bims-polgdi Biomed News
on POLG disease
Issue of 2026–09–13
thirty papers selected by
Luca Bolliger, lxBio



  1. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261478640
      The inaugural United Mitochondrial Disease Foundation (UMDF) Mitochondrial Medicine 2025 Masterclass focused on primary mitochondrial diseases (PMDs) especially primary mitochondrial myopathies (PMMs) and thymidine kinase 2 deficiency (TK2d). The Masterclass featured leading US experts in the field, providing the latest scientific and clinical knowledge, as well as patients and caregivers sharing their lived experience of mitochondrial diseases. In this report, we summarize the key highlights of each presentation. An overview of PMM featuring the etiologies of different PMMs and key features of notable PMMs, was followed by a presentation discussing the practical clinical processes of diagnosing PMM, how the roles of clinicians have evolved as diagnostic technology has improved, and actions clinicians can take to maximize the chances of an early, accurate diagnosis. Real-world case studies highlighted variations in disease presentation among the wide range of PMMs, which was followed by an in-depth review of clinical assessments and symptom management for PMM across organ systems. Multisystemic disorders like PMM require multidisciplinary management, in both a chronic and acute setting, and two experts discussed the practical workflow for clinicians to build a multidisciplinary model of care at their hospitals, the roles and responsibilities of the lead coordinator and each subspecialist, and practical steps that clinicians can take to manage acute care coordination and decrease acute care utilization. A hypothetical case study of TK2d (based on real patients) brought together the different aspects of PMM discussed during the Masterclass, while the patient perspective presentations allowed patients and caregivers to discuss the real-world impact that the diagnostic and care journey had on them and their families. This Educational Masterclass provided detailed knowledge of PMM designed to provide the next generation of clinicians and investigators with practical, actionable guidance and resources they could utilize to make a difference in the lives of patients with PMM.
    Keywords:  TK2d; mitochondrial disease; mitochondrial myopathy
    DOI:  https://doi.org/10.1177/26330040261478640
  2. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261486869
      Rare diseases collectively affect approximately 6% of the global population, yet 95% of affected individuals lack access to effective treatments. Beyond this persistent therapeutic gap, patients and caregivers face a broad spectrum of unmet needs, spanning psychosocial challenges, access to reliable diagnostic information, care coordination, and long-term follow-up, which remain poorly characterised in both clinical and policy contexts. Three interrelated challenges underpin this problem. First, validated instruments capable of systematically capturing unmet needs across diverse patient groups, including adults, minors, and caregivers, are largely absent. Second, even when patient data are collected, they are rarely integrated into clinical trial design, regulatory evaluation, or reimbursement deliberations in a structured and reproducible manner. Third, the responsible governance of rare disease data, particularly across institutional and national boundaries, faces unresolved ethical, legal, and organisational barriers. This perspective paper outlines the conceptual foundations of the INFORM-RD research project (a patient-informed clinical platform to inform patient-centred decision-making for rare diseases), embedded at KU Leuven, Leuven Institute for Rare Diseases and University Hospitals Leuven, Belgium. Drawing on the KCE NEED framework and leveraging a cohort of over 30,000 people with rare diseases, INFORM-RD aims to: 1) develop and validate a scalable methodology for unmet need data collection, 2) translate these data into actionable decision-support tools for clinicians, regulators, and payers, and 3) establish an ethical and legal governance architecture enabling responsible and scalable data sharing at national and international levels. By positioning patients, including underrepresented groups such as children and persons with cognitive limitations, as co-creators throughout the research process, INFORM-RD offers a transferable blueprint for need-driven rare disease care across Europe.
    Keywords:  clinical and regulatory decision-making; healthcare policy and regulation; patient-centred care; rare disease data governance; rare diseases; unmet needs
    DOI:  https://doi.org/10.1177/26330040261486869
  3. Biochim Biophys Acta Mol Cell Res. 2026 Sep 06. pii: S0167-4889(26)00119-9. [Epub ahead of print]1873(8): 120220
      Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.
    Keywords:  Integrated stress response (ISR); Metabolism; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Nucleotides; Replication machinery
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120220
  4. Drug Discov Today. 2026 Sep 08. pii: S1359-6446(26)00204-7. [Epub ahead of print] 104799
      
    DOI:  https://doi.org/10.1016/j.drudis.2026.104799
  5. Brain Dev. 2026 Sep 11. pii: S0387-7604(26)00091-4. [Epub ahead of print]48(6): 104590
       BACKGROUND: POLG encodes mitochondrial DNA (mtDNA) polymerase γ. Pathogenic POLG variants cause mitochondrial diseases, including progressive external ophthalmoplegia. POLG-related disorders are relatively common in Europe, possibly because of the high prevalence of carriers in the general population, but remain rare in Japan for unclear reasons.
    METHODS: We performed long-range PCR on mtDNA from skeletal muscle and/or peripheral blood from 3146 patients with suspected mitochondrial disease between 1993 and 2021. We selected 167 individuals with clinical features suggestive of POLG-related disorders for POLG gene analysis; all lacked pathogenic mtDNA point mutations, and most had multiple mtDNA deletions and/or a family history of mitochondrial disease.
    RESULTS: Among the 167 patients (median age: 52 years, range: 0-83 years, 11% pediatric cases), we identified 12 Japanese patients with POLG-related disorders and six POLG variants, including one novel variant. The six variants were p.Y955C, p.R943H, p.T599I, p.M299L, p.Y1210* (c.3626_3629dupGATA), and the novel variant p.F377S (c.1130T>C). Neither these six variants nor the 10 previously reported cases from Japan included the POLG variants that are more frequent in Europe. We also analyzed three population databases: two whole-genome sequencing databases covering 61,000 and 9850 Japanese individuals, respectively, and one global population database (gnomAD) covering 730,000 individuals worldwide. POLG variants that are more frequent in Europe were not detected in the Japanese databases or among East Asian individuals in gnomAD.
    CONCLUSIONS: Our findings suggest population-specific genetic differences in POLG between Japanese and European populations, explaining the lower frequency of POLG-related disorders in Japan.
    Keywords:  CPEO; Mitochondrial DNA; POLG; Population genetics; Whole genome sequencing analysis
    DOI:  https://doi.org/10.1016/j.braindev.2026.104590
  6. Ren Fail. 2026 Dec;48(1): 2727298
      Cardiorenal syndrome (CRS) comprises five clinically distinct patterns of acute, chronic, or systemic heart-kidney interaction. Mitochondrial dysfunction is shared by cardiac and renal injury, but the cardiorenal setting is distinguished by the possibility that mitochondrial stress arising in one organ is externalized and transmitted to the other. Extracellular vesicles (EVs) are established mediators of intercellular communication, and EVs carrying mitochondrial DNA, proteins, lipids, RNA, or structurally preserved mitochondrial material-collectively referred to here as mitochondrial extracellular vesicles (mitoEVs)-may connect mitochondrial quality control with systemic signaling. Direct CRS-specific evidence, however, remains limited: patient-derived studies support pathogenic effects of total circulating EVs, whereas most mitoEV-specific mechanisms are inferred from related cardiovascular, renal, inflammatory, cancer, or regenerative models. Accordingly, this review presents an evidence-graded conceptual framework rather than a definitive mechanistic summary. We define and classify mitoEVs, outline methodological requirements for their isolation, same-particle identification, cargo-topology analysis, quantification, and functional validation, and map the available evidence across the five CRS subtypes. We further propose the mitoEV-mitophagy-inflammation axis as a working hypothesis in which impaired mitochondrial quality control may favor vesicular export, inflammatory activation in recipient cells, and secondary mitochondrial dysfunction. Finally, we evaluate the biomarker and therapeutic potential of mitoEVs while emphasizing the need for subtype-specific clinical validation, standardized analytical workflows, source-resolved studies, and rigorous distinction between pathological and reparative vesicle populations.
    Keywords:  Cardiorenal syndrome; inter-organ communication; mitochondrial DNA; mitochondrial dysfunction; mitochondrial extracellular vesicles
    DOI:  https://doi.org/10.1080/0886022X.2026.2727298
  7. JIMD Rep. 2026 Sep;67(5): e70125
      Mitochondrial disease is a common inherited multisystem neurometabolic disorder. Pancreatic dysfunction is a recognised manifestation, most frequently presenting as mitochondrial diabetes. Although pancreatitis cases have been reported in association with mitochondrial disease, acute and chronic pancreatitis in this context remain poorly characterised. Following the PRISMA framework, we performed a systematic literature review to identify all published cases in which acute or chronic pancreatitis occurred in individuals with a genetically confirmed mitochondrial disease. Literature search yielded 604 publications, of which 19 fit the inclusion criteria. During revision two additional publications were identified, one of which fit the inclusion criteria. These 20 reports described 24 individuals with mitochondrial disease and documented history of acute or chronic pancreatitis. Mean age at first recorded pancreatitis was 13 years, with median age 10 years (range 3 months to 53 years). Pancreatitis was recurrent or chronic in 63% of cases. The most reported presenting symptoms were abdominal pain (38%) and vomiting (33%). None had established pancreatitis risk factors such as gallstones or alcohol misuse. In those who underwent imaging, no structural abnormalities of the pancreas or biliary tree were identified. Most frequent genetic aetiologies were large-scale mitochondrial DNA (mtDNA) deletions and the m.3243A>G mtDNA variant (29% each). Six patients (25%) died shortly after hospital admission with pancreatitis. Pancreatitis associated with mitochondrial disease often presents in childhood and is frequently recurrent or chronic. Although uncommon, it represents a clinically significant and potentially life-threatening complication that warrants increased awareness.
    Keywords:  m.3243A>G; mitochondrial DNA; mitochondrial disease; pancreatitis; systematic review
    DOI:  https://doi.org/10.1002/jmd2.70125
  8. Transl Pediatr. 2026 Aug 31. 15(8): 355
       Background: Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy caused by homoplasmic MT‑TE m.14674T>C/G variants, characterized by severe infantile onset followed by spontaneous recovery. Nuclear modifiers are thought to modulate its incomplete penetrance, but evidence for digenic inheritance remains limited. We aim to analyze the clinical, genetic, and prognostic features of RIRCD, explore the roles of nuclear modifiers and digenic inheritance.
    Case Description: We report three Chinese RIRCD patients carrying the homoplasmic m.14674T>C variant. All presented with recurrent respiratory infections and feeding difficulties, with gradual developmental recovery after 1 year of age. Notably, we report a case of a homoplasmic m.14674T>C variant (maternal) and a pathogenic EARS2 heterozygous variant (paternal), indicating digenic inheritance of EARS2. Additionally, we report another case of a homoplasmic m.14674T>C variant and a maternally inherited CLCN4 variant associated with language delay and autistic features after recovery from RIRCD, suggesting the presence of additional modifiers or comorbidities. Among 52 published cases and our 3 new cases, 92.16% of cases had onset within 3 months, 85.55% had neuromuscular symptoms, 70.91% required nasogastric feeding, and 43.63% needed mechanical ventilation. Elevated lactate and creatine kinase levels, ragged-red fibers, and mitochondrial ultrastructural abnormalities in muscle biopsies were common pre-recovery. Respiratory chain deficiencies included isolated complex IV and combined I + IV defects. Prognosis was favorable (32.00% full recovery, 58.00% mild residual myopathy). Twenty-four cases (43.64%) had nuclear modifiers, including EARS2 (n=9) and TRMU (n=6).
    Conclusions: RIRCD is a rare mitochondrial myopathy caused by mitochondrial DNA (mtDNA) variants with penetrance regulated by nuclear modifiers. Digenic inheritance contributes to phenotypic heterogeneity, supporting precise diagnosis and future therapy.
    Keywords:  Mitochondrial disease; case report; digenic inheritance; mitochondrial myopathy; reversible infantile respiratory chain deficiency (RIRCD)
    DOI:  https://doi.org/10.21037/tp-2026-0512
  9. JCI Insight. 2026 Sep 08. pii: e209108. [Epub ahead of print]
      Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nuclear-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, We compared the therapeutic efficacy in mutant mice at different ages and pre-symptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provide critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.
    Keywords:  Gene therapy; Genetics; Mitochondria; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/jci.insight.209108
  10. Front Cell Dev Biol. 2026 ;14 1929130
      Although the mitochondria are known as the cellular powerhouse, their function is beyond energy generation. These organelles regulate cellular metabolism, yet maintains a tightly regulated reactive oxygen species (ROS) generation and optimal redox state. In addition, mitochondria serve as mediators of physiological and pathological processes, such as maintenance of calcium balance, and control of apoptosis and mitophagy. All these make the mitochondria a major factor in both cellular and organismal regulation. However, mitochondria dysfunction may occur through many processes, including genetic mutations, increased production of ROS, metabolic failure from impaired electron transport chain activity, and dysregulated dynamics or mitophagy. Several self-perpetuating damages accumulate from these processes and influence clinical pathologies, such as aging, metabolic syndrome, cancer, neurodegeneration, and reproductive disorders. Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction. Examples include targeted antioxidants, such as MitoQ and SkQ1, to selectively neutralize mitochondrial ROS, pharmacological modulators to enhance mitochondrial biogenesis and to restore NAD+ homeostasis via PGC-1α activation, gene-editing technologies, such as mitoTALENs and mtZFNs to selectively eliminate pathogenic mitochondrial DNA mutations, and mitochondrial transplantation as a new technique to replace damaged organelles. Together, these novel approaches highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.
    Keywords:  ROS; mitochondria; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fcell.2026.1929130
  11. EMBO Mol Med. 2026 Sep 08.
      Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.
    DOI:  https://doi.org/10.1038/s44321-026-00497-3
  12. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261480132
       Introduction: Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline).
    Methods: Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception-October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (k mono , DP/k mono ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale.
    Results: Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs.
    Conclusions: Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.
    Keywords:  and stroke-like episodes (MELAS); flow mediated dilatation; lactic acidosis; mitochondrial disease; mitochondrial dysfunction; mitochondrial encephalomyopathy; nitric oxide; vascular endothelium
    DOI:  https://doi.org/10.1177/26330040261480132
  13. Expert Rev Neurother. 2026 Sep 07. 1-4
      
    Keywords:  Leigh syndrome; Leigh syndrome spectrum; mitochondrial DNA; mitochondrial disease; neurodegeneration
    DOI:  https://doi.org/10.1080/14737175.2026.2725112
  14. Front Mol Neurosci. 2026 ;19 1924581
      Neuroinflammatory mechanisms are increasingly recognized in biologically defined subgroups of psychiatric disorders, yet the cellular interfaces linking peripheral immune activation to brain dysfunction remain incompletely understood. This review examines the blood-brain barrier (BBB) and neurovascular unit (NVU) as dynamic immunometabolic structures whose stability depends on mitochondrial bioenergetics, redox signaling, calcium handling, mitophagy, and innate immune regulation. We integrate human postmortem, neuroimaging, cerebrospinal fluid and circulating biomarker findings with mechanistic evidence from cellular and animal models to examine whether mitochondrial dysfunction may be associated with BBB vulnerability, endothelial activation, altered tight-junction organization, and neuroinflammatory signaling. We discuss how this mitochondrial-BBB axis may contribute to transdiagnostic phenotypes such as cognitive impairment, anhedonia, fatigue, negative symptoms, affective dysregulation, and treatment resistance. Candidate biomarkers, including inflammatory mediators, BBB permeability markers, mitochondrial DNA, bioenergetic readouts, mitophagy markers, and neuroimaging measures, are considered as tools for patient stratification rather than diagnosis. Finally, we evaluate therapeutic implications, including mitochondrial-targeted interventions, BBB-protective strategies, anti-inflammatory approaches, metabolic modulation, and precision psychiatry frameworks. We argue that the mitochondrial regulation of BBB homeostasis represents a promising but still emerging framework for understanding neuroinflammatory psychiatric phenotypes and designing biomarker-guided studies.
    Keywords:  blood-brain barrier; immunometabolism; mitochondrial dysfunction; neuroinflammation; neurovascular unit; precision psychiatry; psychiatric disorders
    DOI:  https://doi.org/10.3389/fnmol.2026.1924581
  15. FASEB J. 2026 Sep 15. 40(17): e72288
      Neurodegenerative diseases are characterized by progressive protein aggregation, mitochondrial dysfunction, neuroinflammation, and cognitive decline, yet effective mechanism-based interventions remain limited. Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a multifunctional regulator linking stress adaptation, proteostasis, and metabolic homeostasis to disease progression. Increasing evidence indicates that SIRT1 supports cognitive resilience by coordinating synaptic plasticity, autophagy-lysosomal function, mitochondrial homeostasis, and inflammatory control. In Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), reduced or dysregulated SIRT1 is associated with protein aggregation, mitochondrial dysfunction, and cognitive decline, although its effects may be disease- and stage-dependent, particularly in HD. This review summarizes the structural and catalytic features of SIRT1, examines the mechanisms linking SIRT1 to cognitive impairment across major neurodegenerative diseases, and evaluates the opportunities and limitations of SIRT1-targeted therapeutic strategies.
    Keywords:  SIRT1; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; proteostasis; therapeutics
    DOI:  https://doi.org/10.1096/fj.202602361RR
  16. Metab Brain Dis. 2026 Sep 09. pii: 211. [Epub ahead of print]41(1):
      Primary coenzyme Q10 deficiencies (COQ10D) are rare mitochondrial disorders caused by pathogenic variants in genes involved in coenzyme Q10 (CoQ10) biosynthesis, leading to impaired mitochondrial respiration and heterogeneous neurological phenotypes. In this study, we identified and functionally characterized novel recessive variants in COQ2 and COQ4 using whole-exome sequencing. One proband carried a homozygous COQ2 variant (c.1039 A > G; p.Ser347Gly), while the second harbored compound heterozygous COQ4 variants (c.238 C > T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7). Variant segregation was confirmed by Sanger sequencing, and in silico protein modelling predicted deleterious structural effects. Mitochondrial function was assessed in freshly isolated platelets from probands, family members, and healthy controls using high-resolution respirometry. The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation, whereas the COQ4 proband, already receiving CoQ10, showed near-normal mitochondrial function. Following three months of CoQ10 supplementation, the COQ2 proband showed significant improvement in ATP synthesis and reduced proton leak, accompanied by clinical neurological improvement. mRNA expression analysis revealed feedback regulation, while protein levels of ETC complexes I-V remained unchanged. Importantly, CoQ10 supplementation in healthy individuals did not alter mitochondrial respiration, confirming the specificity of therapeutic benefit in COQ10Ds. Overall, in addition to expanding the genetic spectrum of COQ10Ds, this study also provides functional evidence that defective mitochondrial function in these conditions is, at least in part, reversible with targeted CoQ10 therapy, underscoring the importance of early genetic diagnosis and timely initiation of CoQ10 supplementation.
    Keywords:   COQ2 ; COQ4 ; COQ10D; Coenzyme Q10 ; Mitocondrial respiration; Primary CoQ10 deficiency
    DOI:  https://doi.org/10.1007/s11011-026-01983-w
  17. Front Immunol. 2026 ;17 1917296
      Aging and its associated diseases have become an increasingly severe global health challenge, not only significantly exacerbating the global disease burden but also posing a continuous threat to public health systems worldwide. During the aging process, the aberrant release of endogenous mitochondrial DNA (mtDNA) is a key trigger for the activation of the cGAS-STING innate immune pathway. Existing research has confirmed that the overactivation of the cGAS-STING pathway is the core molecular mechanism driving the senescence-associated secretory phenotype (SASP), chronic inflammation, and organ functional decline. Notably, the mechanisms of mtDNA release and the activation characteristics of the cGAS-STING pathway exhibit significant organ-specificity. Different tissues mediate mtDNA leakage through specific pathways, such as mitochondrial permeability transition, oxidative damage, and defective mitophagy, thereby differentially regulating downstream inflammatory signals. Given the central driving role of the aberrantly activated mtDNA-cGAS-STING axis in age-related organ damage, targeting this pathway has emerged as a promising therapeutic strategy for the systemic mitigation of aging-associated chronic inflammation. This review systematically elucidates the molecular basis of the mtDNA-cGAS-STING pathway, delves into its organ-specific activation mechanisms, and critically evaluates current intervention frameworks and clinical prospects, aiming to provide a theoretical basis and innovative perspectives for the precision prevention and clinical management of age-related diseases.
    Keywords:  aging; cGAS-STING; immunity; mitochondria; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1917296
  18. Trends Pharmacol Sci. 2026 Sep 12. pii: S0165-6147(26)00206-3. [Epub ahead of print]
      Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.
    DOI:  https://doi.org/10.1016/j.tips.2026.08.009
  19. Pharmacol Res. 2026 Sep 11. pii: S1043-6618(26)00356-7. [Epub ahead of print] 108441
      Musculoskeletal disorders (MSDs), including osteoporosis (OP), osteoarthritis (OA), and rheumatoid arthritis (RA), represent a stubborn burden in modern medicine. They share a breakdown in mitochondrial homeostasis. Mitochondrial dysfunction serves as a central pathogenic mechanism unifying these conditions and driving a paradigm shift from symptomatic management to mechanism-based therapeutic strategies. In this review, we examine how mitochondrial defects affect key cell types in bone, cartilage, and muscle, including osteoblasts, osteocytes, osteoclasts, chondrocytes, and skeletal muscle cells, with a focus on osteoporosis (OP), osteoarthritis (OA), and rheumatoid arthritis (RA) as the three primary musculoskeletal conditions that share mitochondrial dysfunction as a unifying mechanism. Impaired energy production, altered dynamics, defective quality control, and redox imbalance each contribute to disease progression. These disturbances drive oxidative damage, metabolic reprogramming, impaired mitophagy, and the release of pro-inflammatory signals known as mtDAMPs. Importantly, such defects are not irreversible, we further synthesize the emerging landscape of mitochondria-targeted strategies. These include antioxidants like MitoQ and SkQ1, metabolic modulators such as metformin and NAD⁺ boosters, mitophagy inducers like urolithin A, fission inhibitors including Mdivi-1, senolytic agents, and even mitochondrial transplantation. We conclude by proposing a precision medicine framework that matches specific mitochondrial abnormalities with mechanism-based interventions. Drawing on recent preclinical and clinical evidence, this review positions mitochondrial crosstalk as a promising foundation for developing disease-modifying therapies in musculoskeletal medicine.
    Keywords:  Mitochondria; musculoskeletal disorders; osteoarthritis; osteoporosis; rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108441
  20. Mov Disord. 2026 Sep 11.
      Childhood-onset movement disorders comprise a heterogeneous group of rare conditions with substantial unmet therapeutic needs. Recent advances in disease gene discovery, mechanistic modeling, and translational platforms have accelerated the development of targeted therapies and enabled innovative clinical trial designs for small patient populations. To review novel and emerging therapies for childhood-onset movement disorders, with a focus on pharmacologic strategies, disease-modifying approaches, and patient-centered precision therapies. We surveyed the literature, major conference proceedings, and expert networks to identify therapies approved, in clinical development, or supported by compelling preclinical data between 2022 and 2025. We focused on small molecules and genetic therapies for conditions in which movement disorders represent a prominent clinical feature. Small molecules were categorized as repurposed or novel drugs, whereas genetic therapies included gene replacement, gene editing, and RNA-based expression modulation. Drug repurposing approaches have shown promise in disorders related to the GNAO1, ATP1A3, ATM, and ADCY5 genes. Novel small molecules have advanced for Friedreich's ataxia and Tourette's syndrome. Gene replacement therapies have demonstrated clinical benefit in select neurotransmitter disorders, whereas gene editing strategies have entered preclinical development for ATP1A3-related disease. Antisense oligonucleotide therapies have yielded encouraging early results across several conditions with prominent movement disorder phenotypes, including KIF1A-related neurological disorder, Angelman syndrome, SCN2A-related neurodevelopmental disorder, and ataxia-telangiectasia. Precision-based therapeutic strategies are rapidly reshaping the treatment landscape for childhood-onset movement disorders. Continued progress will depend on rigorous phenotyping, careful ethical oversight, and deliberate efforts to promote equitable global access to emerging therapies. © 2026 International Parkinson and Movement Disorder Society.
    Keywords:  Antisense oligonucleotides; Gene Therapy; Neurogenetics; Pediatric Movement Disorders; Small molecules
    DOI:  https://doi.org/10.1002/mds.70495
  21. Front Genet. 2026 ;17 1902275
      Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.
    Keywords:  common variants; epilepsy; penetrance; phenotypic heterogeneity; polygenic risk score; rare variants
    DOI:  https://doi.org/10.3389/fgene.2026.1902275
  22. Free Radic Biol Med. 2026 Sep 05. pii: S0891-5849(26)01136-6. [Epub ahead of print]256 392-407
      Homocystinuria (HCU) is an inborn error of metabolism and a conformational disorder chiefly caused by missense mutations in the cystathionine beta-synthase (CBS) gene. These mutations often cause CBS destabilization, misfolding and dysfunction resulting in CBS deficiency and pathological accumulation of homocysteine. Morphological changes in mitochondria were described in HCU patients and mouse models; however, their functional significance has remained unknown. Here, we characterized the impact of CBS deficiency due to expression of the most common HCU-causing variant CBS I278T on mitochondrial function using three cellular models of HCU: mouse hepatocytes, human fibroblasts and newly developed CRISPR/Cas9-modified HEK293 cells. We found that the expression of the CBS I278T variant resulted in the unfolded protein response, oxidative stress and impaired cellular energy metabolism in all three cellular models of HCU. Mitochondrial respiration and ATP production were substantially impaired. Bioenergetic deficit correlated morphologically with mitochondrial swelling and loss of cristae and functionally with decreased membrane potential and cytosolic mitochondrial DNA release. Impaired clearance of damaged, non-functional mitochondria was caused by compromised mitophagy activation and dysfunctional lysosomes. Methionine restriction substantially reduced plasma total homocysteine and rescued mitochondrial function of hepatocytes isolated from treated Tg-I278T HCU mice. Importantly, CBS-knockout HEK293 cells showed normal proteostasis and mitochondrial function indicating that CBS I278T misfolding is the main cause and trigger of the described pathological phenotype. These findings provide the first mechanistic insight into the impaired cellular bioenergetics in HCU.
    Keywords:  Cystathionine beta-synthase; ER stress; Homocysteine; Homocystinuria; Lysosomes; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.002
  23. Aging Med (Milton). 2026 Sep 05.
      Understanding the molecular mechanisms of aging guides the development of prevention, intervention, and treatment strategies to reduce the incidence of common age-associated diseases. Over the past decades, the proposed key features (hallmarks) of aging cells have directly or indirectly provided us clues, furthering our understanding of the causes of disease and assisting with the development of therapeutic strategies for diseases such as rare premature aging diseases like Werner syndrome and ataxia telangiectasia (A-T), as well as the common age-related diseases like dementia and sarcopenia. In this editorial, we take a closer look at three of these hallmarks including genomic instability, defective macroautophagy, and mitochondrial dysfunction, and the applications of these concepts in understanding the progress of complex diseases. Mounting studies from the laboratory, supported by emerging clinical evidence, point to the reduction of the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a commonality between many of these hallmarks of aging. Intriguingly, stimulating mitochondrial autophagy (mitophagy) via improvement of NAD+ availability appears to be a promising and effective therapeutic strategy for many diseases relating to aging. Future studies on the hallmarks of aging should address their internal linkages and clinical interventions.
    Keywords:  DNA repair; NAD+; aging; autophagy; brain; mitophagy
    DOI:  https://doi.org/10.1002/agm2.70107
  24. Hemasphere. 2026 Sep;10(9): e70429
      Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.
    DOI:  https://doi.org/10.1002/hem3.70429
  25. Neuroendocrinology. 2026 Sep 10. 1
      Oxygen is both essential and potentially toxic to the brain, which consumes 20-25% of the body's resting metabolic rate despite comprising only 2% of total body weight. The exquisite sensitivity of neural tissue to oxygen imbalance positions oxygen delivery as a critical determinant of both pathophysiology and therapeutic opportunity in brain disorders. This review synthesizes recent advances in our understanding of how oxygen sensing and delivery can be harnessed for therapeutic benefit across the spectrum of neurological conditions. We examine the molecular machinery of oxygen sensing, including the canonical PHD-HIF-pVHL pathway as well as newly identified oxygen sensors such as Jumonji C domain histone demethylases and cysteine dioxygenase. We then explore how perturbations in oxygen delivery contribute to neurodegenerative diseases, stroke, traumatic brain injury, and neurodevelopmental disorders. Emerging therapeutic strategies are critically evaluated, including normobaric and hyperbaric oxygen therapy, therapeutic acute intermittent hypoxia, hypoxia preconditioning, and pharmacological targeting of oxygen-sensing pathways. Moreover, the emerging concept of tissue-specific oxygen "set points" suggests that both hypoxia and hyperoxia can be pathological, and that restoring optimal oxygenation-rather than simply maximizing oxygen delivery-may represent a more nuanced therapeutic approach. Notably, recent preclinical evidence demonstrating that hypoxia itself can reverse pathology in mitochondrial disease models challenges conventional assumptions and opens new avenues for treating brain disorders characterized by relative hyperoxia. Understanding the mechanisms by which oxygen delivery influences neuroinflammation, mitochondrial function, and neural plasticity will be essential for translating these insights into effective clinical interventions.
    DOI:  https://doi.org/10.1159/nen/advag002
  26. Exp Neurol. 2026 Sep 11. pii: S0014-4886(26)00389-4. [Epub ahead of print] 116022
      Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and pathological aggregation of α-synuclein. Traditional two-dimensional (2D) cell cultures and animal models have provided valuable insights but fail to recapitulate the cellular architecture and pathophysiology of the human midbrain. Three-dimensional (3D) midbrain organoids self-organize into neural structures that mimic key aspects of human midbrain development and disease pathology. This review examines midbrain organoid-based PD modeling through a concept-driven lens, addressing five questions: (i) Which aspects of PD can organoids model? (ii) How are technological advances reshaping the field? (iii) How do organoids complement existing model systems? (iv) What are the current limitations, and how can they be addressed? (v) What is the path toward clinical translation? Organoids reliably reproduce mitochondrial and lysosomal dysfunction and, in SNCA triplication models, α-synuclein accumulation, but seldom progressive neurodegeneration or mature Lewy pathology. By distinguishing established findings from emerging technologies and providing a realistic assessment of current limitations, this review offers a framework for prioritizing organoid applications in PD research and translation.
    Keywords:  Cell therapy; Disease modeling; Dopaminergic neurons; Drug discovery; Induced pluripotent stem cells; Midbrain organoids; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2026.116022
  27. J Psychopharmacol. 2026 Sep 07. 2698811261481085
       BACKGROUND: Extant literature indicates mitochondrial dysfunction may contribute to the pathophysiology of depressive disorders. Preclinical data indicate that anesthetic doses of ketamine are associated with deficits in mitochondrial viability and function. Ketamine and esketamine have demonstrated rapid antidepressant effects in persons with difficult-to-treat depressive disorders. Herein, we aim to synthesize literature reporting on the effect of antidepressant doses of ketamine and esketamine in vivo versus in vitro on mitochondrial viability and function.
    METHODS: We performed a systematic review of previous studies on PubMed, Ovid, and Scopus databases from inception to November 30, 2025. Preclinical studies reporting on the effect of antidepressant doses of ketamine and/or esketamine in mitochondrial viability, structure/morphology, bioenergetics, and metabolic function were sought for inclusion.
    RESULTS: Thirteen studies were included. Lower ketamine/esketamine concentrations generally did not adversely affect membrane potential, oxidative phosphorylation, respiration, or bioenergetics, whereas higher concentrations or prolonged exposure induced mitochondrial dysfunction in some models. Additional evaluation of the safety of ketamine/esketamine on mitochondria in humans is required.
    CONCLUSION: Preliminary research suggests that ketamine at lower concentrations may not adversely affect brain mitochondrial viability or bioenergetic function, but requires further validation. The reported effects on mitochondrial viability and function are preclinical, model- and dose-dependent and derived from limited heterogeneous literature. This study generates the hypothesis that ketamine's antidepressant mechanism of action may be partially mediated by insulin-sensitive metabolic pathways, energetically supporting synaptic remodeling and neurogenesis. Incorporation of mitochondrial and metabolic biomarkers into ketamine clinical trials is a current research imperative.
    Keywords:  bioenergetics; esketamine; ketamine; mitochondria
    DOI:  https://doi.org/10.1177/02698811261481085
  28. Mol Biomed. 2026 Sep 09. pii: 166. [Epub ahead of print]7(1):
      Extracellular vesicles (EVs) are membrane-bound, nano-sized particles released by diverse cell types. They serve as key mediators of intercellular communication by transporting a broad repertoire of proteins, lipids, nucleic acids, and metabolites to recipient cells within a protective lipid bilayer. Owing to their natural origin, intrinsic stability, low immunogenicity, and ability to cross biological barriers, EVs are highly attractive candidates for next-generation therapeutics and drug delivery platforms. In this review, we summarize the biology of EVs and highlight the features critical for their application in therapeutic delivery. We trace their multiple origins, ranging from mammalian and plant cells to bacteria, underscoring their ubiquity across biological systems. We then analyze the advantages of EVs as next-generation delivery vehicles. From a practical standpoint, we examine current strategies for EV isolation, purification, characterization, and engineering. Importantly, we showcase several therapeutic applications of EVs for intractable diseases that are refractory to conventional approaches, such as cancer and immune disorders. We also discuss the major challenges on the path to clinical translation, particularly scalable and standardized production, as well as safety and immunogenicity. To fully realize the clinical potential of EV-based therapies, future research should prioritize the development of robust manufacturing protocols and comprehensive safety evaluations.
    Keywords:  Drug delivery; Exosomes; Extracellular vesicles; Immunotherapy; Vaccine
    DOI:  https://doi.org/10.1186/s43556-026-00571-9
  29. Genet Med Open. 2026 ;4 104488
       Purpose: This retrospective study examined the clinical and genetic characteristics of pediatric patients undergoing clinical exome sequencing (ES) and evaluated the performance of a commercially available artificial intelligence (AI) platform that was integrated into our analysis pipeline.
    Methods: ES was performed in 822 consecutive patients at a single clinical laboratory. AI-based tools were used to jointly assess genetic information and the proband's Human Phenotype Ontology terms to support variant prioritization during the initial case review.
    Results: A definitive molecular diagnosis was established in 22% (181 of 822) of index cases, while 40% (325 of 822) had variants of uncertain significance. Among those with a definitive diagnosis, 93% (168 of 181) had a single finding and 7% (13 of 181) had multiple findings. Of the 152 reported pathogenic/likely pathogenic variants in the fully resolved cases, 98.7% were successfully flagged by AI, and 75.0% ranked among the top 10 "most likely" variants.
    Conclusion: Clinical ES provides a substantial diagnostic yield in complex pediatric disorders. Integration of AI-powered platforms can accelerate phenotype-driven variant prioritization and facilitate rare disease diagnostics, but underscores the need for careful validation and optimization in clinical workflows.
    Keywords:  Artificial intelligence; Clinical exome sequencing; Diagnostic yield; HPO
    DOI:  https://doi.org/10.1016/j.gimo.2026.104488
  30. Aging (Albany NY). 2026 Sep 08. 18(1): 1147-1162
      Organisms vary in their lifespan. Understanding this variation may help us live healthier and longer. Here, we focus on species living twice as long as humans, or more. Out of the 101 multicellular species with a maximum lifespan of 250+ years, 11 are animals and 90 are plants. We surveyed the genetic, transcriptional, proteomic, metabolomic, regeneration-, stress-, and cancer-related components of intraspecific and interspecific lifespan variation, across these species. We examined whether the mechanisms regulating intraspecific lifespan variation across these species are the same or different from mechanisms regulating interspecific lifespan variation. We identified several similarities: both types of variation include mechanisms related to DNA maintenance, stemness, and stress management. Such mechanisms are also typical of early developmental stages and germ cells. Nonetheless, caution should be exercised when attempting to draw robust conclusions based on available data, given the lack of in-depth molecular studies on the healthspan and lifespan across thousands of individuals and species, the methodological variation across published studies, and our partial understanding of the interplay between physiology and the environment across species.
    Keywords:  aging; healthspan; interspecific variation; intraspecific variation; stemness
    DOI:  https://doi.org/10.18632/aging.206419