be targeted therapeutically.
    Keywords:  COX10; ER stress; ceramides; lipid metabolism; mitochondrial myopathy; muscle wasting
    DOI:  https://doi.org/10.1016/j.molmet.2026.102472
  8. Free Radic Biol Med. 2026 Nov 11. pii: S0891-5849(26)01269-4. [Epub ahead of print]
    Mitochondria-Targeted Chlorambucil Derivative Drives Mitochondrial Nucleic-Acid Output and Innate Immune Signaling.
    Anthony Rios, Anal Jana, Yu Hsuan Chen, Seanmory Sothy, Pengcheng Wang, Joshua T Morgan, Linlin Zhao.
      Mitochondrial DNA (mtDNA) damage can impair oxidative phosphorylation and trigger innate immune signaling by releasing mitochondrial nucleic acids. However, the consequences of selective mtDNA alkylation for mitochondrial DNA and RNA output remain poorly understood. Here, we developed a mitochondria-targeted chlorambucil-derived alkylating probe (mtChl) and examined its effects in human bronchial epithelial BEAS-2B cells. Compared with chlorambucil, mtChl retains DNA reactivity in vitro. At sublethal concentrations, mtChl preferentially reduced mtDNA copy number and integrity without detectable nuclear DNA damage. A non-alkylating hydroxyl analog did not affect mtDNA copy number, DNA integrity, membrane potential, or respiration. Low-dose mtChl increased mtDNA fragmentation without measurable bioenergetic impairment, whereas higher exposure increased endonuclease IV-sensitive lesions, decreased mitochondrial membrane potential and oxygen consumption, and altered expression of mitochondrial dynamics-associated genes. In addition, mtChl treatment increased cytosolic mtDNA abundance, mitochondrial RNA transcripts, J2-positive double-stranded RNA accumulation, levels of phosphorylated STING and TANK-binding kinase 1, and expression of type I interferon and inflammatory genes. Pharmacological inhibition of voltage-dependent anion channel- and mitochondrial permeability transition pore-associated processes reduced cytosolic mtDNA and mitochondrial RNA abundance. Innate immune responses were attenuated in mtDNA-depleted (ρ0) BEAS-2B cells. These findings demonstrate that mtChl is a useful tool compound for investigating how mtDNA alkylation couples mitochondrial genome injury to mitochondrial nucleic acid output, bioenergetic dysfunction, and cGAS-STING-associated innate immune signaling. mtChl is also potentially useful in defining the thresholds that separate adaptive mitochondrial signaling from pathological inflammatory signaling, relevant to toxicology and therapeutic development.
    Keywords:  DNA alkylation; cGAS–STING; double-stranded RNA; innate immunity; mitochondrial DNA damage; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.11.018
  9. Doc Ophthalmol. 2026 Nov 09.
    Rare genetic variants in leber hereditary optic neuropathy: molecular mechanisms, diagnosis, and emerging therapies.
    Gabriela Chlebowska, Krzysztof Michalak, Ewa Gancek, Magdalena Lis, Monika Drzazga, Anna Lyp-Broszko, Tomasz Klaudel, Mateusz Strojek, Rafał Pławszewski.
      Hereditary optic neuropathies, such as Leber's hereditary optic neuropathy (LHON), remain a focus of active research. Diagnostic challenges and severe clinical consequences often result in atypical presentations, creating significant obstacles for neuro-ophthalmology. The field has garnered increased attention due to advances in molecular biology and genetic engineering. Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA disrupt oxidative phosphorylation, reduce adenosine triphosphate production, and increase reactive oxygen species generation, to which retinal ganglion cells are particularly vulnerable. Rare genetic variants have been identified in LHON and related mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and Leigh syndrome. Phenotypic heterogeneity, variable heteroplasmy levels, and limited sensitivity of targeted genetic testing complicate the detection and interpretation of rare variants. As a result, comprehensive next-generation sequencing is increasingly necessary for accurate molecular diagnosis and timely treatment initiation. Recent therapeutic interventions include genotype-specific approaches, such as adeno-associated virus serotype 2-mediated allotopic expression, and genotype-independent therapies, such as idebenone. Diagnostic standards for mitochondrial optic neuropathies have shifted from focusing solely on the three primary pathogenic mtDNA variants to a broader molecular diagnostic framework. Future research should prioritize mtDNA sequencing in cases with inconclusive diagnoses using conventional methods, incorporate mitochondrial and nuclear genomics, and leverage artificial intelligence-based approaches. Accurate identification and classification of rare variants, together with a deeper understanding of their phenotypic consequences, will facilitate the development of individualized therapeutic strategies to prevent further visual decline. This review outlines potential directions for multifaceted treatment strategies in patients with rare LHON-associated variants and critically evaluates current evidence regarding the clinical significance of rare mitochondrial and nuclear genetic variants in LHON and related mitochondrial optic neuropathies.
    Keywords:  Leber hereditary optic neuropathy; Mitochondrial optic neuropathies; Rare genetic variants; Retinal ganglion cells
    DOI:  https://doi.org/10.1007/s10633-026-10166-y
  10. Pediatrics. 2026 Nov 11. pii: e2026077835. [Epub ahead of print]
    Adolescent Hypertrophic Cardiomyopathy Can Be the First Clue to Multisystem Mitochondrial Disease.
    Harrison Ngue, Antonio R Perez-Atayde, Praveen N Meka.
      Up to 40% of children with mitochondrial disease develop hypertrophic cardiomyopathy (HCM) during their disease course, but HCM is almost never the first presenting manifestation. When it is, the underlying mitochondrial disorder is easily missed: the cardiomyopathy is managed in isolation, and extracardiac findings that emerge later may be dismissed as unrelated. We describe an adolescent whose severe HCM was the first major manifestation of clinicopathologically confirmed multisystem mitochondrial disease with a phenotype consistent with Leber hereditary optic neuropathy. Her cardiomyopathy was managed in isolation for over a year before optic atrophy, primary ovarian insufficiency, osteopenia, and exercise intolerance were ultimately recognized as part of a single mitochondrial process. Endomyocardial and skeletal muscle biopsy confirmed mitochondrial pathology. The diagnosis directly changed management: cofactor supplementation was initiated, her visual acuity stabilized on idebenone, and perioperative planning for transplantation was adapted to prevent catabolic decompensation. Her cardiac disease progressed to heart failure requiring transplantation at age 16 years, but she remains clinically stable with preserved graft function more than 15 years later. This case challenges the assumption that mitochondrial disease should enter the differential only after neurologic dysfunction appears. General pediatricians, who see the whole child longitudinally, are uniquely positioned to recognize when dysfunction in other high-energy tissues points toward a unifying mitochondrial diagnosis in a child with cardiomyopathy.
    DOI:  https://doi.org/10.1542/peds.2026-077835
  11. Front Aging Neurosci. 2026 ;18 1914316
    Mitochondrial dysfunction in Parkinson's disease and aging.
    Xiaoyu Lu, Zhiyan Huang, Zhongming Ying.
      Parkinson's disease (PD) is a neurodegenerative disorder for which advancing age is the major risk factor. Aging and PD share several features, including chronic neuroinflammation and pathological protein accumulation. This overlap suggests that mechanisms driving the aging process may also contribute to the onset and progression of PD. In this narrative review, we examine mitochondrial dysfunction as a shared feature of aging and PD, focusing on energy production, calcium buffering, apoptosis, inflammation, and reactive oxygen species (ROS) generation. The literature reviewed here suggests shared alterations in mitochondrial dynamics, increased mitochondrial DNA (mtDNA) instability, NAD+ depletion, Complex I inhibition, redox imbalance, and disrupted calcium homeostasis. We also summarize mitochondria-targeted interventions investigated in PD.
    Keywords:  Parkinson's disease; aging; calcium homeostasis; mitochondria; mitochondrial dynamics; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fnagi.2026.1914316
  12. bioRxiv. 2026 Oct 21. pii: 2026.10.20.759735. [Epub ahead of print]
    Nanoscale remodeling of mitochondrial architecture during mtRNA surveillance failure.
    Eve V Kakudji, Kevin Rose, Jaewon Lee, Eric Herrmann, Priya Gatti, James H Hurley, Samantha C Lewis.
      Mitochondria within a cell exhibit heterogeneity in their composition and metabolic functions, and how this specialization shapes the responses of individual organelles to stress is unclear. We applied fluorescence microscopy and in situ cryo-electron tomography to examine the composition of mitochondrial stress bodies and their relationship to inner mitochondrial membrane architecture in the context of a mitochondrial genome expression defect. We discovered that defective mitochondrial RNA processing prompted a loss of inner membrane domain identity, leading to the mislocalization of ATP synthase from cristae edges to the boundary membrane, perturbed cristae morphometrics, and complete cristae loss in a subset of organelles. Mitochondrial stress bodies were enriched with nucleic acid and protein components linked to oxidative pathways, while separate and distinct mitochondrial domains became enriched with oligomerized P5CS, a marker of reductive proline synthesis. We found that consolidation of mitochondrial RNA into stress bodies, as well as ATP synthase remodeling, were regulated independently from P5CS concentration into a subset of the mitochondria. We propose that stress compartmentalization enables independent tuning of the quality control of oxidative pathway components via spatial sequestration from the rest of the mitochondrial network.
    DOI:  https://doi.org/10.64898/2026.10.20.759735
  13. Yale J Biol Med. 2026 Sep;99(3): 466-487
    Toward Understanding the Molecular Basis and Precise Diagnosis of Mitochondrial Diabetes: A Comprehensive Review.
    Sebastian Skoczylas, Katarzyna Banach, Agnieszka Zmysłowska.
      Pathogenic variants in mitochondrial DNA cause mitochondrial dysfunction and a variety of clinical symptoms. Some mtDNA variants are strongly associated with diabetes. Mitochondrial diabetes is primarily caused by β-cell dysfunction and impaired insulin secretion, although insulin resistance may also be present. Mitochondrial dysfunction leads to reduced adenosine triphosphate production in pancreatic β-cells and impaired glucose-stimulated insulin secretion. The most common variant associated with mitochondrial diabetes is m.3243A>G, located in the MT-TL1 gene. This article provides a comprehensive overview of the genetic basis of mitochondrial diabetes and its molecular diagnosis. In addition, it presents significant advances in diagnostic methods, with an emphasis on the use of next-generation sequencing. The molecular mechanism of the m.3243A>G mutation is complex and not fully understood. This paper also discusses the potential of new, noninvasive biomarkers, such as FGF21, GDF15, and mitomiR, and presents prospects for the future. Due to the symptomatic treatment of mitochondrial diabetes syndromes, future patient care should focus on multidisciplinary care, causal therapy, and the identification of markers that predict symptoms and disease progression in individual patients.
    Keywords:  MIDD; Mitochondrial diabetes; Next-Generation Sequencing; biomarkers; m.3243A>G; mitomiRs
    DOI:  https://doi.org/10.59249/GBKY6240
  14. Life Sci Alliance. 2027 Jan;pii: e202603770. [Epub ahead of print]10(1):
    Mitochondrial protein import stress augments α-synuclein aggregation and neural damage.
    Liam P Coyne, Arnav Rana, Xiaowen Wang, Joseph Mauro, Sanaea Bhagwagar, Yumiko Umino, Eduardo C Solessio, Frank Middleton, Xin Jie Chen.
      Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease. The underlying mechanism is incompletely understood. In addition to bioenergetic defects, nonbioenergetic pathways have been largely unexplored. Validating the nonbioenergetic mitochondrial stressors as independent pathogenic factors is challenging because most mouse models of mitochondrial stress are confounded by bioenergetic defects. Here, we show that expression of Ant1P.A114P,A123D, previously shown to cause mitochondrial protein import clogging in cultured human cells, does not affect the overall bioenergetic capacity, yet it induces proteostatic stress responses in the cytosol that suggests accumulation of unimported precursor proteins. In a Parkinson's disease model expressing α-synuclein (A53T), Ant1P.A114P,A123D increased the size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation, and worsened motor coordination defects. Importantly, we found no evidence of bioenergetic defects in either α-synuclein (A53T) or α-synuclein (A53T) + Ant1P.A114P,A123D mice. These data suggest that Ant1P.A114P,A123D likely induces mitochondrial protein import stress, and contributes to neural damage through cytosolic proteostatic stress and altered aggregation dynamics of neuropathogenic proteins independent of bioenergetics.
    DOI:  https://doi.org/10.26508/lsa.202603770
  15. Elife. 2026 Nov 11. pii: RP109761. [Epub ahead of print]15
    Engineering ATP import in yeast uncovers a synthetic route to extend cellular lifespan.
    Naci Oz, Hetian Su, Vedat Sari, Paraveen Patnaik, Rohil Hameed, Jong Hee Song, Derek C Prosser, Vyacheslav M Labunskyy, Vadim N Gladyshev, Nan Hao, Alaattin Kaya.
      Mitochondrial dysfunction and declining ATP production are common features of aging, yet whether ATP availability itself directly regulates cellular lifespan is unclear. However, the causal relationship between cellular ATP homeostasis and aging has not been established. Here, we developed a synthetic system to manipulate intracellular ATP independently of endogenous energy production by expressing a plasma membrane-targeted nucleotide transporter, NTT1, from the intracellular parasite Encephalitozoon cuniculi in Saccharomyces cerevisiae. NTT1 expression depleted intracellular ATP in the absence of extracellular ATP, whereas ATP supplementation produced robust NTT1-dependent ATP uptake, and increased intracellular ATP abundance. ATP availability strongly influenced replicative lifespan: ATP depletion shortened lifespan, whereas ATP supplementation restored and extended lifespan in NTT1-expressing cells. Unexpectedly, extracellular ATP also extended lifespan in wild-type cells that lack ATP import, revealing an NTT1-independent response to extracellular ATP. Transcriptomic analyses showed that NTT1-mediated ATP import suppresses glucose uptake, carbohydrate catabolism, mitochondrial respiration, and autophagy, whereas extracellular ATP elicits a distinct transcriptional response in wild-type cells involving metabolic, mitochondrial, and signaling pathways. Single-cell aging analyses further showed that ATP supplementation extends lifespan across distinct aging trajectories and shifts cells away from the mitochondrial dysfunction-associated aging state. Finally, experiments in cells lacking mitochondrial DNA separated these effects mechanistically: NTT1-associated lifespan phenotypes and high-ATP toxicity required functional mitochondria, whereas extracellular ATP extended lifespan in wild-type cells independently of mitochondrial respiration. Together, these findings demonstrate that ATP availability is a direct regulator of cellular aging and reveal distinct metabolic and extracellular ATP-responsive routes through which cellular energy state influences longevity.
    Keywords:  ATP; S. cerevisiae; aging; cell biology; energy metabolism; mitochondria; nucleotide transport; yeast
    DOI:  https://doi.org/10.7554/eLife.109761
  16. Cell Discov. 2026 Nov 10. pii: 80. [Epub ahead of print]12(1):
    ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12.
    Xiayuhe Pei, Shuqian Zhang, Peiyang Li, Yutong Wu, Yiru Cheng, Xia Feng, Yiqian Wu, Xiaoshuai Huang, Ning Huang, Bei Liu, Junlin Teng, Jianguo Chen, Craig Blackstone, Pengli Zheng.
      Endoplasmic reticulum (ER)-mitochondria contact sites facilitate lipid transfer, calcium signaling, and mitochondrial division; however, their role in mitochondrial transport remains unclear. Here, we identify hereditary spastic paraplegia (HSP)-associated protein C19orf12 as an ER-anchored regulator of mitochondrial trafficking. The loss of C19orf12 leads to perinuclear mitochondrial clustering in cells, impaired anterograde transport in neurons, and progressive locomotor dysfunction in mice that recapitulates key features of HSP in humans. Mechanistically, C19orf12 forms a discrete complex with the mitochondrial Rho GTPase Miro1 and the Kinesin-1 motor Kif5b, thereby providing a molecular link between ER-mitochondria contacts and microtubule-based anterograde transport. Ca2+ also modulated C19orf12-Miro1 behavior in vitro and showed a biphasic association with mitochondrial motility in live cells. Therefore, our findings establish ER‒mitochondria contact sites as logistical hubs for Kinesin-1 motor loading and highlight the importance of the Ca2+-tunable C19orf12 scaffold in sustaining directional mitochondrial transport, providing a mechanistic framework for how C19orf12 loss may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41421-026-00934-0
  17. Res Sq. 2026 Oct 20. pii: rs.3.rs-11310455. [Epub ahead of print]
    MitoFLUX-EM reveals damaged mitochondria are captured by pre-existing mitolysosomes during PINK1-dependent mitophagy in the heart.
    Derek Narendra, Jennifer Petersen, Xiaoping Huang, Christelle Guillermier, Melissa Wilson, Damian Di Florio, Hsin-Pin Lin, Theresa D'Silva, Yan Li, Wolfdieter Springer.
      Damaged mitochondria are cleared by PINK1-Parkin mitophagy, but the pathway is incompletely understood in vivo. Here, we developed MitoFLUX-EM, combining electron microscopy with nanoscale ¹⁵N isotope tracing to resolve the temporal sequence of mitophagy intermediates in vivo, and applied it to a cardiomyopathy mouse model (CHCHD10 S59L) with high PINK1-dependent mitophagy. Unexpectedly, we found that damaged mitochondria are directly captured by pre-existing mitolysosomes, resulting in multisegmented mitolysosomes that sequestered as many as 33 mitochondria at distinct stages of ultrastructural degradation. Autophagosomal-like membranes arising from the mitolysosomes preferentially engaged the intact outer membrane of damaged mitochondria and neither protein removal nor rupture of the outer membrane was required for mitophagy, contrary to prior models. Pink1 loss disrupted this pathway, causing accumulation of aggregates within mitochondria and reduced survival. These findings reveal that PINK1-dependent mitophagy proceeds through a novel form of microautophagy to safeguard cardiac mitochondrial quality in vivo and establish MitoFLUX-EM as a platform for resolving organelle turnover.
    DOI:  https://doi.org/10.21203/rs.3.rs-11310455/v1
  18. Methods Mol Biol. 2027 ;3105 265-278
    Mitochondrial-Wide Association Studies: Integrating Population-Based Data and Mitochondrial Genetics.
    Yanxi Li, Changyeob Lee, Thalida Em Arpawong.
      Mitochondrial-wide association studies (MiWAS) extend genome-wide association frameworks to systematically test mitochondrial DNA variants for their associations with aging-related phenotypes. Unlike nuclear DNA, the mitochondrial genome is maternally inherited, lacks recombination, and encodes core components of oxidative phosphorylation, making it central to energy metabolism and cellular stress responses. This chapter provides a comprehensive protocol for conducting MiWAS using population-based aging cohorts, with a focus on practical implementation using publicly available datasets such as the Health and Retirement Study. We describe essential steps, including obtaining institutional approvals and data access, preparing phenotype files with appropriate covariates, extracting mitochondrial variants from genotype arrays, performing ethnic-stratified association testing, and interpreting results with multiple testing corrections. Key considerations include accounting for population stratification through mitochondrial genetic ancestry, selecting appropriate minor allele frequency thresholds, and validating findings through sensitivity analyses and replication. By making methods to assess mitochondrial genetic variation, such as MiWAS, accessible to aging researchers, this opens new opportunities to identify genetic determinants of longevity, age-related disease risk, and mitochondrial-nuclear interactions that shape healthy aging.
    Keywords:  Association studies; Ethnicity; Human data; Mitochondrial genetics; SNPs
    DOI:  https://doi.org/10.1007/978-1-0716-5703-4_15
  19. Cell Mol Neurobiol. 2026 Aug 13. pii: 164. [Epub ahead of print]46(1):
    Mitochondria-RNA Binding Protein Crosstalk in Neurodegeneration: Mechanisms Linking Mitochondrial Stress, RNA Dysregulation and Neuronal Vulnerability.
    Aditya Goswami, Leia Lauer, Sofie Robinson, Reet Goyal, Kristian Herman, Ramkumar Mathur.
      Mitochondria have long been organelles, recognized as bioenergetic organelles. Additionally, mitochondria have recently emerged as central hubs of RNA regulatory networks. A growing body of evidence demonstrates that mitochondria and RNA-binding proteins (RBPs) engage in a two-way dialogue to integrate stress responses, proteostasis, and adaptive cellular programs. Several RBPs linked to neurodegenerative diseases, such as TDP-43, FUS, TIA-1, TIAR, and Pumilio family proteins, directly impact mitochondrial biogenesis, fusion-fission dynamics, and mitophagy. In turn, mitochondrial signaling can reprogram RBP behavior via post-translational modification, recruitment to mitochondrial membranes, and stress-induced translocation to cytoplasmic ribonucleoprotein granules. Interference with this regulatory axis significantly impacts on neuronal homeostasis. Mislocalization of RBPs is often linked to mitochondrial fragmentation, compromised oxidative phosphorylation, decreased ATP production, and increased reactive oxygen species (ROS) production. Notably, mitochondrial dysfunction is a common early event, even before apparent neuron loss, in several neurodegenerative diseases. Emerging data also points to a role for the mitochondria RBP interface in selective neuronal vulnerability, particularly in motor neurons that rely heavily on both mitochondrial bioenergetics and highly regulated RNA metabolism. Here, we review recent work that has helped define the molecular underpinnings of mitochondrial RBP crosstalk, discussing emerging tools that have facilitated these findings (including super-resolution microscopy, RNA interactome mapping, and mitochondrial proteomics), while highlighting therapeutic approaches that seek to restore mitochondrial and RNA homeostasis. Understanding the interface between mitochondria and RBPs provides a novel paradigm for neurodegeneration and may open new therapeutic opportunities.
    DOI:  https://doi.org/10.1007/s10571-026-01788-6
  20. Int J Mol Sci. 2026 Nov 07. pii: 9993. [Epub ahead of print]27(21):
    Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies.
    Prarthana Kalerammana Gopalakrishna, Thirupathirao Vishnumukkala, Zaw Myo Hein, Barani Karikalan, Srikumar Chakravarthi, Farida Hussan, Riya Sandeep Deoghare, Saravanan Jagadeesan, Narendiran Krishnasamy, Soe Ei Phyu, Pamela David, Mohd Amir Kamaruzzaman.
      Mitochondria are critical for bioenergetics, calcium and redox homeostasis, and apoptosis in neurons. Neurons are especially susceptible to mitochondrial malfunction since they are terminally differentiated and have extraordinary energy requirements. Mechanisms such as defective oxidative phosphorylation, altered fission-fusion dynamics, defective mitophagy, impaired axonal transport and excessive reactive oxygen species (ROS) generation are increasingly appreciated as important mechanisms in major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). The review discusses the structure and function of mitochondria with emphasis on oxidative phosphorylation, ROS and reactive nitrogen species (RNS) signalling, calcium-mediated excitotoxicity, lipid metabolism, and apoptotic and non-apoptotic cell-death mechanisms including necroptosis, ferroptosis, pyroptosis and parthanatos. In particular, disease-specific processes are highlighted, such as impaired mitophagy by amyloid β/tau in AD, PTEN-induced kinase 1 (PINK1)/Parkin dysfunction and complex I inhibition in PD, Superoxide Dismutase 1 (SOD1)/C9orf72-associated mitochondrial defects in ALS, and bioenergetic dysfunction by mutant huntingtin in HD. Therapeutic approaches include mitochondria-targeted antioxidants, fusion and biogenesis enhancers, fission inhibitors, inflammasome modulators, Mitochondrial Permeability Transition Pore (mPTP) inhibitors and gene therapy. Also highlighted are recent advancements such as Ubiquitin-Specific Peptidase 30 (USP30) inhibition, intercellular mitochondrial transfer and regulatory approval of a mitochondria-targeted peptide, together with evidence supporting causality and hurdles underpinning clinical translation. Graded against human-genetic, patient-tissue and model-based evidence, mitochondrial dysfunction is best supported as a primary driver in PD and genetic ALS, and as an early amplifier of proteinopathic or mutant-huntingtin toxicity in sporadic AD and HD.
    Keywords:  mitochondria-targeted antioxidants; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurodegeneration; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms27219993
  21. J Biol Chem. 2026 Nov 13. pii: S0021-9258(26)02625-6. [Epub ahead of print] 113753
    SUMO-2/3 modification of PINK1 restrains basal mitophagy through MAPL-dependent regulation of mitochondrial surveillance.
    Nitheyaa Shree Ramesh, Richard Seager, Kevin A Wilkinson, Jeremy M Henley.
      The mitochondrial kinase PTEN-induced kinase 1 (PINK1) initiates mitophagy in response to mitochondrial damage, yet mechanisms that constrain its activation under basal conditions remain incompletely defined. Here, we identify a non-canonical SUMO 2/3 modification of PINK1 that suppresses basal mitophagy. We show that the mitochondrial E3 ligase mitochondrial-anchored protein ligase (MAPL/MUL1) promotes PINK1 SUMO-2/3 modification, while MAPL depletion reduces SUMOylation and enhances basal mitophagy. Targeted deSUMOylation augments mitophagy. These findings reveal a novel SUMO-based checkpoint for basal PINK1 activation and mitochondrial quality control.
    Keywords:  MAPL; PINK1; SUMO-2/3; SUMOylation; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2026.113753
  22. J Otol. 2026 Oct;21(4): 280-288
    Mitoribosome dysfunction in sensorineural hearing loss: genetic mechanisms and clinical implication.
    Luhang Cai, Chao Chen, Jia Chen, Jianguo He, Min-Xin Guan.
      Mitochondrial translation depends on coordinated contributions from the mitochondrial and nuclear genomes and is essential for oxidative phosphorylation. Disruption of this system can cause isolated sensorineural hearing loss or auditory impairment within multisystem disease. This review examines how mitochondrial rRNA variants, nuclear-encoded mitoribosomal protein defects, and environmental exposures converge on mitochondrial translation to impair hearing. The mitochondrial 12S rRNA 1555A>G and 1494C>T mutations alter decoding-site architecture and increase susceptibility to aminoglycoside ototoxicity, whereas pathogenic variants in nuclear mitoribosomal protein genes can compromise subunit assembly, stability, or abundance. Nuclear modifiers, particularly TRMU, and secondary mitochondrial tRNA variants illustrate how RNA modification and tRNA function influence the consequences of a primary rRNA defect. We propose mitochondrial translational reserve as a testable framework for incomplete penetrance and cochlear vulnerability, while recognizing that its quantitative relationship to hearing outcomes remains unresolved. Current clinical applications include molecular diagnosis, genotype-informed aminoglycoside prescribing, cascade testing of maternal relatives, and individualized hearing rehabilitation. Patient-derived auditory models and genetic rescue studies provide opportunities to clarify disease mechanisms and evaluate interventions, although modifier correction and pharmacological otoprotection remain experimental. Integrating molecular mechanisms with clinical assessment can strengthen prevention of avoidable ototoxicity and guide care for mitochondrial hearing loss.
    Keywords:  12S rRNA; aminoglycoside ototoxicity; mitochondrial ribosome; mitochondrial translation; nuclear modifiers; sensorineural hearing loss
    DOI:  https://doi.org/10.26599/JOTO.2026.9540084
  23. Int J Mol Sci. 2026 Oct 24. pii: 9513. [Epub ahead of print]27(21):
    Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant.
    Irene Marrone, Blendi Ura, Fulvio Celsi, Luisa Zupin, Eduardo Maria Sommella, Valentina Golino, Paolo Peruzzo, Chiara Ciardi, Maria Teresa Bonati, Elena Genova, Massimo Zeviani, Alessandro Mauro Spinelli, Valeria Capaci.
      Pathogenic variants in MT-RNR1 are classically associated with aminoglycoside-induced sensorineural hearing loss through disruption of the mitochondrial 12S rRNA decoding center. Their contribution to pediatric neurological disease remains poorly defined. We identified a novel homoplasmic MT-RNR1 variant, m.1014A>G, in a patient with drug-resistant focal epilepsy beginning at 9 months of age who remained undiagnosed after trio whole-exome sequencing filtered using an extensive epilepsy gene panel. The variant was also detected in her mother. Structural modeling suggests that the variant, affecting a highly conserved region of the mitochondrial 12S rRNA, may alter the mitochondrial small ribosomal subunit assembly. To investigate its pathogenicity, we performed comprehensive functional studies in patient-derived fibroblasts. Unlike canonical MT-RNR1 variants, m.1014A>G did not confer aminoglycoside toxicity. Functional in vitro studies on patients' fibroblasts demonstrated increased 12S/16S rRNA ratios, reduced abundance of both mitoribosomal subunit proteins, decreased levels of mitochondrially encoded respiratory-chain subunits, and impaired oxidative phosphorylation. These abnormalities were accompanied by mitochondrial network fragmentation, increased mitochondria-lysosome colocalization suggestive of enhanced mitophagy and reduced mitochondrial DNA copy number. Altogether, the findings are consistent with defective mitoribosome assembly and altered mitochondrial translation, resulting in a bioenergetic defect. Our study points to a previously unrecognized candidate pathogenic mechanism associated with MT-RNR1 and may expand the phenotypic spectrum of MT-RNR1-related disorders to include maternally inherited infantile-onset epileptic encephalopathy. These findings highlight the importance of dedicated mitochondrial DNA analysis in children with unexplained early-onset epilepsy despite negative nuclear genomic testing.
    Keywords:  MT-RNR1; bioenergetics; mitochondrial disease; mitoribosome; translation defect
    DOI:  https://doi.org/10.3390/ijms27219513
  24. Nat Metab. 2026 Nov 13.
    Brown adipose tissue sustains thermogenesis through metabolic flexibility in glucose utilization.
    Nakul Karandikar, Celina Beyer-Teal, Lishu Yue, Ece Kilic, Zeran Lin, Lucie Yammine, Ksenia Morozova, Colleen K Hadley, Santiago Barber, Timothy E McGraw, Paul Cohen.
      Brown adipose tissue (BAT) is a cold-activated organ that uncouples mitochondrial respiration from ATP synthesis to produce heat. Activated BAT can consume an extreme amount of glucose, per gram of tissue, in both mice and humans. However, the contexts, mechanisms and necessity for BAT glucose utilization remain surprisingly undefined in vivo. Here we show that while BAT thermogenesis is maintained across diverse dietary contexts, its glucose utilization is particularly responsive to diet. Importantly, we find cold-induced BAT glucose uptake and thermogenesis to be independent of the previously proposed critical transporter, GLUT1. Instead, inducible GLUT4 loss eliminates cold-induced glucose uptake and compromises BAT thermogenesis only when dietary lipids are low during cold stress. We furthermore illustrate the unexpected capacity for brown adipocytes to sustain ATP levels without glycolysis, even during substantial mitochondrial uncoupling, when alternative nutrients are abundant. Collectively, our work demonstrates that BAT sustains thermogenesis through marked metabolic flexibility across nutrient contexts.
    DOI:  https://doi.org/10.1038/s42255-026-01652-3
  25. Front Pharmacol. 2026 ;17 2017406
    Mitochondrial cristae remodeling in ischemic stroke: mechanisms and therapeutic perspectives.
    Dawei Zhang, Hongbo Zhang, Ruoxin Tu, Shuo Zhang, Hao Tian, Yue Meng, Xiaolin Lv, Hongna Yin.
      Mitochondrial cristae arrange the respiratory machinery within the inner membrane and change as ischemia gives way to reperfusion. Their organization depends on mitochondrial contact site and cristae organizing system assemblies, optic atrophy 1, adenosine triphosphate synthase, and cardiolipin. Disruption of these systems can impair energy production, facilitate neuronal death, and expose mitochondrial DNA to inflammatory sensors. This review brings structural work together with experimental stroke studies to examine how crista remodeling contributes to injury and recovery. Genetic manipulation of selected regulators has preserved mitochondrial structure and reduced injury in neurons and microglia. Most of these interventions preceded ischemia, leaving the speed and feasibility of repair after stroke onset uncertain. Pharmacological modulation and mitochondrial delivery offer ways to address this gap, particularly around reperfusion. Emerging strategies combine modulation of crista protein assemblies with cardiolipin directed treatment, mitochondrial antioxidant nanomedicine, organelle delivery, and control of local drug exposure. Their therapeutic evaluation can be aligned with distinct opportunities at reperfusion and during subsequent tissue recovery. Progress toward treatment will require evidence that a candidate reaches the affected brain cells, modifies the intended membrane assembly, and produces lasting neurological benefit. The available studies place crista remodeling within neuroprotective pathways and identify the experimental steps needed to evaluate it as a therapeutic target.
    Keywords:  OPA1; cardiolipin; ischemic stroke; mitochondrial cristae; neuroinflammation
    DOI:  https://doi.org/10.3389/fphar.2026.2017406
  26. Curr Opin Neurobiol. 2026 Nov 12. pii: S0959-4388(26)00124-8. [Epub ahead of print]101 103288
    Mitochondria on the move: Mitochondrial release and transfer in nervous system health and disease.
    Tessa Onraet, Steven Zuryn.
      While studies of mitochondria in the nervous system traditionally focus on their roles as key energy producers, mitochondria are increasingly recognised as essential determinants of nervous system development, function, and disease. The conventional understanding of mitochondria places them within the confines of individual neurons and glial cells, where they support nervous system function and remain steadfast against cellular threats. However, emerging research is redefining the properties of mitochondria as highly dynamic modulators of the nervous system that can be released or transferred between neurons and glia as active repair or signalling effectors or for targeted glia-based degradation. Here, we discuss recent key reports of this dynamic transfer of mitochondria in the context of nervous system health and disease.
    DOI:  https://doi.org/10.1016/j.conb.2026.103288
  27. Cell Rep Methods. 2026 Nov 11. pii: S2667-2375(26)00367-X. [Epub ahead of print] 101666
    MitoTALENs reduce mutant mitochondrial DNA carryover following pronuclear transfer.
    Noemi Castelluccio, Andrei Rybouchkin, Sandra R Bacman, Gabriele Ferrari, Wim Trypsteen, Delphine De Sutter, Krishna C Pavani, Sofie Symoens, Sven Eyckerman, Carlos T Moraes, Ward De Spiegelaere, Dominic Stoop, Björn Heindryckx.
      Preventing transmission of maternally inherited mitochondrial diseases remains a major challenge in reproductive medicine. Nuclear transfer (NT) offers a promising strategy by replacing mutant mitochondrial DNA (mtDNA) while preserving the nuclear genome; nevertheless, residual mtDNA carryover can persist in reconstructed embryos and potentially expand, leading to disease recurrence. Using a heteroplasmic mouse model harboring the pathogenic m.5024C>T mutation, we evaluated two approaches to reduce mtDNA carryover following pronuclear transfer (PNT): mitochondrially targeted transcription activator-like effector nucleases (mitoTALENs) and induced mitophagy. PNT alone markedly lowered heteroplasmy, reducing mutant mtDNA from 68.5% to 2.4%, on average. Application of mitoTALENs post-PNT further reduced residual mutant mtDNA below 1%, with levels as low as 0.2%, without compromising embryonic development. In contrast, mitophagy induction via SQSTM1 overexpression failed to reduce heteroplasmy, consistent with inefficient lysosomal recruitment in embryos. Additionally, we validated digital PCR (dPCR) as a sensitive and robust method for quantifying mtDNA copy number and low-level heteroplasmy.
    Keywords:  CP: biotechnology; CP: developmental biology; MitoTALENs; digital PCR; heteroplasmy; mitochondrial disease; mitophagy; pronuclear transfer
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101666
  28. Biochem Biophys Rep. 2026 Dec;48 102856
    Do Golgi-mitochondria membrane contact sites regulate lipid flux and local apoptotic fate decisions?
    Zainab Abdullah Waheed, Zenah Hadi Saied, Mohamed El Bouamri, Hadeel Amoori Abd Ali.
      Membrane contact sites (MCSs) between intracellular organelles serve as vital platforms for non-vesicular lipid transfer and metabolic signaling, challenging traditional views of organellar autonomy. While endoplasmic reticulum (ER)-mediated junctions such as mitochondria-associated ER membranes (MAMs) have been extensively characterized, the interface between the Golgi apparatus and mitochondria (Golgi-mitochondria contact sites, or GMCs) remains less defined despite its strategic biochemical position. The Golgi complex acts as the principal hub for sphingolipid modification and phosphoinositide sorting, whereas mitochondria rely on imported lipid species to maintain structural integrity and govern cell death cascades. This review synthesizes current evidence regarding the molecular architecture, lipid transport dynamics, and apoptotic regulatory roles of GMCs. We evaluate proposed tethering mechanisms, distinguishing between established yeast pathways (such as the Snf1-dependent Vps53 axis) and unvalidated mammalian hypotheses (including potential AMPK regulation). Furthermore, we treat GDAP1 as a contact-site modulator rather than a confirmed physical tether, and discuss how non-vesicular fluxes of ceramide, phosphatidylinositol-4-phosphate (PI(4)P), and cholesterol alter outer mitochondrial membrane dynamics.
    Keywords:  Apoptosis; Ceramide; Golgi apparatus; Membrane contact sites; Mitochondria; Non-vesicular lipid flux; Outer mitochondrial membrane permeabilization; VDAC2
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102856
  29. Yale J Biol Med. 2026 Sep;99(3): 558-575
    Leveraging Deep Learning to Reveal Fine-Scale In Vivo Mitochondrial Dynamics and Axonal Transport.
    John Y Park, Mirry Chae, Hyun Sung.
      In axons, mitochondrial transport is essential for neuronal function and survival, and its disruption is increasingly recognized as an early pathological hallmark in multiple neurodegenerative diseases. Despite its importance, quantitative analysis of mitochondrial transport dynamics remains challenging due to complex and heterogeneous motility patterns and reliance on labor-intensive manual tracking methods. Here, we present a deep learning-assisted framework for semiautomated quantification of mitochondrial axonal transport. Using time-lapse confocal imaging of individual in vivo axons in the well-established Drosophila nervous system, we comprehensively validated transport parameters, including displacement and velocity. We further assessed the fidelity of our method in recapitulating expert-derived measurements and its potential to overcome the limitations of conventional manual tracking. Notably, our framework enables detailed characterization of dynamic behaviors during transport, including intensity-based variations and concurrent morphological changes within individual mitochondria, potentially reflecting mitochondrial physiological states that were difficult to resolve with traditional approaches. Collectively, our study establishes the feasibility of next-generation analysis for axonal transport and highlights its potential to uncover previously inaccessible aspects of mitochondrial dynamics, providing a scalable and objective framework for investigating mitochondrial in vivo transport dysfunction in neurodegenerative disease models.
    Keywords:  Axonal transport; Deep learning; Drosophila; In vivo dynamics; Mitochondria
    DOI:  https://doi.org/10.59249/ZSDT8892
  30. Int J Mol Sci. 2026 Oct 24. pii: 9500. [Epub ahead of print]27(21):
    Integrated Multi-Omics Convergence Scoring Reveals Modular Network Architecture with Age-Associated Mitochondrial Signatures in Sarcopenia.
    Dahyun Park, Jiwon Park, Ock K Chun, Eun-Young Kwon, Heekyong R Bae.
      Sarcopenia arises from convergent genetic, epigenetic, transcriptomic, metabolic, and microbiome-associated perturbations, yet conventional multi-omics analyses often yield fragmented, layer-specific feature lists. We developed an integrated multi-omics convergence scoring framework that calculates an Integrated Convergence Score (ICS) by combining standardised layer-level statistical evidence, layer-specific pathway context, network features and sarcopenia-specific disease-relevance evidence. We applied it to skeletal muscle transcriptomes from five independent cohorts (208 participants), ageing-associated muscle DNA methylation, and genome-wide association studies of muscle mass and strength, each analysed against its own null distribution. Gene-level changes were few and did not replicate, whereas mitochondrial respiration, mitochondrial translation and contraction pathway scores were lower in sarcopenia in the pooled analysis. These mitochondrial signatures were also lower in ageing-, frailty-, and pre-sarcopenia-related comparisons, indicating a component shared with muscle ageing. The three layers implicated largely distinct mechanisms. Compared with rank-based combined statistics, the ICS top-ranked genes formed a more connected network, which partly reflects the network component of the score. A context map placed the modules within mitochondrial respiration, creatine-based energy buffering, and NAD-PGC-1α signalling. This framework organises fragmented multi-omics evidence into a systems-level gene network associated with sarcopenia and prioritises candidate genes and mechanisms for future functional studies.
    Keywords:  DNA methylation; ageing; genome-wide association study; mitochondria; multi-omics integration; network analysis; replication; sarcopenia; skeletal muscle transcriptome
    DOI:  https://doi.org/10.3390/ijms27219500
  31. Proc Natl Acad Sci U S A. 2026 Nov 17. 123(46): e2613433123
    Lipid droplets buffer hydrogen sulfide-induced redox imbalance.
    David A Hanna, Roshan Kumar, Yuanyuan Ji, Harrison K A Wong, Costas A Lyssiotis, Jace W Jones, Ruma Banerjee.
      The electron transport chain is a signaling hub for hydrogen sulfide (H2S) that serves both as a respiratory substrate and an inhibitor. While acute sulfide toxicity is well characterized, cellular adaptations to chronic H2S, particularly microbially-derived sulfide exposure in colon, is poorly understood. We report that chronic, low-level H2S exposure (4 to 20 µM) drives robust carbon sequestration in lipid droplets (LD) across several human cell lines, driven by a coordinated remodeling of redox and nucleotide metabolism. Specifically, H2S-induced reductive shifts in nicotinamide adenine dinucleotide (NAD) and coenzyme Q (CoQ) pools are accompanied by glycerol-3-phosphate accumulation and cytidine triphosphate (CTP) depletion. Lipidomic analysis reveals increased neutral lipid synthesis and triacylglyceride accumulation concomitant with decreased CTP-dependent synthesis of membrane phospholipids. Mitochondrial expression of a water-generating NADH oxidase attenuates LD accumulation and spatially confines the origin of H2S-induced reductive stress signaling to this compartment. Interestingly, LD abundance increases even after H2S withdrawal, continuing over 48 h, during which time the reductively-shifted NAD and CoQ pools slowly reoxidize. Inhibition of fatty acid synthesis during sulfide exposure impairs cellular recovery of respiration. These findings establish an active role for LDs in stress response and reveal that lipid biogenesis is a strategy for countering H2S-induced redox imbalance. The sulfide-LD-redox axis uncovered in this study has implications for understanding how gut-derived H2S, shaped by diet and microbiome, can influence metabolic health.
    Keywords:  lipid droplet; metabolism; redox
    DOI:  https://doi.org/10.1073/pnas.2613433123
  32. Neuropsychiatr Dis Treat. 2026 ;22 639235
    Mitochondrial Quality Control and Apoptotic Thresholds in Major Depressive Disorder: A Structured Narrative Review.
    Caiyan Hou, Zhixiang Li, Dingren Niu, Wei Zou.
      Major depressive disorder (MDD) is clinically heterogeneous, and many patients do not achieve sustained remission with monoaminergic treatments. Mitochondrial dysfunction has been associated with chronic stress, impaired synaptic function, altered cellular energetics, and neuronal vulnerability, but evidence concerning mitochondrial dynamics, mitophagy, redox imbalance, calcium signaling, and intrinsic apoptosis remains distributed across experimental systems. This structured narrative review integrates human brain and peripheral studies, patient-derived cellular evidence, animal models, and general cell biology. We propose the mitochondrial quality control-mitochondrial outer membrane permeabilization (MQC-MOMP) threshold model as a conceptual framework, not an experimentally established disease mechanism. In this model, cumulative failure of mitochondrial repair and clearance may shift stress responses toward Bax/Bak-dependent MOMP and caspase activation. Human findings are largely associative and do not establish widespread mitochondria-driven neuronal apoptosis in living patients with MDD; mechanistic support is strongest in preclinical and cellular models. The framework therefore differs from prior topic-based reviews by organizing heterogeneous evidence according to evidence source, certainty, and proximity to clinical translation. Here we highlight testable priorities for biomarker validation, patient stratification, cell-type-resolved studies, longitudinal cohorts, and mechanism-based interventions.
    Keywords:  PINK1/Parkin pathway; bax/bcl-2; major depressive disorder; mitochondrial apoptosis; mitophagy; oxidative stress
    DOI:  https://doi.org/10.2147/NDT.S639235
  33. Nature. 2026 Nov 11.
    Mitochondrial protein import defects enhance tumour immunogenicity.
    Thomas D Jackson, Jonathan M Palozzi, Christopher D McGann, Tevis Vitale, Ruth Choa, Hieu H M Nguyen, Joao A Paulo, Pedro Latorre-Muro, Jonathan G Van Vranken, Matthew Ravichandran, Bingsen Zhang, Manisha Yadav, Steven P Gygi, Pere Puigserver.
      Tumour cells evade detection and elimination by the immune system through a suite of adaptations1, including the repression of antigen presentation, which is required for the recognition of tumour cells by CD8+ T cells. Mitochondria have emerged as targets for enhancing antitumour immunity; however, the extensive mitochondrial proteome has remained largely unstudied for its ability to modulate immune responses. Here we show that defects in the mitochondrial protein import machinery promote tumour immunogenicity and synergize with immune checkpoint blockade treatment in melanoma models. Mitochondrial protein import perturbation, specifically through depletion of the TIM23 import complex subunit TIMM50, enhances tumour immunogenicity through a pathway involving mitochondrial DNA escape, cGAS-STING pathway activation and interferon-β (IFNβ) secretion. Secreted IFNβ signals through the type I IFN receptor to activate the JAK-STAT pathway, resulting in increased antigen presentation on MHC class I complexes. Mitochondrial DNA escape in Timm50-depleted cells is linked to the formation of mitochondrial-derived vesicles. Depletion of SNX9 and RAB9, involved in mitochondrial-derived vesicle formation2, suppresses mitochondrial DNA-dependent type I IFN production and signalling. By disrupting mitochondrial proteostasis and membrane architecture, defective protein import in Timm50-depleted cells drives the immune phenotype. This study shows that mitochondrial protein import inhibition causes tumour immunogenicity, including sensitization to immune checkpoint blockade, by promoting mitochondrial DNA escape and IFNβ-driven MHC class I antigen presentation.
    DOI:  https://doi.org/10.1038/s41586-026-11249-1
  34. Neurobiol Dis. 2026 Nov 10. pii: S0969-9961(26)00419-5. [Epub ahead of print] 107673
    Neuronal and mitochondrial phenotypes in iPSC-derived bipolar disorder models with and without a family history of mitochondrial disease.
    Dana El Soufi El Sabbagh, Jaehyoung Choi, Lakshmini Balachandar, Eileen Haydarian, Jude Demyati, Zaara Mazhar, Angela Duong, Chiara Cristina Bortolasci, Courtney Irwin, Karun K Singh, Michael Berk, Ken Walder, L Trevor Young, Peter L Carlen, Ana Cristina Andreazza.
      Psychiatric disorders frequently accompany primary mitochondrial diseases (PMDs), suggesting shared biological pathways between mitochondrial function and psychiatric vulnerability. In this exploratory study, we investigated whether bipolar disorder (BD) occurring in the context of a family history of primary mitochondrial disease is associated with differences in neuronal and mitochondrial phenotypes. We generated induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and cortical neurons (CNs) from three non-psychiatric controls, three individuals with BD without a family history of mitochondrial disease, and three individuals with BD who did not themselves have mitochondrial disease but had relatives with clinically diagnosed mitochondrial (BD-FHMD). Our primary endpoints were distinguished network activity and cytosolic and mitochondrial Ca2+ dynamics, complemented by measurements of mitochondrial and cellular function and metabolomic profiles across differentiation. Across neurodifferentiation, we assessed neuronal network activity, calcium dynamics, mitochondrial and cellular health, and metabolomic signatures. BD neurons exhibited sustained hyperexcitability with increased firing and burst activity. In contrast, BD-FHMD neurons showed lower network activity with enhanced cytosolic calcium responses and prolonged mitochondrial calcium transients. BD-FHMD also exhibited stage-dependent mitochondrial alterations, while BD and BD-FHMD showed distinct developmental metabolic signatures. Together, these findings identify two distinct mitochondrial-associated phenotypes within BD. BD is characterized by a hyperexcitable neuronal phenotype associated with altered developmental metabolic programming, whereas BD-FHMD exhibits calcium dysregulation and altered mitochondrial developmental trajectories consistent with increased bioenergetic vulnerability. These findings suggest that BD occurring in the context of a family history of primary mitochondrial disease may be characterized by a distinct pattern of neuronal and mitochondrial dysfunction. Replication in larger, independently characterized cohorts will be important to determine whether this family-history-defined phenotype can contribute to biologically informed subtyping and therapeutic approaches in BD.
    Keywords:  Bipolar disorder; Cortical neurons; Electrophysiology; Hyperexcitability; Mitochondrial dysfunction; iPSC
    DOI:  https://doi.org/10.1016/j.nbd.2026.107673
  35. ACS Appl Bio Mater. 2026 Nov 12.
    Poly(N-isopropylacrylamide)-Grafted Hyaluronic Acid Semi-Gels for Localized Mitochondrial Transplantation in Spinal Cord Injuries.
    A Jamie Ahmed, Krithika Iyer, Davis Anum, Sajeev Kaur, Maria F Zapata-Jaramillo, Patrick G Sullivan, Jason E DeRouchey, Thomas D Dziubla, Samir P Patel.
      Mitochondrial transplantation (MT) represents a promising strategy for treating conditions associated with mitochondrial dysfunction, including neurodegenerative diseases, metabolic syndromes, and tissue regeneration scenarios such as spinal cord injury (SCI). Unlike conventional approaches that address symptoms, MT aims to restore cellular energy homeostasis by replacing impaired mitochondria with functional organelles. However, clinical translation has been limited by the short extracellular lifetime of isolated mitochondria and by their rapid dispersion from the injection site. To address these barriers, we developed a thermoresponsive carrier based on hyaluronic acid covalently grafted with poly(N-isopropylacrylamide) (HA-PNIPAAm), which combines the biocompatibility and bioactivity of HA with the temperature-induced chain collapse of PNIPAAm. The copolymers form injectable semi-gels that thicken above the transition temperature, resist dispersion under flow, and dissolve over hours to release their cargo. We characterized their composition, phase transition behavior, viscoelasticity, and mitochondrial release kinetics, and showed that encapsulation preserved mitochondrial respiratory function and membrane potential relative to free mitochondria over the time window relevant to delivery. In a rat contusion SCI model, subdural delivery of mitochondria in HA-PNIPAAm semi-gels restored spinal cord mitochondrial respiration to uninjured levels at 48 h post-injury. These findings establish HA-PNIPAAm semi-gels as a tunable, injectable platform for localized, cell-compatible mitochondrial delivery and support further evaluation of MT for SCI and other conditions characterized by mitochondrial dysfunction.
    Keywords:  hyaluronic acid; injectable semi-gel; mitochondrial transplantation; spinal cord injury; thermoresponsive copolymers
    DOI:  https://doi.org/10.1021/acsabm.6c01366
  36. Indian J Pediatr. 2026 Nov 07.
    Mitochondrial Complex III Deficiency with Nutritional Vitamin B12 Deficiency.
    Vykuntaraju K Gowda, Anagha Sr, Varunvenkat M Srinivasan, Archana Varghese.
      
    DOI:  https://doi.org/10.1007/s12098-026-06556-4
  37. bioRxiv. 2026 Oct 23. pii: 2026.10.21.760700. [Epub ahead of print]
    FMNL1 polymerized actin filaments complete mitochondrial division downstream of Golgi-derived vesicles.
    Brandon Tabori, Amrapali Ghosh, Maite R Zavala, Rajarshi Chakrabarti.
      Mitochondrial division includes contributions from several organelles yet the molecular machinery that facilitates the final Drp1-induced scission of the OMM is largely elusive. We elucidate that FMNL1, a formin family actin assembly factor, is recruited to the mitochondrial division sites through the TGN vesicles in a calcium dependent pathway to complete mitochondrial division. FMNL1 is activated specifically by Cdc42 that generates actin filaments to complete division of the OMM in Drp1 and actin-dependent pathway. Depletion of FMNL1 enhances early events in mitochondrial division pathway characterized by enhanced ER-mitochondrial contacts and increased Drp1 and TGN vesicles on mitochondria which still results in failed mitochondrial division.
    DOI:  https://doi.org/10.64898/2026.10.21.760700
  38. Mol Neurodegener Adv. 2026 ;2(1): 51
    Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies.
    Laura Cáceres-Palomo, María Alfonso-Triguero, Arantzazu Belloso-Iguerategui, Estibaliz Santiago-Mujika, Marta Mirón-Alcalá, Amaia M Arranz.
      Human-rodent chimeric CNS models provide a unique platform for investigating human-specific aspects of neurodegeneration within the physiological environment of the living CNS. These models are generated by transplanting human pluripotent stem cell-derived neurons, astrocytes, microglia, oligodendrocytes, or neural or glial progenitor cells into the CNS of permissive host animals. Following transplantation, human cells mature, functionally integrate within host tissue, and retain key species-specific molecular and cellular features. Here, we review recent advances in the use of chimeric models to investigate disease mechanisms in Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and demyelinating disorders. We highlight the unique insights these models have provided into human-specific cellular vulnerabilities, genotype-dependent phenotypes, glial responses, and neuroimmune interactions in vivo. We also discuss emerging translational applications, including cell replacement therapies, engineered glial delivery platforms, and remyelination strategies, some of which have progressed toward clinical translation. Finally, we outline the current limitations and future directions for developing next-generation multi-lineage humanized models with enhanced disease fidelity and translational potential.
    Keywords:  Cell replacement therapy; Glia; Human pluripotent stem cells; Human-rodent chimeras; Neurodegenerative diseases; Xenotransplantation
    DOI:  https://doi.org/10.1186/s44477-026-00059-4
  39. Proc Natl Acad Sci U S A. 2026 Nov 17. 123(46): e2622689123
    Structural insights into the evolution of mitochondrial protein import from the trypanosome ATOM complex.
    Shanshan Wang, Congxi Zhang, Hongjun Cai, De-Hua Lai, Long Li.
      The translocase of the outer membrane (TOM) mediates the import of most mitochondrial preproteins. In the protozoan parasite Trypanosoma brucei, this machinery is replaced by the atypical translocase of the outer membrane (ATOM), whose composition differs substantially from the canonical TOM complexes of fungi and metazoans. Here, we report the cryoelectron microscopy structure of the T. brucei ATOM complex at 2.8 Å resolution. The structure resolves all previously identified components together with an additional, previously uncharacterized subunit. Despite its divergent composition, ATOM retains a conserved dimeric channel architecture and a protein-conducting pathway closely resembling those of opisthokont TOM complexes, indicating that the core mechanism of mitochondrial protein translocation was established early in eukaryotic evolution. In contrast, the receptor and intermembrane-space regions exhibit distinct architectures, revealing extensive evolutionary diversification and multiple examples of convergent evolution. Together, these findings provide a near-atomic view of the ATOM translocase and offer insights into the origin, conservation, and diversification of the mitochondrial protein import machinery across eukaryotes.
    Keywords:  ATOM complex; Cryo-EM; Trypanosoma brucei; mitochondrial protein import; protein translocation
    DOI:  https://doi.org/10.1073/pnas.2622689123
  40. Circulation. 2026 Nov 10.
    Generation of Human Cardiomyocytes With Adult-Like Metabolism by a Chemically Defined Medium for Mitochondrial Disease Modeling.
    Chengyi Tu, Arianne Caudal, Yu Liu, Nadjet Belbachir, Ana Kojic, Brett Stern, Lu Ren, Erin Hu, Nathan Cunningham, Brian Yu, Yi-Ing Chen, Patrick Jurney, Jill S Napierala, Marek Napierala, Julia Ritterhoff, Rong Tian, Joseph C Wu.
       BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC cardiomyocytes) as a model for cardiac disease have become increasingly important, bolstered by the Food and Drug Administration's initiative to promote novel alternative methods for biomedical research. A key limitation of metabolically immature iPSC cardiomyocytes is their limited ability to accurately recapitulate mitochondria-dependent pathologies, such as Friedreich ataxia-associated cardiomyopathy. Adult cardiomyocytes are characterized by a high density of interfibrillar mitochondria, abundant respiratory complexes (I-V) that form supercomplexes, and efficient utilization of fatty acids to drive mitochondrial respiration. These unique metabolic structures and functions are largely missing in iPSC cardiomyocytes. Further, whether iPSC cardiomyocytes can efficiently utilize fatty acids for respiration in the presence of glucose, a unique adult feature, remains unclear.
    METHODS: We developed a chemically defined, 11-component maturation medium (MM11) designed using a bioinformatics-guided strategy that identified high-fidelity transcriptional markers of adult cardiac metabolic maturity. Human iPSC cardiomyocytes were treated with MM11 for 2 weeks and evaluated at the molecular, structural, and functional levels, with an emphasis on mitochondrial maturity. We benchmarked our results with isolated primary adult human cardiomyocytes. Last, we tested whether this method could enable us to more accurately model Friedreich ataxia cardiomyopathy.
    RESULTS: MM11 treatment increased expression of metabolic pathways, including mitochondrial respiration and fatty acid metabolism, at the transcript and protein levels. Ultrastructural analyses revealed the formation of interfibrillar mitochondria and mitochondrial respiratory supercomplexes, a feature never shown in previous reports. Functionally, MM11-treated iPSC cardiomyocytes exhibited substantially increased oxidative phosphorylation and a metabolic preference for fatty acid utilization in the presence of physiologic substrates, as determined by oxygen consumption assays and 13C isotope tracing.
    CONCLUSIONS: MM11 promotes robust metabolic maturation of human iPSC cardiomyocytes, enabling sophisticated mitochondrial architecture and substrate utilization. These metabolically matured cardiomyocytes more faithfully model mitochondria-dependent cardiac pathologies, including ischemia-reperfusion injury and Friedreich ataxia cardiomyopathy, improving the use of iPSC cardiomyocytes for mechanistic studies of human heart disease.
    Keywords:  cardiomyocyte; cardiomyopathies; induced pluripotent stem cells; metabolism; mitochondria; stem cells
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080472
  41. Biology (Basel). 2026 Nov 02. pii: 1971. [Epub ahead of print]15(21):
    LSP Methylation in Skeletal Muscle and Cross-Tissue Candidate NUMT Signals Reveal Complementary Features of Mitonuclear Aging in Mice.
    Xijia Wang, Wenpeng Li, Xingbo Zhao.
      Aging disrupts communication between mitochondria and the nucleus, but compact molecular readouts of this interface remain limited. Here, we examined mitochondrial DNA light-strand promoter (LSP) methylation signals in skeletal muscle across natural-aging and mitochondrial-background models, and independently profiled candidate nuclear mitochondrial DNA insertion (NUMT) junction signals in brain and skeletal muscle across age groups. Natural aging was associated with reduced motor performance, altered skeletal-muscle mitochondrial status, and lower LSP methylation signals. Reciprocal F1 crosses and conplastic mice showed coordinated associations among mitochondrial background, LSP methylation signals, bioenergetic parameters, nuclear mitochondrial-gene expression, and physical performance. In parallel, short-read whole-genome sequencing revealed a non-monotonic candidate NUMT signal pattern, with the highest mean signal at 12 months. A Ptprc-associated candidate mitochondrial-nuclear junction was supported by split-read inference and junction-specific droplet digital PCR in a candidate-positive sample. Together, these findings identify LSP methylation signals and candidate NUMT junction signals as complementary but independently measured molecular features of mitonuclear aging.
    Keywords:  LSP methylation; NUMT; Ptprc; aging; mitochondrial-nuclear crosstalk
    DOI:  https://doi.org/10.3390/biology15211971
  42. bioRxiv. 2026 Oct 13. pii: 2026.10.11.758340. [Epub ahead of print]
    Single-cell variant landscape of the human mitochondrial genome reveals cell type-specific functions and disease mechanisms.
    Chunjie Liu, Ting Peng, Zimu Cen, Peiran Lu, Prasanth Potluri, Po Hu, Shiping Zhang, Marie T Lott, Gabrielle Widjaja, Douglas C Wallace, Yi Xing, Liming Pei.
      Mitochondrial DNA (mtDNA) heteroplasmy is a significant source of cellular genetic diversity and can cause disease yet its distribution and functional importance across different human cell types are poorly understood. Here we present scMOCHA (Single-Cell Mitochondrial Omics for Cellular Heteroplasmy Analysis), a scalable computational framework that resolves high-confidence, single-cell resolution mtDNA heteroplasmy directly from standard single-cell RNA sequencing (scRNA-seq) data. Using this tool to interrogate publicly available scRNA-seq datasets from human peripheral blood mononuclear cells (PBMC) and bone marrow (BM) uncovered the single-cell landscape of mtDNA single-nucleotide variants (SNVs) and heteroplasmy across ages in human hematopoietic cell types. PBMCs and BM share many inherited homoplasmic and highly heteroplasmic SNVs, whereas somatic SNVs are tissue- and cell type-specific and distributed across the mtDNA genome, suggesting that they arise largely stochastically. mtDNA replication error is a dominant force shaping homoplasmic variants, while oxidative stress potentially drives a significant portion of heteroplasmic and somatic mutations. Importantly, we discover previously unknown cell type-specific and human disease-associated mtDNA SNVs. By coupling mtDNA genotypes with matched single-cell nuclear transcriptomes and structural modeling, we uncover potential molecular mechanisms by which disease-associated mtDNA SNVs impact cellular processes such as inflammation and contribute to disease. Together, these findings define the single-cell variant landscape of the human mitochondrial genome and reveal previously unrecognized lineage- and disease-associated patterns of mtDNA variation in the human hematopoietic system.
    DOI:  https://doi.org/10.64898/2026.10.11.758340
  43. Int J Mol Med. 2027 Jan;pii: 1. [Epub ahead of print]59(1):
    Mitochondria‑associated small RNAs in breast cancer: An asymmetric evidence landscape from metabolic rewiring to immune selection (Review).
    Hung-Yu Lin, Hui-Wen Ho, Hao-Wen Hsiao, Yi-Ru Shen, Hao-Yi Li, Pei-Yi Chu.
      Mitochondria enable breast cancers (BC) to switch among metabolic, redox and stress‑adaptive states, but the associated small‑RNA literature often merges molecules with different origins, itineraries and sites of action. The present critical narrative Review separates bona fide nuclear‑encoded mitochondrial microRNAs (mitomiRs), candidate mitochondrial miRNAs, mtDNA‑derived miRNA‑like RNAs, other mitochondrial small RNAs, cytosolic mitochondrial regulators, extracellular RNA cargo and engineered systems. Their reported functions are organized within a 3R Mito‑Ecosystem: Rewiring of cell‑autonomous metabolism, mitochondrial‑origin RNA‑dependent growth signaling, organelle quality and ferroptosis competence; directional Relay of RNA cargo or intact mitochondria; and Release of mitochondrial signals and their immune‑sensing consequences. LIFT records Localization, Interaction, Function and Translation separately, while context tiers distinguish BC RNA perturbation from non‑RNA enabling biology, cross‑system support and hypotheses. A revision‑stage PubMed search informed an illustrative mechanistic comparison, with source and selection limits stated explicitly. Rewiring includes directly perturbed metabolic and ferroptotic relationships and reported mitochondrial‑origin tiRNA‑Met activity. Relay includes causal extracellular RNA effects and organelle‑transfer studies. Release includes miR‑25/93‑dependent NCOA3‑cGAS immune sensing, without demonstrated control over mtDNA‑release quantity. A causal chain connecting an endogenous mitochondria‑resident or mitochondria‑derived small RNA, altered release of a defined mitochondrial signal and a lineage‑resolved immune outcome remains unestablished in the evaluated material. Ferroptosis provides a testable interface rather than a universally immune‑activating endpoint. Target binding was distinguished from functional rescue and propose source‑, time‑ and lineage‑resolved experiments and operational immune‑activating or suppressive Release states. These criteria require validation and are not patient classifiers or treatment rules.
    Keywords:  breast cancer; extracellular vesicle; ferroptosis; immune selection; metabolic plasticity; mitochondrial transfer; mitochondria‑associated small RNA; mitomiR; molecular provenance
    DOI:  https://doi.org/10.3892/ijmm.2026.6048
  44. Yale J Biol Med. 2026 Sep;99(3): 600-616
    Mechanisms of Mitochondrial DNA Leakage as Primary Upstream Catalysts for NLRP3 Inflammasome Activation in Neurodegenerative Pathology: A Systematic Review.
    Umarkhon Uzakov, Akobirkhon Anvarkhonov, Akbarova Azizakhon.
      Chronic neuroinflammation drives progressive neurodegenerative pathology, including Alzheimer and Parkinson diseases. While the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a central mediator of this response, its upstream, nonlinear activation mechanics remain poorly defined. Recent studies suggest that the translocation of damaged mitochondrial DNA (mtDNA) into the cytosol serves as a critical immunogenic catalyst bridging metabolic stress with inflammatory cascades. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, a systematic review was conducted across PubMed, Embase, and Scopus for primary experimental studies. Eligibility focused on quantitative metrics of cytosolic mtDNA leakage and subsequent NLRP3 conformational assembly kinetics in neurodegenerative models. The data demonstrate that chronic oxidative stress and toxic protein aggregation induce mitochondrial outer membrane permeabilization via BCL2-associated X protein/BCL2 antagonist/killer 1 (BAX/BAK) macropores. The resulting efflux of oxidized mtDNA (8-OHdG) escapes cytoplasmic exonuclease degradation, binding directly to the leucine-rich repeat domain of NLRP3 to trigger enzymatic activation. This synthesis establishes that mtDNA leakage acts as a distinct, cooperative biochemical switch rather than a linear cascade. Characterizing these nonlinear threshold dynamics bridges clinical pathology with predictive systems biology, providing the quantitative parameters necessary to constrain advanced computational models of early-stage neurodegeneration.
    Keywords:  Mitochondrial DNA leakage; NLRP3 inflammasome; Neurodegeneration; Non-linear thresholds; PRISMA systematic review.; Systems biology
    DOI:  https://doi.org/10.59249/JQKE9160
  45. Bioorg Med Chem Lett. 2026 Nov 13. pii: S0960-894X(26)00282-9. [Epub ahead of print] 130815
    Mapping of Ligandable tyrosine and lysine residues in proteins implicated in mitochondrial DNA depletion and therapeutic relevance.
    Ffion L Jones, Nathan M Alba, Nasha J Palsetia, Lyn H Jones.
      Chemoproteomic mapping of ligandable lysine and tyrosine residues has expanded covalent drug discovery and chemical biology beyond cysteine. Analysis of 950 ligandable proteins revealed a significant enrichment of genes associated with mitochondrial DNA depletion syndromes (MDDS). Several MDDS-associated proteins contained ligandable lysine or tyrosine residues, highlighting opportunities for therapeutic intervention in genetically validated mitochondrial disease targets. We discuss two representative examples: SUCLG1, which contains a ligandable active-site lysine that may enable covalent inhibition, and AGK, which contains a ligandable tyrosine that may provide an allosteric strategy for modulating mitochondrial and immune signaling. These findings extend emerging links between chemoproteomic ligandability and human genetics to mitochondrial DNA depletion disorders, suggest new opportunities for chemical probe and drug discovery, and provide a framework for prioritizing disease-relevant targets identified through covalent chemoproteomics.
    Keywords:  AGK; Chemoproteomics; Mitochondrial DNA; SUCLG1
    DOI:  https://doi.org/10.1016/j.bmcl.2026.130815
  46. Mol Med Rep. 2027 Jan;pii: 11. [Epub ahead of print]35(1):
    PINK1‑regulated mitophagy dysfunction in the pathogenesis of Parkinson's disease (Review).
    Han-Liang Dan, Shu-Er Liu, Yu-Jie Zhao, Zi-Fan Zhu, Hao-Gang Li, Yi-Xiang Huang, Mei Chen, Yi-Hui Zhang, Hui-Xin Ai, Xiao-Hui Huang, Hai-Yun Zhao, Zheng Liu, Pan Zou, Maslinda Musa.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α‑synuclein forming Lewy bodies. Emerging evidence highlights mitochondrial dysfunction as an important and early event in PD pathogenesis. Among the key regulators of mitochondrial quality control, PTEN‑induced kinase 1 (PINK1) plays a pivotal role by initiating mitophagy, the selective clearance of damaged mitochondria. Under physiological conditions, PINK1 is rapidly degraded, whereas mitochondrial depolarization stabilizes PINK1 on the outer mitochondrial membrane, where it recruits and activates Parkin, an E3 ubiquitin ligase, to promote mitophagy. Loss‑of‑function mutations in PINK1 also disrupt this process, leading to the accumulation of dysfunctional mitochondria, oxidative stress, abnormal calcium homeostasis and neuronal apoptosis. Furthermore, PINK1 deficiency has been shown to exacerbate α‑synuclein aggregation, impair synaptic transmission and activate neuroinflammatory pathways, collectively accelerating dopaminergic neurodegeneration. Therapeutic strategies aimed at restoring or enhancing PINK1‑mediated mitophagy through pharmacological activation, gene delivery or modulation of parallel pathways‑represent a promising avenue for PD intervention. Continued elucidation of the molecular functions of PINK1 will provide critical insights into mitochondrial homeostasis and novel therapeutic targets for PD.
    Keywords:  PINK1; Parkinson's disease; mitochondrial autophagy
    DOI:  https://doi.org/10.3892/mmr.2026.14069
  47. Cytokine Growth Factor Rev. 2026 Nov 07. pii: S1359-6101(26)00087-0. [Epub ahead of print]92 101540
    Cytosolic DNA sensing through the cGAS-STING pathway contributes to neuroinflammation and dopaminergic neuron loss in Parkinson's disease.
    Yiran Sun, Libo He, Quekun Peng.
      Current therapies for Parkinson's disease (PD) relieve symptoms but do not slow neurodegeneration. Chronic neuroinflammation driven by innate immunity is increasingly implicated in dopaminergic neuron loss, and the cytosolic DNA sensor cGAS and its adaptor STING are candidate mediators. cGAS-STING converts misplaced self- or pathogen-derived double-stranded DNA into type I interferon and NF-κB responses. We summarize the signaling cascade and its structural basis, and review evidence from post-mortem tissue, genetic studies and animal models that mitochondrial DNA leakage, lysosomal dysfunction and α-synuclein pathology activate cGAS-STING in microglia and astrocytes. We propose an Aging-BBB-virus-cGAS-STING hypothesis to explain delayed onset and selective nigral vulnerability. Finally, we evaluate natural compounds, autophagy enhancers and STING inhibitors, and argue that brain penetration and combination approaches will determine whether cGAS-STING inhibition becomes disease-modifying.
    Keywords:  CGAS; Neuroinflammation; Parkinson's disease; STING
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.101540
  48. bioRxiv. 2026 Oct 20. pii: 2026.10.18.759986. [Epub ahead of print]
    Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells.
    Luis Cedeño-Rosario, Queren A Alcantara, Nicole A Sierra, Praveena Prasad, Jillian Wright, Geanette Lam, Nimo Abdi, Jaide Florence, Alex J Bott, Katarina Heyden, Joshua C Youngs, Álvaro J Narbona-Pérez, Lorenzo Gastelum Mena, Monika A Makurath, Jesse N Velasco-Silva, Mi-Young Jeong, Sarah Fogarty, Gregory S Ducker, Jennifer Lippincott-Schwartz, Melanie R McReynolds, Jared Rutter.
      Metabolic state is tightly linked to cell fate, and expression of the mitochondrial pyruvate carrier (MPC), which imports pyruvate into mitochondria, is a robust marker of it. The transcriptional regulators that set metabolic state, however, remain poorly defined. In the liver, β-catenin is one of the determinants of metabolic zonation, and activating CTNNB1 mutations are frequent in hepatocellular carcinoma. Here we show that β-catenin regulates metabolic state in liver cancer cells. An unbiased CRISPR screen that uses endogenous MPC1 transcript abundance as the marker identifies CTNNB1 . Activating β-catenin pharmacologically or genetically reduces MPC1 and MPC2 transcript and protein levels, and MPC expression is also low in β-catenin-driven liver tumors in vivo. Beyond the MPC, β-catenin activation impairs assembly of respiratory Complexes III and IV, reduces mitochondrial DNA content and respiratory capacity, elongates mitochondrial networks and remodels the lipidome. Stable isotope tracing shows reduced entry of glucose- and lactate-derived carbon into the TCA cycle alongside increased oxidation of palmitate and oleate. These findings identify β-catenin as a regulator of metabolic state that drives a fuel switch from carbohydrate to fatty acid oxidation in liver cancer cells.
    DOI:  https://doi.org/10.64898/2026.10.18.759986
  49. Mol Med Rep. 2027 Jan;pii: 10. [Epub ahead of print]35(1):
    Mitochondrial LONP1: Linking structure and function to context‑dependent roles in disease (Review).
    Du Chen, Qifeng Li, Yuanxi Zhang, Zehua Zhang, Dengqiu Xu.
      Mitochondrial proteostasis is essential for maintaining organellar integrity, metabolic adaptation and cellular survival under physiological and stress conditions. Among mitochondrial quality control mechanisms, Lon peptidase 1 (LONP1) is an ATP‑dependent AAA+ serine protease localized predominantly in the mitochondrial matrix and plays a central role in the recognition and degradation of damaged or misfolded proteins. Recent structural, molecular and multi‑omics studies have expanded our understanding of LONP1 beyond proteolysis, implicating it in protein quality control, mitochondrial DNA maintenance, metabolic regulation and responses to oxidative and cellular stress. Increasing evidence also indicates that LONP1 functions are highly dependent on cellular and disease context, with both loss and gain of LONP1 activity associated with distinct pathological outcomes. The present review integrated recent structural and functional advances to establish a structure‑function framework for understanding how LONP1 coordinates proteolytic and chaperone‑like activities and how these functions are shaped by cellular and disease context. The present review further examined its roles in metabolic, neurodegenerative, reproductive, cardiovascular and malignant diseases, with particular emphasis on the context‑dependent consequences of LONP1 dysregulation and its emerging therapeutic potential. Finally, the present review highlighted unresolved questions concerning substrate recognition and specificity, the relative contributions of protease and chaperone‑like functions, disease‑specific directionality and the safety and feasibility of therapeutic modulation. These challenges need to be addressed to establish the functional and translational boundaries of LONP1.
    Keywords:  Lon peptidase 1; diseases1; mitochondrial quality control; oxidative stress; proteostasis
    DOI:  https://doi.org/10.3892/mmr.2026.14068
  50. Methods Mol Biol. 2027 ;3105 279-323
    Imaging of Organelle and Actin Cytoskeletal Morphology During Aging.
    Aeowynn J Coakley, Eric K F Donahue, Juri Kim, Maxim Averbukh, Gilberto Garcia, Ryo Higuchi-Sanabria, Kristopher Burkewitz.
      Aging is accompanied by progressive declines in cellular and organismal function that are tightly linked to structural and functional changes in subcellular organelles. In particular, age-associated remodeling of the actin cytoskeleton, mitochondria, and endoplasmic reticulum (ER) is increasingly recognized as a hallmark of cellular aging, and numerous standardized methods exist for visualization of organelles in live cells and animals. Caenorhabditis elegans specifically provides a powerful model for interrogating age-dependent organelle dynamics due to its optical transparency, short lifespan, genetic tractability, and conservation of aging pathways. Here, we present a comprehensive collection of optimized protocols for imaging and quantifying actin cytoskeletal organization, mitochondrial morphology, and ER structure across tissues and throughout adulthood in C. elegans. We describe genetically encoded fluorescent reporters, sample preparation strategies, and microscopy approaches tailored to each organelle and tissue, including wide-field and confocal imaging. In addition, we outline quantitative and semi-quantitative analysis pipelines, ranging from blinded manual scoring to automated image analysis workflows, that enable reproducible quantitative analysis of age-associated structural changes. Where appropriate, we discuss functional assays that complement imaging-based readouts and provide insight into organelle health. Together, these methods offer a practical and scalable framework for studying organelle structure-function relationships during aging.
    Keywords:  Actin cytoskeleton; Aging; Caenorhabditis elegans; Endoplasmic reticulum; Fluorescence imaging; Mitochondria; Organelle morphology
    DOI:  https://doi.org/10.1007/978-1-0716-5703-4_16
  51. Redox Biol. 2026 Nov 10. pii: S2213-2317(26)00479-9. [Epub ahead of print]98 104480
    Mitofusin-2 deficiency impairs neutrophil maturation and reduces non-glucose substrate utilization.
    Wei Liu, Liang Hu, Yunfeng Chen, Meng Zhao, Zhichao Fan.
      Neutrophils are essential for innate immunity, and they must mature properly to maintain immune homeostasis. Although mitochondrial dynamics influence hematopoietic fate, how specific fusion machinery controls neutrophil development in vivo remains poorly understood. Although our earlier study suggested a role for mitofusin-2 (MFN2) in neutrophil development using cell line models, the need for MFN2 during primary hematopoietic neutrophil maturation and the associated metabolic changes have remained unclear. Using a hematopoietic-specific knockout model (MFN2flox/floxVav-iCre+/-), we found that MFN2 deletion results in the accumulation of immature neutrophils in both the bone marrow and peripheral blood. Surprisingly, MFN2 deficiency was associated with increased mitochondrial membrane potential in immature neutrophils. Super-resolution imaging showed altered mitochondrial morphology characterized by reduced elongation. Functional metabolic profiling using single-cell energetic metabolism by profiling translation inhibition (SCENITH) showed that, despite preserved overall translational activity and mitochondrial contribution, MFN2-deficient neutrophils exhibited selectively reduced utilization of non-glucose substrates, reflected by decreased fatty acid and amino acid oxidation (FAO and AAO)-supported translation in immature and mature neutrophils. Together, these findings identify an association between MFN2 deficiency, impaired neutrophil maturation, and reduced utilization of non-glucose substrates, supporting a potential link between mitochondrial substrate use and terminal neutrophil development.
    Keywords:  Fatty acid and amino acid oxidation; Mitochondria; Mitofusin; Neutrophil maturation; Neutrophils; Single-cell energetic profiling
    DOI:  https://doi.org/10.1016/j.redox.2026.104480
  52. Anal Chem. 2026 Nov 10. 98(44): 30398-30405
    A Reliable Ratiometric Fluorescent Probe for the Quantification of Mitochondrial Peroxynitrite in Cells and Tissues.
    Xiaodi Rong, Caiyun Liu, Bing Xue, Fengli Hou, Zhongpeng Wang, Wei Shu, Baocun Zhu.
      Peroxynitrite (ONOO-) is a reactive oxygen species predominantly generated in mitochondria. Its concentration-dependent dynamics exhibit complex bidirectional effects, making quantitative measurement essential for understanding its pathological roles. Despite advances in fluorescent probes for ONOO- imaging, design limitations and interference from complex cellular environments still compromise detection reliability. Herein, we report the first reliable ratiometric fluorescent probe RDC for quantitative detection of ONOO- in mitochondria. Under single-wavelength excitation, the probe exhibits two emission peaks at 563 nm and 690 nm. Upon reaction with ONOO-, the 690 nm signal remains constant as an internal reference, while the 563 nm signal increases significantly, allowing the ratio (F563/F690) to achieve quantitative detection. The probe exhibits excellent selectivity and high sensitivity (LOD = 96 nM). Cell imaging reveals a linear relationship between the ratiometric signal and exogenous ONOO- concentration, validating its quantitative capability in living cells. Moreover, during pyroptosis, the probe reveals a marked increase in mitochondrial ONOO- levels, which is reversed by a pyroptosis inhibitor, indicating ONOO- as a key effector in pyroptosis. The probe also enables ONOO- detection in tissue samples, demonstrating its potential in complex biological systems. This probe serves as a reliable tool for quantifying mitochondrial ONOO- in cells and tissues and for studying its roles in pyroptosis and related diseases.
    Keywords:  fluorescence imaging; mitochondria; peroxynitrite; pyroptosis; quantitative detection
    DOI:  https://doi.org/10.1021/acs.analchem.6c03303
  53. Cells. 2026 Nov 07. pii: 2031. [Epub ahead of print]15(21):
    Mitochondrial Morphology and TOMM20/TIMM44 Abundance During Prolonged HEK293 Cell Culture Under Different Glucose and Medium-Replacement Conditions.
    Kiyoharu Kawakami, Mirai Koike, Nozomi Ito, Rei Watanabe, Takahiro Tsukimura, Kazuhiko Nakadate.
      Glucose availability is essential for cellular metabolism and maintaining mitochondrial homeostasis. However, the effects of sustained changes in glucose availability on mitochondrial protein abundance and morphology remain unclear. In this study, we examined the mitochondrial responses to different glucose concentrations and medium replacement conditions. HEK293 cells were cultured for 4 days in standard or high-glucose medium without medium replacement. TOMM20 and TIMM44 abundance was evaluated using immunofluorescence and Western blotting, and mitochondrial morphology was assessed using transmission electron microscopy. The mitochondrial cross-sectional area and density were quantified. Glucose concentrations and medium pH were monitored throughout the culture period. In a separate experiment, the culture medium was replaced every 24 h. Without medium replacement, high-glucose culture was associated with greater TOMM20 and TIMM44 abundance and larger mitochondria than standard-glucose culture, whereas mitochondrial density did not differ significantly. With daily medium replacement, differences in TOMM20 and TIMM44 abundance were no longer detected, and mitochondrial size did not differ significantly between the glucose conditions. Moreover, mitochondrial density did not differ significantly between the glucose conditions. These findings indicate that mitochondrial morphology and TOMM20/TIMM44 abundance during prolonged culture are associated with both the initial glucose concentration and subsequent changes in the extracellular culture environment.
    Keywords:  HEK293 cells; TIMM44; TOMM20; extracellular environment; glucose availability; medium replacement; mitochondrial morphology; mitochondrial protein import; mitochondrial remodeling; transmission electron microscopy
    DOI:  https://doi.org/10.3390/cells15212031
  54. Prog Biophys Mol Biol. 2026 Nov 13. pii: S0079-6107(26)00085-4. [Epub ahead of print] 101968
    DNMT1-II: Emerging extranuclear functions and their significance in health and disease.
    K Naga Mohan.
      DNA methyltransferase 1 (DNMT1) in mammals is primarily investigated for a long time in the context of post-replicative maintenance methylation of nuclear DNA and gene regulation. Although in certain cell types and developmental stages, DNMT1 is detected outside the nucleus (cytoplasm, mitochondria, etc.), the data is either mostly emerging or equivocal. For instance, DNMT1 relocation to cytoplasm or mitochondria and differences in the levels of mitochondrial DNA methylation have been associated with some neurodegenerative disorders and cancer-promoting agents. However, the presence of methylation in mitochondrial DNA and DNMT1's localization to mitochondria itself is quite debated. This review summarizes our current understanding on cytoplasmic factors governing subcellular localization of DNMT1, stability and influence on (i) genome-scale and gene-specific hypomethylation, (ii) mRNA methylation and stability, (iii) microtubule dynamics and (iv) methylation of mitochondrial DNA and its effects. Some of these roles appear to be independent of its catalytic activity, as in the case of regulation of a subset of nuclear genes. Future studies aimed at detailed understanding of the mechanisms of cytoplasmic and mitochondrial localization, and their influence on cellular physiology help clarify, consolidate and expand the role of DNMT1 in normal development, health and disease.
    Keywords:  Cancer; Cytoplasmic localization; Cytoskeleton; DNMT1; Early development; Mitochondrial DNA methylation; Mitochondrial DNMT1; Neurodegenerative disease; RNA methylation
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.101968
  55. Int J Mol Sci. 2026 Nov 03. pii: 9837. [Epub ahead of print]27(21):
    Restoring Bioenergetics in the Traumatized Eye: The Emergence of Mitochondrial Implantation as a Treatment for Acute Ocular Injury.
    Emma Peveri, Daniella Beiner, Andrew J W Huang, Jian-Xing Ma, Amish Asthana, Anthony Atala, Giuseppe Orlando, Yuanyuan Zhang.
      Acute ocular injuries-such as chemical burns, ischemic insults, and mechanical trauma-frequently lead to irreversible vision loss by triggering rapid intracellular adenosine triphosphate (ATP) depletion, mitochondrial calcium overload, severe oxidative stress, and profound mitochondrial dysfunction. Current clinical management primarily focuses on suppressing inflammation and preventing secondary infection, but it fails to address the underlying bioenergetic collapse that drives cellular degeneration. While stem cell and extracellular vesicle therapies have been widely investigated, direct mitochondrial transplantation has recently emerged as a novel strategy for metabolic rescue. This review evaluates the therapeutic potential of exogenously administered mitochondria to mitigate mitochondrial dysfunction and acute trauma in the eye. Emerging preclinical studies demonstrate that transplanted mitochondria can be internalized by selected ocular cell types, conferring short-term cytoprotection, preserving retinal ganglion cell viability, and accelerating corneal epithelial repair. However, robust evidence regarding long-term mitochondrial integration, functional fusion, durable metabolic rescue, and clinical efficacy remains limited. Despite critical challenges in delivery, stability, and dosing, mitochondrial transplantation represents a promising frontier in regenerative ophthalmology that directly targets bioenergetic failure to preserve vision.
    Keywords:  acute ocular injury; bioenergetic failure; metabolic rescue; mitochondrial transplantation; ocular trauma
    DOI:  https://doi.org/10.3390/ijms27219837
  56. Front Immunol. 2026 ;17 1883589
    Mitochondrial dysfunction in asthma: damage signals sustain airway inflammation and remodeling.
    Yuqian Zhang, Lujia Liu, Mengdi Shi, Yiqiao Li, Suning Mu, Yan Wang, Youpeng Wang.
      Asthma is a heterogeneous disease characterized by chronic airway inflammation and airway remodeling. Growing evidence suggests that mitochondrial dysfunction is not only a consequence of inflammatory injury but may also contribute to disease persistence and progression. In asthma, mitochondrial redox balance, energy metabolism, Ca2+ homeostasis, dynamics, biogenesis, and quality control can all become dysregulated. These abnormalities are interconnected and can alter mitochondrial energy supply, structural integrity, and quality maintenance. Mitochondrial damage can increase mitochondrial reactive oxygen species, promote the mislocalization of mitochondrial nucleic acids, alter membrane lipid oxidation and remodeling, and induce the release of mitochondrial proteins and other components. These changes generate diverse mitochondria-derived damage signals that can regulate inflammation-related gene transcription, nucleic acid sensing, and inflammasome activation. More broadly, mitochondrial abnormalities also alter immune cell function, airway epithelial repair, smooth muscle cell accumulation, and extracellular matrix production. Together, these effects may contribute to persistent airway inflammation and airway remodeling. This review summarizes the major forms of mitochondrial dysfunction in asthma. It also examines how these abnormalities generate mitochondria-derived damage signals, engage inflammatory sensing, and alter immune and airway structural cell functions.
    Keywords:  airway inflammation; airway remodeling; asthma; innate immune sensing; mitochondria-derived damage signals; mitochondrial dysfunction; mitochondrial oxidative stress; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fimmu.2026.1883589
  57. Cell. 2026 Nov 12. pii: S0092-8674(26)01272-9. [Epub ahead of print]189(23): 7593-7615.e13
    An integrative single-cell epigenomic atlas annotates the regulatory genome of the adult mouse brain.
    Zhaoning Wang, Songpeng Zu, Ethan J Armand, Timothy H Loe, Jonathan A Rink, Wanying Wu, Yang Xie, Lei Chang, Chenxu Zhu, Nicholas D Johnson, Jasper Lee, Jackson K Willier, Silvia Cho, Stella Cao, Ariana S Barcoma, Nora Emerson, Hanqing Liu, Kangli Wang, Bharath Saravanan, Guojie Zhong, Zane A Gibbs, Xiaomeng Gao, Sunan Xu, David Guo, Zhuowen Tu, Yang E Li, Joseph R Ecker, M Margarita Behrens, Bing Ren.
      Histone modifications underpin the cell-type-specific gene regulatory programs that drive the remarkable cellular diversity of the mammalian brain. Here, we jointly profiled four histone modifications and the transcriptome in 2.5 million nuclei from the adult mouse brain. By integrating these data with chromatin accessibility, DNA methylation, and three-dimensional genome organization, we constructed a unified epigenomic atlas spanning over 100 brain cell subclasses and assigned active, primed, and repressive chromatin states across 81% of the genome. Active chromatin states marked by combinatorial histone modifications better nominate candidate enhancers with functional support than chromatin accessibility alone, while H3K27me3- and H3K9me3-marked chromatin states delineate distinct modes of cell-type-specific gene repression. Finally, this multimodal resource enables the development of deep learning models that predict cell-type-specific epigenomic features and gene expression from DNA sequence, providing a comprehensive framework for annotating the brain regulatory genome and interpreting non-coding disease risk variants.
    Keywords:  Paired-Tag; brain enhancers; chromatin state; cis-regulatory elements; histone modification; neuronal gene regulation; repressive elements; sequence-to-function modeling; single-cell epigenomics; transposable elements
    DOI:  https://doi.org/10.1016/j.cell.2026.10.022
  58. Yale J Biol Med. 2026 Sep;99(3): 498-505
    Mitochondrial Regulation of Brown Adipose Tissue During Hypoxia in Rodents.
    Matthew E Pamenter, Hang Cheng.
      Brown adipose tissue (BAT) is a mitochondria-rich thermogenic organ that supports nonshivering thermogenesis through uncoupling protein 1-mediated proton leak. Because this process requires exceptionally high rates of oxidative metabolism, BAT function is critically dependent on oxygen availability. Environmental hypoxia therefore imposes a major energetic challenge, forcing organisms to balance thermogenic heat production against preservation of oxygen and adenosine triphosphate for essential cellular functions. This mini-review examines how BAT mitochondria respond to hypoxia in hypoxia-intolerant laboratory rodents vs hypoxia-tolerant social African mole rats, with a particular focus on mitochondrial regulation, reversibility of suppression, and implications for metabolic disease. In laboratory rodents, BAT suppression is largely constraint driven and associated with hypoxia-inducible factor-dependent transcriptional reprogramming, impaired β-adrenergic signaling, reduced uncoupling protein 1 expression, altered lipid metabolism, mitochondrial fragmentation, diminished oxidative phosphorylation, and increased reactive oxygen species production. These changes are often maladaptive and accompanied by persistent mitochondrial dysfunction. In contrast, social African mole rats exhibit coordinated and reversible metabolic suppression in which BAT thermogenesis is actively downregulated to match reduced oxygen availability. This adaptive response preserves mitochondrial integrity through controlled reductions in oxidative phosphorylation, reversible suppression of uncoupling protein 1, regulated mitochondrial fission, and avoidance of excessive mitophagy or oxidative damage. These divergent strategies provide a valuable comparative framework for understanding mitochondrial control of energy expenditure in hypoxia. Importantly, many mechanisms observed in hypoxia-intolerant BAT parallel mitochondrial dysfunction in obesity and type 2 diabetes, highlighting BAT mitochondria as potential therapeutic targets for metabolic disease and hypoxic injury.
    Keywords:  African mole rat; hypometabolism; hypoxia-tolerant; naked mole-rat; nonshivering thermogenesis; thermoregulation; uncoupling protein 1
    DOI:  https://doi.org/10.59249/ECCQ1130
  59. Cell Death Dis. 2026 Aug 18. pii: 964. [Epub ahead of print]17(1):
    TSPO: a conserved mitochondrial conduit linking cellular homeostasis to disease.
    Asif Rasheed, Eva Sidlauskaite, Michelangelo Campanella.
      The translocator protein (TSPO) is an evolutionarily conserved 18 kDa protein localised to the outer mitochondrial membrane and increasingly recognised as a multifunctional regulator of cellular homeostasis. Although initially identified as the peripheral benzodiazepine receptor, TSPO has since been implicated in a range of mitochondrial processes. This review integrates current evidence on TSPO function across evolution and in mammalian systems, with a focus on its interactions with mitochondrial gatekeeping proteins. TSPO has been implicated in regulating cholesterol transport, redox homeostasis, calcium (Ca2+) signalling, and mitochondrial quality control. Mechanistically, TSPO has been proposed to modulate Ca2+ flux and reactive oxygen species (ROS) production through VDAC1-associated pathways, linking mitochondrial dynamics to cellular stress responses. We also evaluate the context-dependent effects of TSPO ligands across disease models. Collectively, these findings position TSPO as a potential integrator of mitochondrial signalling with important implications for understanding disease mechanisms and therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41419-026-09126-w
  60. J Biol Chem. 2026 Nov 12. pii: S0021-9258(26)02614-1. [Epub ahead of print] 113742
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Isaac Johnson, Ushodaya Mattam, Omar Chaudhry, Karleigh Porter, Saanvi Maadaadi, Dina Secic, Megan E Bischoff, Karthickeyan Chella Krishnan, Rhett A Kovall, John T Cunningham, Maria F Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance on oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that inducing genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a key chaperone for COX copper cofactor assembly, and by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is reversed by copper supplementation. Expression of an SLC25A3 isoform A variant that is equivalent to a variant in isoform B that exclusively transports copper also rescues myotube viability. Taken together these data support a model wherein SLC25A3 is critical for survival in mature myotubes, likely due to its role in providing copper to COX.
    Keywords:  copper; copper transport; cytochrome c oxidase (Complex IV); myogenesis; skeletal muscle
    DOI:  https://doi.org/10.1016/j.jbc.2026.113742
  61. Cell Mol Neurobiol. 2026 Aug 12. pii: 162. [Epub ahead of print]46(1):
    Early Metabolic Rewiring and Mitochondrial Remodeling in Response to Mitochondrial Impairment in a Rotenone Model of Parkinson's Disease.
    Alissa Costantini, Marcella Bonanomi, Gessica Sala, Assunta Virtuoso, Anastasia Rella, Martina Motto, Claudio Gioia, Gabriele Taverna, Francesca Martorana, Federica Aprea, Matteo Formenti, Michele Papa, Carlo Ferrarese, Daniela Gaglio, Anna Maria Colangelo.
      Mitochondrial dysfunction is a central pathogenic mechanism in Parkinson's disease (PD), yet early mitochondrial events linking respiratory impairment to neuronal vulnerability remain incompletely defined. Here, we investigated the impact of acute and chronic exposure to subtoxic and toxic doses of the mitochondrial Complex I inhibitor rotenone on oxidative stress, mitochondrial bioenergetics/metabolism, and mitochondrial dynamics in primary cortical neurons. Using live-cell imaging, bioenergetics and metabolomic profiling, we show that nanomolar concentrations of rotenone rapidly induce accumulation of reactive oxygen species (ROS), lipid peroxidation, and loss of mitochondrial membrane potential preceding overt neuronal death. Notably, high-content morphometric analysis revealed that even subtoxic doses of rotenone trigger an early structural remodeling characterized by mitochondrial network fragmentation into small spherical puncta (0.5-3 μm) and localized organelle swelling at both neuritic and synaptic levels. Instead, at the molecular level, whole-cell biochemical degradation of mitochondrial remodeling proteins, suppression of regulated, physiological fission-fusion cycling and accumulation of the autophagy adaptor SQSTM1/p62, indicative of defective quality control, fully manifest only at higher, toxic rotenone concentrations. Furthermore, subtoxic doses elicit widespread metabolic alterations including persistent redox imbalance, impaired glutathione (GSH) biosynthesis, and downregulation of anabolic processes such as folate/one-carbon and amino sugar metabolism. Collectively, our findings newly reveal that localized mitochondrial morphometric remodeling and metabolic pathway rewiring represent early, interconnected adaptive responses to complex I impairment, contributing to the baseline thresholds of neuronal vulnerability in PD models.
    Keywords:  Metabolite set enriched analysis (MSEA); Metabolomics; Mitochondrial bioenergetics; Mitochondrial dynamics; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s10571-026-01794-8
  62. J Clin Med. 2026 Oct 26. pii: 8336. [Epub ahead of print]15(21):
    A Homozygous Missense Variant in DCLK2 as a Potential Modifier of Disease Severity in PDHA1-Associated Primary Pyruvate Dehydrogenase Complex Deficiency.
    Dalal A Al-Mutairi, Fahad K Al-Mutairi, Athbi A Naief, Trevor F Batten.
      Introduction: Primary pyruvate dehydrogenase complex deficiency (PDCD) is a genetically heterogeneous mitochondrial disorder with marked clinical variability. PDHA1 is the most common cause of PDCD, but additional genetic factors may contribute to disease severity. Methods: A consanguineous family with two affected male siblings with clinical features of PDCD underwent clinical and genetic investigation. Whole-exome sequencing (WES), X-chromosome analysis, genome-wide autozygosity mapping, and segregation analysis were performed. Clinical, biochemical, neuroimaging, ophthalmological, and longitudinal medical records were reviewed. In silico analyses were performed for the identified variants. Results: Both siblings presented with neonatal lactic acidosis and severe neurological disease, including Leigh brain abnormalities, followed by progressive neuromuscular and multisystem manifestations. WES identified a novel hemizygous PDHA1 missense variant (c.754C>G; p.Leu252Val; rs1555934383), consistent with X-linked inheritance and providing the primary genetic explanation for PDCD. Autozygosity mapping identified a shared identical-by-descent interval on chromosome 4, within which a novel homozygous DCLK2 missense variant (c.101G>A; p.Ser34Asn) was identified. The variant was present in both affected siblings and segregated within the family. Despite sharing both variants, the siblings showed marked differences in disease severity. The younger sibling developed severe neurological and respiratory complications and died in childhood following a surgical procedure, whereas the older sibling survived into late adolescence but developed substantial neurological, metabolic, respiratory, and ophthalmological complications, including profound visual impairment and bilateral optic atrophy. Conclusions: The PDHA1 variant represents the primary genetic cause of PDCD, while the co-segregating homozygous DCLK2 variant is a candidate modifier of disease severity. Its localization within the shared IBD interval and biological relevance to neuronal stress responses support this hypothesis and suggest that DCLK2 may contribute to the phenotypic variability and severity of PDHA1-associated disease.
    Keywords:  DCLK2; Leigh syndrome; PDHA1; ataxia; consanguinity; lactic acidosis; neuromuscular degeneration; ophthalmoplegia; primary pyruvate dehydrogenase complex deficiency
    DOI:  https://doi.org/10.3390/jcm15218336
  63. Orphanet J Rare Dis. 2026 08 13. pii: 412. [Epub ahead of print]21(1):
    Expanding the cardiac phenotype of homozygous PPA2 variants: insights from a large Finnish family.
    Krista Heliö, Aurelia Ahokas, Sonja Sulkava, Mikko I Mäyränpää, Katriina Aalto-Setälä, Sini Weckström, Liliya Euro, Juha Koskenvuo, Anu Suomalainen, Tiina Heliö, Tiina Ojala.
       BACKGROUND: Cardiomyopathies in children associate with significant morbidity and mortality. PPA2 deficiency is a rare mitochondrial disorder linked to sudden cardiac death in children and adolescents. Most reported cases are post-mortem, with limited data on surviving individuals. To expand the phenotypic understanding of PPA2-related disease, we describe the cardiac features of nine previously unreported homozygous carriers of the PPA2 c.380G > T, p.(Arg127Leu) variant.
    METHODS: This study included 23 individuals (22 living, one deceased) from a large Finnish family. All participants underwent genetic testing. Twenty individuals were interviewed by telephone, 16 underwent cardiac evaluation, and hospital records were reviewed for six participants.
    RESULTS: Nine individuals homozygous for the PPA2 p.(Arg127Leu) variant were identified. Two 15-year-old males experienced severe cardiac events following alcohol exposure: one suffered sudden cardiac death, while the other developed fulminant myocarditis. In the deceased male, a recent respiratory infection also preceded the fatal event. The remaining seven homozygotes, aged 24 to 81 years, reported no cardiac symptoms, had limited alcohol exposure restricted to communion, and showed no pathological findings on cardiac evaluation. No participants displayed neurological symptoms attributable to PPA2-related disease. All 14 heterozygous carriers were asymptomatic.
    CONCLUSIONS: PPA2 deficiency represents a rare but potentially fatal cause of sudden cardiac death or fulminant myocarditis, particularly in the setting of alcohol exposure. Our findings indicate that individuals homozygous for the PPA2 c.380G > T, p.(Arg127Leu) variant may remain asymptomatic into adulthood.
    Keywords:  Cardiomyopathy; Mitochondrial diseases; PPA2; Sudden cardiac death
    DOI:  https://doi.org/10.1186/s13023-026-04523-y
  64. Neurogenetics. 2026 Nov 07. pii: 88. [Epub ahead of print]27(1):
    Bioinformatic analysis of ACAD9 genetic variability.
    Mateus Laranjeira, Luís Ferreira, Luísa Azevedo, Brígida R Pinho, Jorge M A Oliveira, Maria Marchese, Filippo M Santorelli, Cristina Pereira, Laura Vilarinho, Célia Nogueira.
      Mitochondrial diseases (MD) are a heterogeneous group of disorders with a diagnostic rate often below 50%, mostly due to the difficulty of interpreting Variants of Unknown Significance (VUS). ACAD9 is a nuclear gene that encodes a mitochondrial protein involved in fatty acid β-oxidation and the assembly of respiratory complex I. This study aimed to refine the classification of ACAD9 missense VUS through an integrative computational approach combining in silico, evolutionary and structural analysis. A gene-specific dataset of missense pathogenic, benign and uncertain significance variants was curated from public databases (HGMD, ClinVar, GnomAD, UniProt or LOVD) and in-house sequencing data. Thirty-five in silico pathogenicity predictors were retrieved from the dbNSFP v5.3 and benchmarked using the datasets. Predictor performance was evaluated using 10 metrics and the top predictors were integrated with evolutionary conservation (ConSurf), structural modelling (PyMOL, HOPE) and thermodynamic stability analysis (FoldX) to re-evaluate 17 VUS. Predictor performance for ACAD9 variants varied significantly. Because no statistically significant differences were detected among the ten highest-ranked predictors, ClinPred, MetaRNN, PHACTboost, MutationTaster and REVEL were selected as the top stability-informed predictors. The integrative predictive and structural analysis reclassified 8 variants as "likely pathogenic" and 5 as "likely benign", while 4 remained classified as VUS due to conflicting evidence. A gene-specific, multi-layered computational strategy substantially improves VUS classification in ACAD9. These in silico findings provide strong, albeit non-definitive, evidence to guide diagnostic efforts. It should be complemented with functional validation, which remains essential to confirm pathogenicity.
    Keywords:  ACAD9; Bioinformatical analysis; Mitochondrial diseases; Variants of unknown significance
    DOI:  https://doi.org/10.1007/s10048-026-00957-5
  65. Mitochondrion. 2026 Nov 10. pii: S1567-7249(26)00125-X. [Epub ahead of print] 102235
    Miro1 and mitochondrial dysfunction in Huntington's disease: Emerging mechanistic links and therapeutic perspectives.
    Sanjeevan Gupta, Snehashis Mandal, Priti Dipa, Neha, Khadga Raj Aran.
      Huntington's disease (HD) is a chronic, hereditary, and ultimately fatal neurological disorder that is transmitted in an autosomal dominant manner through an abnormal expansion of trinucleotide CAG repeats in the huntingtin gene, which encodes a mutant protein with an expanded polyglutamine tract. HD occurs in approximately 5-10 individuals per 100,000 people worldwide, and is associated with increasing motor dysfunction, cognitive decline and profound neuropsychiatric disorder with a selective vulnerability of the striatal medium spiny neurons. Early and integral to HD pathogenesis is mitochondrial dysfunction, before the onset of clinical symptoms and obvious neurodegeneration. In the context of mitochondrial regulation, the atypical Rho GTPase Miro1 has emerged as a key regulator that integrates mitochondrial motility, calcium sensing, fusion/fission dynamics, and mitophagy. Mutant huntingtin interferes with the assembly of motor-adaptor complexes containing Miro1, mitochondrial transport along axons, the regulation of motility arrest by Ca2+-sensing mechanisms, and the degradation of Miro1 by PINK1/Parkin, leading to impaired mitochondrial quality control and propagation of bioenergetic stress. These converging abnormalities are linked to molecular pathology characterised by mitochondrial mislocalization, insufficient mitochondrial turnover and synaptic failure resulting in selective degeneration of HD neurons. A study using zQ175 HD model mice demonstrated that Miro1overexpression partially rescued impaired anterograde mitochondrial transport in striatal neurons. However, this gain-of-function rescue does not establish endogenous Miro1 deficiency or demonstrate that Miro1 dysfunction is a primary driver of HD pathology. This review critically analyses the molecular mechanisms underlying mitochondrial dysfunction in HD, particularly Miro1, its implications for HD neurodegeneration, and its therapeutic potential.
    Keywords:  Huntington's disease; Miro1; Mitochondrial dysfunction; Mitochondrial trafficking; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.mito.2026.102235
  66. Nat Commun. 2026 10 13. pii: 11577. [Epub ahead of print]17(1):
    Mitochondria-localized circRNA BRAKE restrains adipogenesis under nutrient overload by disrupting ATP synthase assembly in mice.
    Yanrui Huang, Tianxin Zhu, Xiaosi Hong, Yulin Yang, Jianyou Liao, Jiayu Liu, Chunni Li, Wei Wang, Sifan Chen, Phei Er Saw, Yanbing Li, Haipeng Xiao, Meng Ren, Shicheng Su, Yanrui Huang.
      Impaired adipogenesis contributes to obesity-associated metabolic disorders, in which mitochondrial dysfunction plays an important role. Emerging evidence suggests that mitochondria-localized circular RNAs (circRNAs) influence mitochondrial function; however, whether they regulate adipogenesis and systemic metabolism is unclear. By profiling circRNAs in mitochondria isolated from the white adipose tissue (WAT) of obese male mice, we observe an upregulation of Birc6-circRNA Repressing Adipogenesis and Krebs-cycle Energy (BRAKE) in mitochondria. In vivo, adipocyte-specific circRNA BRAKE knockdown in male mice reduces body weight, restricts fat expansion, and improves insulin sensitivity. In vitro studies show that circRNA BRAKE inhibits adipogenesis. Mechanistically, circRNA BRAKE binds ATP5A and disrupts ATP synthase assembly, thereby reducing ATP production and mTORC1 signaling and suppressing adipogenesis. In omental WAT (oWAT) of patients with obesity, mitochondrial circRNA BRAKE levels are elevated and inversely correlated with mitochondrial bioenergetic function. Collectively, our data identify a mitochondria-localized circRNA that regulates energy metabolism and adipogenesis, suggesting that circRNA BRAKE may represent a potential therapeutic target for obesity-related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-026-78378-z
  67. Sci Rep. 2026 ;16 36122
    The hidden burden of structural variants in neurodegenerative and neuromuscular disorders.
    Gavin Monahan, Carolin K Scriba, Jasmine Chew, Jessica Baker, Christina Vo, Chiara Folland, Jevin Parmar, Samantha Bryen, Lein Dofash, Shelby Mullin, Audrey V Rick, Elyshia McNamara, Joseph Donnelly, Tanavi Sharma, Daniella H Hock, Tegan Stait, Matthew J Welland, David R Thorburn, Harry Fraser, Miriam Rodrigues, Nikki Gelfand, Mark Davis, Rebecca Gooding, Michael Farrell, Catherine Kiraly-Borri, Twinkle Ghia, Richard Warne, Carolyn F Orr, David A Stroud, Wai Yan Yau, Anita Cairns, Catriona McLean, Michael Fahey, Richard Roxburgh, Phillipa J Lamont, Gianina Ravenscroft.
      Neurodegenerative and neuromuscular disorders are genetically heterogeneous, and many patients remain without a genetic diagnosis after multiple rounds of clinical gene panels or exome sequencing. These approaches often fail to detect structural variants (SVs), contributing to missed diagnoses. We investigated 286 individuals with neurodegenerative or neuromuscular diseases who previously received an uninformative report from diagnostic testing. Short-read genome sequencing (srGS) was used for single nucleotide variant/indel, copy number variant, and SV calling with variant prioritisation in seqr. Findings were corroborated by long-read sequencing, orthogonal validation (PCR/MLPA/Sanger), transcriptomics, and proteomics. We also assessed the utility of Talos (an automated variant prioritisation tool) to find clinically relevant SVs. Overall, 65/286 cases (22.7%) were solved; SVs accounted for 11/65 solved cases (16.9%); four of these would not be detectable with targeted panel or exome sequencing. We describe 10 illustrative diagnoses spanning diverse SV classes: an intronic interspersed duplication disrupting SPAST (SPG4); SVs supporting phenotype expansions associated with SPG11 (neuronal ceroid lipofuscinosis), heterozygous large in-frame deletions in TTN (distal arthrogryposis), and SPTAN1 (autosomal-dominant hereditary spastic paraplegia); an intergenic balanced translocation downstream of FOXG1; and a pathogenic SVA insertion in TAF1 detected as breakends in srGS. Talos prioritised seven of these 10 SV diagnoses. Here, we show SVs contribute substantially to diagnoses in neurogenetic disease cohorts and can evade panel/exome pipelines due to intronic breakpoints, balanced rearrangements, microhomology, and partial-exon events. srGS combined with automated reanalysis can shorten diagnostic timelines and improve diagnostic equity through a single, genome-wide test, although the clinical interpretation of SVs remains a significant challenge.
    Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-69714-w.
    Keywords:  Arthrogryposis; Charcot-Marie-Tooth disease; Dementia; Dystonia; Lipofuscinosis; Neurodegenerative disorders; Neuromuscular disorders; Neuropathy; Spastic paraplegia; Structural variants; Titinopathy; Whole genome sequencing
    DOI:  https://doi.org/10.1038/s41598-026-69714-w
  68. Mitochondrion. 2026 Nov 09. pii: S1567-7249(26)00123-6. [Epub ahead of print] 102233
    B30Research advances on mitochondrial non-coding RNAs in cardiovascular diseases: Mechanisms, applications, and challenges.
    Youhua Tong, Sichun Liu, Huaiyuan Hu, Heng Tang.
      Mitochondrial non-coding RNAs (mt-ncRNAs) are non-protein-coding RNAs that are either encoded by the mitochondrial genome or transcribed from the nuclear genome and subsequently localized to mitochondria. Based on genomic origin, they fall into two groups: nuclear genome (nDNA)-encoded ncRNAs that are transported into mitochondria, and mitochondrial genome (mtDNA)-encoded ncRNAs that act predominantly within mitochondria, with only a few members exported to the nucleus, cytosol, or extracellular space. Current evidence indicates that mt-ncRNAs play critical roles in cardiovascular diseases through regulation of mitochondrial genome stability, energy metabolism, oxidative stress responses, and calcium homeostasis. This review examines the classification, functional mechanisms, and clinical potential of mt-ncRNAs, with particular emphasis on the genomic-origin distinction between mtDNA-encoded and nuclear-encoded categories. It further synthesizes emerging clinical evidence, including circulating biomarker validation and early-phase trials of mitochondria-targeted delivery systems, and discusses current technical challenges and future research directions. A comprehensive understanding of mt-ncRNA functional mechanisms may facilitate the development of innovative strategies for cardiovascular disease diagnosis and treatment.
    Keywords:  Biomarkers; Cardiovascular disease; Mitochondrial dysfunction; Mt-ncRNAs
    DOI:  https://doi.org/10.1016/j.mito.2026.102233
  69. Int J Mol Sci. 2026 Nov 06. pii: 9949. [Epub ahead of print]27(21):
    Mitochondrial DNA Abnormalities in Idiopathic Inflammatory Myopathies: Innate Immune Signaling and Therapeutic Prospects.
    Guanyuan Wang, Yurui Wang, Xinran Wang, Karl J A McCullagh, Aijing Liu.
      Mitochondrial DNA (mtDNA) encodes essential components of oxidative phosphorylation and can stimulate innate immunity when released from mitochondria. Its genetic and immunological functions provide a rationale for investigating mtDNA abnormalities in idiopathic inflammatory myopathies (IIMs), where muscle dysfunction and inflammation coexist. Large-scale deletions and depletion have been documented in inclusion body myositis and polymyositis with mitochondrial pathology, while dermatomyositis studies reveal regional depletion and oxidative modifications in distinct biological compartments. These findings raise the possibility that mtDNA abnormalities contribute to both impaired mitochondrial function and inflammatory signaling. This review integrates subtype-specific findings with mechanistic studies of mtDNA release, DNA sensing, and inflammasome activation in IIM-related and non-IIM systems. It evaluates the evidence for mtDNA-based biomarkers and therapies targeting mitochondrial injury or downstream inflammation. The reported clinical benefits do not establish mtDNA-specific therapeutic effects. Defining how mitochondrial genome abnormalities and inflammatory signaling interact within each subtype is a priority for biomarker validation and therapeutic research.
    Keywords:  NLRP3 inflammasome; TLR9; biomarkers; cGAS–STING pathway; idiopathic inflammatory myopathies; mitochondrial DNA; therapeutic strategies
    DOI:  https://doi.org/10.3390/ijms27219949
  70. Fluids Barriers CNS. 2026 Aug 14. pii: 125. [Epub ahead of print]23(1):
    Mitochondria and blood-brain barrier dysfunction: a promising target for cerebrovascular disorders.
    Dominick Cicala, Werner J Geldenhuys, Enrique Carerra, Maryam Maghareh, A S M Roknuzzaman, Rapty Sarker, Jason D Huber.
      The blood-brain barrier (BBB) functions as a highly selective regulatory system governing molecular transport between systemic circulation and the central nervous system. The maintenance of this strict permeability relies on the continuous, high-energy interactions of the neurovascular unit (NVU) primarily fueled by mitochondria. Sustaining the electrochemical gradients and active transport systems essential for this regulation imposes an immense metabolic burden, rendering the NVU uniquely susceptible to bioenergetic failure. This review critically evaluates the mechanistic link between mitochondrial dysfunction and specific, aberrant BBB phenotypes. We detail evidence surmising how mitochondrial dynamics within multiple NVU cell populations, including brain microvascular endothelial cells, pericytes, astrocytes and microglia, govern barrier stability. We specifically examine how mitochondrial reactive oxygen species (mtROS), aberrant fission/fusion cycles and impaired quality control precipitate tight junction disassembly and inflammatory activation. Furthermore, we explore the emerging paradigm of "mitoceuticals," a class of therapeutics engineered to correct these bioenergetic deficits. By targeting molecular mechanisms such as mitoNEET stability and mitochondrial dynamics, these agents offer a unique strategic opportunity to preserve NVU function. We conclude by evaluating the potential of these agents to therapeutically reinforce the bioenergetic infrastructure of the NVU as a vital, yet under-explored, avenue for treating ischemic and neurodegenerative disorders.
    Keywords:  Astrocytes; Bioenergetics; Endothelial cells; Ferroptosis; Microglia; Mitochondria; Neurovascular unit; Oxidative stress; Pericytes; Tight junctions
    DOI:  https://doi.org/10.1186/s12987-026-00854-x
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