bims-polgdi Biomed News
on POLG disease
Issue of 2026–10–25
39 papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
  2. Human Induced Pluripotent Stem Cells in Rare Neurological Disorders: Opportunities and Challenges for Disease Modeling and Drug Discovery.
  3. Human induced pluripotent stem cells and organoid models in space for investigating severe pediatric metabolic and congenital disorders.
  4. Mitochondrial genome homeodynamics across scales.
  5. Extracellular Mitochondrial Components as Emerging Biomarkers and Therapeutic Targets in Human Diseases.
  6. Grouped but not unified: mechanistic diversity in mitochondrial skeletal disorders.
  7. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  8. Mitochondrial DNA mediated Kupffer cell activation in the pathogenesis and progression of liver diseases.
  9. Research engagement of rare disease patient advocacy groups in Poland: between participation and constrained co-production.
  10. A Droplet Digital Polymerase Chain Reaction Assay for Detecting and Quantifying Pre-Existing Mutations and De Novo Editing Events in Mitochondrial DNA.
  11. Estradiol-PGC-1 signaling in mitochondrial health: Implications for perimenopause and cardiovascular disease.
  12. Imaging Characteristics in the Ataxia-Neuropathy Spectrum Related to POLG Mutation.
  13. Established determinants of replicative lifespan, including mitochondrial DNA, play a limited role in early yeast stress-resistance decline.
  14. Apparent methylation of mitochondrial DNA in WGBS is dominated by technical artifacts.
  15. Developing a rare disease registry for inherited metabolic disorders in Pakistan.
  16. The sirtuin family: from mechanisms to therapy.
  17. Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
  18. Investigator-Initiated Trials as a Clinical Development Approach for Orphan Drugs Compared with Industry-Sponsored Trials in Japan.
  19. Mitophagy coordinates organelle crosstalk in health and diseases.
  20. Navigating the landscape of stem cell therapeutics: Overcoming translational hurdles via emerging technologies and regulatory frontiers.
  21. DHDDS variants in epilepsy and movement disorders: Two novel mutations and an updated literature review.
  22. RYR1-related diseases patient-led international research workshop: Novel perspectives, treatments and interventions.
  23. Placental mitochondrial impairment in preeclampsia patients.
  24. Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.
  25. Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
  26. A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
  27. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  28. The new frontier of newborn screening: integrating genomics, metabolomics, and data science for inborn errors of metabolism.
  29. Patient access to cell and gene therapies in Europe: stakeholder perspectives on impeding factors across the medicine lifecycle.
  30. Global epidemiological and genetic burden of rare neurological diseases in children.
  31. Biotin-dependent carboxylases and related disorders: Comparative mechanisms and therapeutic advances.
  32. Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction.
  33. Learning global and local representations for generalized category discovery in neurodegenerative diseases.
  34. Ataxia Therapeutics: A Comprehensive Overview of the Clinical Development Pipeline.
  35. Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.
  36. Mitochondria-Macrophage Interactions in Sepsis at Different Immune Stages: Integrating Immunometabolic Reprogramming, Organ Damage, and Therapeutic Strategies.
  37. Iron Homeostasis and Liver Diseases.
  38. How tech billionaires are disrupting biomedical science.
  39. Context-specific hypermetabolism in humans with mitochondrial defects.
  1. Nat Rev Neurol. 2026 Oct 23.
    Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
    Elena Rossini, Matteo Garibaldi, Michael G Hanna, Robert D S Pitceathly, Chiara Pizzamiglio.
      Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.
    DOI:  https://doi.org/10.1038/s41582-026-01274-z
  2. Stem Cells Int. 2026 ;2026 1130043
    Human Induced Pluripotent Stem Cells in Rare Neurological Disorders: Opportunities and Challenges for Disease Modeling and Drug Discovery.
    Anja Harej Hrkać, Valentino Rački, Andrej Belančić, Jasna Kriz, Dinko Vitezić, Jasenka Mršić-Pelčić, Ganesh Acharya, Mukesh Varshney, Kristina Pilipović.
      Rare disease is a condition that affects a small fraction of the population. In most cases, it has a known genetic cause but could also be associated with other contributing factors. As the affected individuals may exhibit diverse symptoms due to the genetic and phenotypic heterogeneity, non- or misdiagnosis of rare diseases is common. Their low incidence and prevalence present an obstacle to developing new therapies despite a major unmet need with only a few treatment options available. This is particularly relevant to rare neurological disorders as there are major difficulties in studying the mechanisms of initiation and progression of the central nervous system (CNS) disorders. Recent advances in biotechnology, specifically the use of human induced pluripotent stem cells (iPSCs) for modeling diseases, have been instrumental in providing a flexible platform that not only reflects the effects of genetic disturbances on the development of CNS disorders but also is capable of providing insights into complex multifactorial disorders. Whether the human iPSCs are harvested from the affected individuals or using the gene-editing tools on cells from healthy individuals, valuable models can now be made available for studying these orphan conditions. In this narrative review, we explore the benefits of using human iPSC models over the existing platforms of other primary cell lines and animal models for the disease modeling and drug discovery and discuss the limitations and future aspects of the iPSC use in the investigation of rare neurological disorders.
    Keywords:  disease models; genetic heterogeneity; induced pluripotent stem cells; nervous system diseases; rare diseases
    DOI:  https://doi.org/10.1155/sci/1130043
  3. Precis Clin Med. 2026 Dec;9(4): pbag028
    Human induced pluripotent stem cells and organoid models in space for investigating severe pediatric metabolic and congenital disorders.
    Sara Benedetti, Hana Štupica, Gian Vincenzo Zuccotti, Volkmar Weissig, Davide Marotta, Carlo Pappone, Alba Tull, Kathleen H Rubins, Afshin Beheshti, Christopher E Mason, Simona Ferraro.
      As biomedical research in space expands, microgravity and spaceflight-associated stressors are revealing cellular responses that may provide new insights into rare and severe metabolic and congenital disorders. Human induced pluripotent stem cells (hiPSCs) and organoids are particularly promising as they enable patient-specific modelling in the space environment. In this review, we examine the current literature on space-based hiPSC experimental models, highlighting their relevance to pediatric disorders with well-defined genetic backgrounds, namely mitochondrial diseases and congenital heart disorders. We summarize the evidence that spaceflight conditions alter mitochondrial function, cytoskeletal organization, oxidative stress, calcium handling, cellular maturation, and gene expression, and discuss how these responses may converge with metabolic disease-associated phenotypes. We highlight both adaptive and pathological responses reported in space-based hiPSC studies and identify key experimental and mechanistic gaps. Finally, we consider how advances in stem cell technologies and space-based biomedical research may enable the development of personalized, patient-specific disease models and therapeutics for rare pediatric diseases, ultimately accelerating translational discovery and clinical innovation.
    Keywords:  3D cell culture; congenital heart defect; hiPSC; mitochondrial disorder; organoids; rare diseases
    DOI:  https://doi.org/10.1093/pcmedi/pbag028
  4. Trends Genet. 2026 Oct 21. pii: S0168-9525(26)00242-8. [Epub ahead of print]
    Mitochondrial genome homeodynamics across scales.
    Juan C Landoni, Suliana Manley.
      Mechanisms that maintain the mitochondrial genome, termed mitochondrial DNA homeodynamics, span vastly different spatial and temporal scales. A multiscale framework may help to reconcile seemingly disparate mechanisms, unifying canonical and emerging processes and providing a shared conceptual and mechanistic foundation for future investigations.
    DOI:  https://doi.org/10.1016/j.tig.2026.09.006
  5. Int J Biol Sci. 2026 ;22(15): 8390-8407
    Extracellular Mitochondrial Components as Emerging Biomarkers and Therapeutic Targets in Human Diseases.
    Kuan-Hao Tsui, Emmanuel Naveen Raj, Andy P Tsai, Boyang Wang, Chen-Yueh Wen, Chia-Jung Li.
      Mitochondria serve as the bioenergetic hub of eukaryotic cells while simultaneously acting as a major source of cellular stress and toxicity. Classical mitochondrial quality control (MQC) has long been viewed as a lysosome-dependent process centered on mitophagy. However, aging is accompanied by progressive lysosomal dysfunction, limiting the efficiency of canonical mitochondrial clearance and contributing to mitochondrial accumulation and cellular deterioration. Emerging evidence suggests that under conditions of lysosomal overload and metabolic stress, cells engage alternative quality-control pathways by selectively exporting mitochondrial components into the extracellular environment through mitochondrial-derived vesicles (MDVs) and exophers. In this review, we integrate current findings to propose a unified framework of age-associated mitochondrial disposition and discuss how cells dynamically balance intracellular degradation with extracellular mitochondrial secretion. We further examine the molecular machinery underlying MDV and exopher biogenesis and evaluate their roles in reshaping intercellular metabolic communication. Particular emphasis is placed on their translational relevance in cancer and neurodegenerative disorders, where extracellular mitochondrial trafficking may contribute to disease progression, therapeutic resistance, and tissue remodeling. We also discuss the technical and analytical bottlenecks that currently constrain this field. Finally, we discuss the emerging potential of mitochondrial secretion pathways as diagnostic biomarkers and therapeutic targets for age-associated diseases.
    Keywords:  intercellular transfer; lysosomes; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.7150/ijbs.140360
  6. Mitochondrion. 2026 Oct 23. pii: S1567-7249(26)00117-0. [Epub ahead of print] 102227
    Grouped but not unified: mechanistic diversity in mitochondrial skeletal disorders.
    N Sushma Sri, Sai Latha Sabbu, Katta M Girisha, Aarti Sevilimedu.
      Mitochondrial disease is a term assigned to a diverse group of genetic disorders caused by impaired mitochondrial function, resulting in defective oxidative phosphorylation and ATP synthesis, with clinical manifestations that affect primarily energy-demanding tissues such as the brain and muscle. However, a subset of these conditions is characterized by prominent primary skeletal manifestations and has been designated Mitochondrial Skeletal disorders (MSDs). Since the initial review of MSDs in 2020, the number of genes in this category has expanded considerably, based on the updated Nosology of Genetic Skeletal disorders (2023) and MitoCarta3.0 (2021). In this review, we evaluate the clinical, genetic and functional evidence supporting the inclusion of the new genes and revisit the question of a shared mechanistic basis underlying this growing subgroup. Clinically, MSDs display pleiotropic and variable phenotypes, including dysplasia, craniofacial abnormalities and growth restriction. Functionally, the implicated proteins perform diverse essential roles in the mitochondria, extending beyond protein homeostasis to include maintenance of mtDNA integrity, mitochondrial metabolism, and membrane dynamics and composition. We hypothesize that these primary mitochondrial defects converge on the downstream activation of mitochondria-driven inflammatory pathways, disrupting osteogenic differentiation and bone formation through key signaling pathways (Wnt and Hedgehog), and transcription factors (RUNX2). However, consolidating this hypothesis will require deeper mechanistic studies using in vivo models, perturbation studies and multi-omic integration, ultimately enabling a more informed path towards the development of targeted therapeutic interventions.
    Keywords:  Genetic skeletal disorder; Inflammation; Mitochondrial dysfunction; Mitochondrial skeletal disorders (MSD); Protein homeostasis; Skeletal dysplasia; mtDNA maintenance and integrity
    DOI:  https://doi.org/10.1016/j.mito.2026.102227
  7. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  8. Autoimmun Rev. 2026 Oct 21. pii: S1568-9972(26)00222-3. [Epub ahead of print] 104208
    Mitochondrial DNA mediated Kupffer cell activation in the pathogenesis and progression of liver diseases.
    Zijun Li, Lifu Zhu, Luqing Pan, Jinjun Ma, Haibo Xie, Jiaxiang Zhang.
      The liver serves as a pivotal metabolic and immunological hub, yet its homeostatic equilibrium is highly susceptible to mitochondrial dysfunction. Recent studies have implicated mitochondrial DNA (mtDNA) as an important damage-associated molecular pattern (DAMP) that links mitochondrial injury to sterile hepatic inflammation and KCs (KCs) activation. This review provides a comprehensive synthesis of the mtDNA mediated KCs across four major hepatic pathologies: Alcohol-associated Liver Disease (ALD), Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Hepatic Ischemia-Reperfusion Injury (IRI), and Hepatocellular Carcinoma (HCC). We discuss emerging evidence that Z-DNA-binding protein 1 (ZBP1) associated PANoptosis and nerve injury-induced protein 1 (NINJ1) mediated plasma membrane rupture may contribute to inflammatory cell death in severe liver injury, complementing rather than superseding canonical pyroptotic mechanisms. However, the extent to which mtDNA directly activates this axis remains unresolved. Furthermore, we delineate the cell-type-specific dichotomy of cyclic GMP-AMP synthase (cGAS) signaling, which fuels pro-inflammatory storms in KCs via the stimulator of interferon genes (STING) pathway while promoting protective mitophagy in hepatocytes through a STING-independent cGAS-Beclin-1 interaction. In the context of immunometabolism, we also summarize preclinical evidence linking cytidine/uridine monophosphate kinase 2 (CMPK2) dependent mtDNA synthesis to inflammasome activation and mitochondrial calcium uniporter (MCU) acetylation to age-associated mtDNA release during IRI. Finally, we evaluate the clinical translational potential of targeting these molecular hubs and the emergence of cell-free mitochondrial DNA (cf-mtDNA) fragmentomics-including 5' end motif analysis and diversity scoring as a transformative liquid biopsy tool for precision diagnosis. Collectively, available evidence positions mtDNA mediated KCs activation as an important, context-dependent contributor to liver disease and a potential therapeutic target, while underscoring the need for cell-specific and human validation.
    Keywords:  Inflammatory response; Kupffer cells; Liver diseases; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.autrev.2026.104208
  9. BMC Health Serv Res. 2026 Jul 22. pii: 1429. [Epub ahead of print]26(1):
    Research engagement of rare disease patient advocacy groups in Poland: between participation and constrained co-production.
    Jan Domaradzki, Dariusz Walkowiak.
       BACKGROUND: Rare diseases (RDs) present complex challenges, including diagnostic uncertainty, limited treatment options, and fragmented research and care systems. These constraints contribute to inequities in access to care, information, and research participation among patients and caregivers across social and institutional contexts. In this setting, rare disease patient advocacy groups (RDPAGs) have emerged as key actors, not only providing support to patients and caregivers but also increasingly engaging in research. However, empirical evidence regarding their research engagement and organisational capacities remains limited, particularly in Central and Eastern Europe. This study examines the engagement of RDPAGs in research and intersectoral collaboration in Poland.
    METHODS: A cross-sectional survey was conducted between January and April 2026 among representatives of 64 Polish RDPAGs using a structured, web-based questionnaire. The questionnaire covered organisational characteristics, research engagement, collaboration, and perceived barriers. Data were analysed using descriptive statistics.
    RESULTS: Most RDPAGs reported at least occasional engagement in research, although involvement was heterogeneous and often limited in scope. RDPAGs were primarily active in non-clinical research domains, including social research, patient registries, and dissemination of research findings. Participation in clinical and translational research was less frequent and largely supportive, particularly in recruitment and patient support. A majority of RDPAGs did not initiate research activities, and only a small proportion reported high levels of engagement. Key barriers included a lack of funding, limited human resources, and restricted influence on research processes. Despite these constraints, collaboration with physicians was common, although often informal. The findings indicate that RDPAGs function as intermediary actors and knowledge brokers, partially compensating for structural gaps in healthcare and research systems by facilitating access to information, support, and research participation for patients and caregivers. The findings further suggest a model of constrained co-production, in which RDPAGs participate in research but remain insufficiently integrated into research decision-making and knowledge production.
    CONCLUSIONS: RDPAGs play an important but structurally constrained role in research and knowledge co-production. Strengthening their contribution requires formalised collaboration frameworks, improved access to resources, capacity-building initiatives, and earlier and more meaningful involvement across the research cycle. Enhancing their role may contribute to more inclusive and effective research systems in the rare disease field.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Experiential knowledge; Intersectoral collaboration; Knowledge co-production; Patient advocacy groups; Patient organisations; Patient participation; Patient-centred research; Rare diseases; Research engagement
    DOI:  https://doi.org/10.1186/s12913-026-15202-w
  10. J Vis Exp. 2026 Oct 21.
    A Droplet Digital Polymerase Chain Reaction Assay for Detecting and Quantifying Pre-Existing Mutations and De Novo Editing Events in Mitochondrial DNA.
    Pei-Lun Kao, Qinglan Ling.
      Development of mitochondria-targeted base editors as a gene therapy strategy for mitochondrial deoxyribonucleic acid (mtDNA)-related diseases, such as MT-ATP6 Leigh syndrome (LS), requires using in vitro models for proof-of-concept evaluations. Here, we developed a droplet digital polymerase chain reaction (ddPCR)-based assay that uses detection probes specific to wild-type, mutant, or edited mtDNA alleles to determine the heteroplasmy level in cells carrying different mtDNA variants. We used a pathogenic human MT-ATP6 allele as an example to demonstrate the development and optimization pipeline of this assay. We optimized assay parameters and designed experiments to validate the precision of the assay in quantifying MT-ATP6 variants and their fraction among the total mtDNA copy number. In addition, our data indicated that this assay is highly sensitive. To allow high-throughput screening, we then developed an R-based analysis pipeline to streamline the analysis workflow for determining MT-ATP6 variant fractional abundance. Our data demonstrated that the assay achieved the high resolution required to differentiate various heteroplasmic MT-ATP6 alleles. Future studies can build upon the current protocol and develop similar ddPCR assays to perform high-throughput screening for the identification of cell lines or tissue samples with specified mtDNA alleles.
    DOI:  https://doi.org/10.3791/73416
  11. Physiol Rep. 2026 Oct;pii: e71155. [Epub ahead of print]14(20):
    Estradiol-PGC-1 signaling in mitochondrial health: Implications for perimenopause and cardiovascular disease.
    Alyssa L Parten, Glenn C Rowe.
      Cardiovascular disease (CVD) is the leading cause of death in aging women. While CVD etiology is multifactorial, mitochondrial dysfunction, characterized by reduced content, impaired energy production, and increased oxidative stress, is an underlying contributor. These impairments reduce the ability of the heart and vasculature to support peripheral tissues. Estradiol, a key sex hormone with widespread physiological effects, supports mitochondrial function, lipid oxidation, vascular endothelial cell and smooth muscle function, and redox balance, contributing to its cardioprotective effects in women. Perimenopause is marked by hormonal variability and an overall decline in estradiol concentrations that may compromise mitochondrial quality and vascular function, increasing CVD risk. Mitochondrial quality and maintenance are largely controlled by the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators. Impairments in PGC-1 isoform expression have been linked to cardiovascular and metabolic decline and may be exacerbated by estradiol loss during the menopause transition. However, the mechanisms by which estradiol signaling regulates PGC-1 isoforms, and how this interaction contributes to mitochondrial dysfunction and CVD development following menopause, have not been comprehensively described. Thus, this review aims to highlight current evidence on the individual and overlapping roles of estradiol and PGC-1 isoforms and examine how their interaction may contribute to the development of CVD following menopause.
    Keywords:  PGC‐1; cardiovascular; estradiol; estrogen; menopause; mitochondria
    DOI:  https://doi.org/10.14814/phy2.71155
  12. Cureus. 2026 Sep;18(9): e116575
    Imaging Characteristics in the Ataxia-Neuropathy Spectrum Related to POLG Mutation.
    Abraham Alhatou, Omar M Alhatou, Mohamed Ghamoodi, Mohammed Alhatou.
      Mutations in the mitochondrial DNA polymerase gamma (POLG) gene cause a broad spectrum of neurodegenerative disorders, including the ataxia-neuropathy spectrum (ANS). Substantial phenotypic heterogeneity and overlapping clinical features can delay diagnosis. We report a 38-year-old woman with no significant past medical history who presented with a three-year history of slowly progressive sensory ataxia that worsened in the dark. Examination revealed mild dysarthria, large-fiber sensory loss, and a positive Romberg sign. Extensive metabolic, toxic, autoimmune, and infectious work-up was unrevealing. Nerve conduction studies confirmed a mild peripheral sensory neuropathy. Brain magnetic resonance imaging (MRI) demonstrated distinct bilateral, symmetric T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensities in the dorsomedial thalami and cerebellar white matter. Whole-exome sequencing confirmed a homozygous W748S mutation in the POLG gene, establishing a diagnosis of POLG-related ANS. This imaging pattern, though not specific to POLG-related disease, may support earlier consideration of targeted genetic testing when present alongside a compatible clinical picture.
    Keywords:  ataxia-neuropathy spectrum; dorsomedial thalamus; mitochondrial disease; polg mutation; sensory ataxia; w748s
    DOI:  https://doi.org/10.7759/cureus.116575
  13. Biogerontology. 2026 Oct 19. pii: 182. [Epub ahead of print]27(6):
    Established determinants of replicative lifespan, including mitochondrial DNA, play a limited role in early yeast stress-resistance decline.
    Aglaia V Azbarova, Kseniia V Galkina, Dmitry A Knorre.
      Baker's yeast is a long-standing model for studying mechanisms of aging. Due to asymmetric division, yeast mother and daughter cells are distinguishable, and mother cells usually cease division after 15-25 budding events. However, yeast suspensions consist predominantly of young cells. Here we investigated whether, under harsh environmental conditions, replicative aging-defined by the number of buds produced-manifests at early replicative ages. To test this, we adapted a flow-cytometry-based pulse-chase labeling method to track the survival of cells of increasing replicative age, from daughter cells to mother cells that had produced up to eight buds on average. We found that stress-induced mortality increased with replicative age across all nine stress conditions tested. Mitochondrial dysfunction, caused by depletion of mitochondrial DNA, altered basal stress resistance for some stresses but largely preserved the age-dependent decline in stress resistance across conditions. Similarly, deletion of FOB1, which extends replicative lifespan under optimal conditions, did not markedly alter this decline under heat shock or acetic acid. In contrast, deletion of SIR2, which shortens replicative lifespan, steepened the age-mortality slope under acetic acid stress but not under heat shock. Together, our data indicate that aging manifests early in life under various extreme environments, and that the genetic determinants of maximum replicative lifespan tested here are largely dispensable for the early decline in stress resistance.
    Keywords:  Early onset of aging; Mitochondria; Replicative aging; Stress resistance; Yeast
    DOI:  https://doi.org/10.1007/s10522-026-10528-8
  14. Epigenetics Chromatin. 2026 Jul 26. pii: 44. [Epub ahead of print]19(1):
    Apparent methylation of mitochondrial DNA in WGBS is dominated by technical artifacts.
    Jing-Jing Yin, Zhi-Chao Gong, Shi-Qing Mao.
       BACKGROUND: DNA methylation is a critical epigenetic modification that occurs on cytosine residues and plays essential roles in regulating gene expression, cellular differentiation, and genomic imprinting. However, the existence of cytosine methylation in mitochondrial DNA (mtDNA) remains highly controversial. Whole-genome bisulfite sequencing (WGBS) has been widely used to assess mtDNA methylation, but signals detected in mitochondrial DNA are frequently influenced by technical artifacts.
    RESULTS: We systematically evaluated technical factors that influence mtDNA methylation measurements using zebrafish WGBS datasets derived from a wide range of tissues and experimental conditions, complemented by analyses of human and mouse datasets. mtDNA methylation measurements varied widely among samples within CpG, CHG, and CHH contexts, and mtDNA CpG methylation estimates above 2% were often accompanied by comparable CHG and CHH methylation estimates, even when lambda DNA CpG methylation remained below 2%. Notably, samples lacking documented DNA fragmentation tended to show substantially elevated mtDNA methylation compared with those subjected to fragmentation. Although strand-specific sequencing biases were common, they were not a sufficient cause of elevated false-positive methylation signals. The degree of strand coverage imbalance did not predict high methylation in datasets with documented fragmentation, and high methylation in undocumented samples was preferentially observed where strand coverage was balanced rather than imbalanced. Kit annotations were associated with dataset-level variation in mtDNA methylation, particularly for library preparation kits, but elevated signals were not confined to any single bisulfite conversion or library preparation kit. Cross-species analyses showed that human and mouse datasets displayed comparable patterns of elevated mtDNA methylation.
    CONCLUSIONS: Our findings indicate that high mtDNA methylation signals detected in WGBS data are dominated by technical artifacts, particularly DNA fragmentation status and bisulfite conversion efficiency. These results highlight the need for careful interpretation of mitochondrial methylation signals and provide a framework for distinguishing technical noise from potential biological signals in WGBS-based analyses.
    Keywords:  Bisulfite conversion; DNA fragmentation; Epigenetics; Mitochondrial DNA (mtDNA) methylation; Strand bias; Technical artifacts; Whole-genome bisulfite sequencing (WGBS)
    DOI:  https://doi.org/10.1186/s13072-026-00692-z
  15. Orphanet J Rare Dis. 2026 Jul 24. pii: 372. [Epub ahead of print]21(1):
    Developing a rare disease registry for inherited metabolic disorders in Pakistan.
    Lena Jafri, Hafsa Majid, Sibtain Ahmed, Azeema Jamil, Saba Abdul Mateen, Akhtar Shah, Aysha Habib Khan.
       BACKGROUND: Inherited metabolic disorders (IMDs) underrecognized and underreported in Pakistan because of fragmented data systems, limited surveillance, and constrained diagnostic resources. We aimed to establish a continuous registry for IMDs to generate structured epidemiological, clinical, and biochemical data in a genetically heterogeneous population with high rates of consanguinity.
    METHODS: A single-center rare disease registry for IMDs was developed at the Biochemical Genetics Laboratory, Aga Khan University Hospital, Pakistan, and implemented between 2024 and March 2026 using retrospective consolidation of cases from January 2013 onward, followed by prospective real-time data capture. Demographic, clinical, and biochemical data were collected through structured case report forms and linked laboratory records. Registry performance was monitored using predefined indicators, including case volume, number of diagnostic categories, and data quality assessed through three audit cycles, 12 staff training rounds, and source verification procedures.
    RESULTS: The registry included 3,880 unique cases from January 2013 to March 2026 and documented 59 distinct IMDs across all four provinces of Pakistan. Parental consanguinity was reported in 66.5% of cases (n = 2,584). The most frequently identified disorders were methylmalonic aciduria (n = 555), biotinidase deficiency (n = 287), and urea cycle disorders (n = 218). The final data dictionary comprised 14 categories and 384 common data elements. Quality control measures, including 12 training rounds and periodic audits, improved data accuracy and completeness from 60% to 96% to enable successful registry integration. Piloting data collection tools achieved > 90% completeness in demographic and clinical fields.
    CONCLUSION: This first registry for IMDs in Pakistan provides a structured, quality-assured epidemiological resource for defining the burden and spectrum of these disorders. The registry establishes a foundation for improved diagnosis, service planning, policy development, and future multicenter rare disease research.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Amino acids; Inherited metabolic disorders; Organic acids; Rare; Registry
    DOI:  https://doi.org/10.1186/s13023-026-04510-3
  16. Mol Biomed. 2026 Oct 23. pii: 225. [Epub ahead of print]7(1):
    The sirtuin family: from mechanisms to therapy.
    Jiaying Xiao, Yiling Li, Yuyao Xie, Yuan Chen, Qihan Liu, Hao Li, Rui Sun.
      Sirtuins (SIRT1-SIRT7) are evolutionarily conserved NAD+-dependent deacylases that function as metabolic sensors, coupling cellular metabolic state to epigenetic, transcriptional and post-translational regulatory programs across distinct subcellular compartments. Despite two decades of research, isoform- and disease-specific aspects remain poorly integrated, limiting both conceptual clarity and therapeutic translation. This review synthesizes recent advances in sirtuin biology into a family-wide framework. Rather than functioning as isolated longevity factors, sirtuins operate as a distributed compartmentalized regulatory network in which nuclear SIRT1, SIRT6 and SIRT7, cytosolic SIRT2 and mitochondrial SIRT3, SIRT4 and SIRT5 collectively govern glucose and lipid metabolism, mitochondrial quality control, autophagy, inflammation and immune tolerance. This network operates across metabolic disorders, cardiovascular and neurodegenerative diseases, inflammatory conditions and cancer, where dysregulated sirtuin signalling influences disease development in a disease- and tissue-specific manner. Therapeutic strategies are evaluated, ranging from isoform-selective small-molecule modulators and NAD+-targeted interventions to emerging protein-degradation approaches, with isoform selectivity, off-target effects and the systemic consequences of NAD+ modulation identified as key translational barriers that have contributed to heterogeneous clinical outcomes. Viewing sirtuins as a context-sensitive compartmentalized network, not isolated targets, offers a coherent framework to guide mechanistic interrogation and the design of more precise sirtuin-based therapies, with priority areas including tissue-selective degradation and network-level biomarkers.
    Keywords:  Immunity; Metabolism; NAD+ ; Sirtuins; Therapeutics
    DOI:  https://doi.org/10.1186/s43556-026-00631-0
  17. ACS Chem Biol. 2026 Sep 18. 21(9): 2441-2450
    Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
    Harman Kaur, John Soukar, Nikita Gudekar, Vinit C Shanbhag, Michael J Petris, Akhilesh K Gaharwar, Vishal M Gohil.
      Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.
    DOI:  https://doi.org/10.1021/acschembio.6c00564
  18. Ther Innov Regul Sci. 2026 Oct 23.
    Investigator-Initiated Trials as a Clinical Development Approach for Orphan Drugs Compared with Industry-Sponsored Trials in Japan.
    Shingo Yamaguchi, Eiji Nakatani, Ryuta Asada.
      Orphan drug development faces substantial economic and operational challenges, particularly in small patient populations where conventional industry-sponsored trials (ISTs) may be difficult to conduct. In Japan, investigator-initiated trials (IITs) have been used to support the development of treatments for rare diseases and other areas of high unmet medical need; however, the characteristics of orphan drug approvals supported by IITs compared with those supported by ISTs have not been fully evaluated. This study analyzed pivotal trials supporting orphan drug approvals in Japan between 2015 and 2024 and compared the trial and regulatory characteristics of IIT- and IST-supported approvals. Among 1,269 drugs approved, 260 orphan drugs were included in the final analysis. IITs were used as pivotal trials in 11.2% of approvals. All IITs were Japan-only trials, whereas 52.4% of ISTs involved global trials. The Japanese patient population coverage ratio was higher for IIT-supported than IST-supported approvals in the overall comparison (median 2.2% vs. 0.5%, p = 0.003). However, the difference was attenuated when the comparison was restricted to Japan-only ISTs. Multivariable logistic regression analysis identified additional indications, Phase II trials, and smaller estimated target populations in Japan (100-999 patients) as characteristics associated with IIT-supported approvals. When the number of study sites was modeled continuously in a sensitivity analysis, fewer study sites were associated with IIT-supported approvals. Among orphan drugs approved in Japan, IIT-supported approvals showed distinct trial characteristics compared with IST-supported approvals. These findings describe characteristics of approved IIT-supported medicines and may inform future academia-led orphan drug development.
    Keywords:  Clinical trials; Drug development strategy; Investigator-initiated trials; Orphan drugs; Regulatory approval
    DOI:  https://doi.org/10.1007/s43441-026-01063-2
  19. Signal Transduct Target Ther. 2026 Oct 20. pii: 458. [Epub ahead of print]11(1):
    Mitophagy coordinates organelle crosstalk in health and diseases.
    Mengyao Wu, Pengyi He, Yajun Lian, Tuo Zhang, Yiqi Wu, Lu Wang, Daolin Tang, Yongming Yao, Renqi Yao.
      Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.
    DOI:  https://doi.org/10.1038/s41392-026-02812-3
  20. Pharmacol Ther. 2026 Oct 21. pii: S0163-7258(26)00160-9. [Epub ahead of print] 109133
    Navigating the landscape of stem cell therapeutics: Overcoming translational hurdles via emerging technologies and regulatory frontiers.
    Se-Young Oh, Yoon Shin Park, Byung Hyune Choi, Han Su Kim, Sung-Chul Jung, Inho Jo.
      Global population aging has increased the incidence of intractable diseases. Accordingly, regenerative medicine using stem cell therapies offers a critical shift from symptom management to functional tissue restoration. Hematopoietic, mesenchymal, and pluripotent stem cells (embryonic and induced pluripotent stem cells) have shown promising therapeutic potential. However, their clinical translation is constrained by persistent biological, manufacturing, and regulatory hurdles associated with genomic instability, tumorigenic risk, and batch-to-batch heterogeneity. This review provides a comprehensive overview of the current stem cell research landscape, highlighting the strategic shift from traditional cell-centric development to a multi-disciplinary and technology-driven approach. Emerging technologies, including three-dimensional organoids, advanced biomaterials, genome editing, and artificial intelligence-integrated automated manufacturing, are actively resolving long-standing translational bottlenecks to ensure scalable, safe, and reproducible clinical implementation. Regulatory approaches differ across major countries; however, the trend toward incorporating patient needs is growing. This has accelerated access to innovative therapies, with ongoing efforts to ensure that these advances do not compromise safety or efficacy. Moving forward, the successful clinical integration of next-generation stem cell therapeutics is likely to be shaped by the synergy between harmonized regulatory requirements and reliable real-world evidence. Collectively, these factors serve to bridge the transition from early patient access to definitive licensing.
    Keywords:  Advanced bioengineering; Clinical translation; Regenerative medicine; Regulatory and clinical landscape; Stem cell therapy
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109133
  21. Seizure. 2026 Oct 13. pii: S1059-1311(26)00308-0. [Epub ahead of print]143 132-140
    DHDDS variants in epilepsy and movement disorders: Two novel mutations and an updated literature review.
    Guoping Ren, Ruijuan Lv, Shengsong Wang, Jiaqing Yan, Yueqian Sun, Tao Cui, Weixiong Shi, Jiechuan Ren, Chunqing Yang, Chao Chen, Zhimei Li, Maomao Liu, Xiaoqiu Shao, Qun Wang.
       INTRODUCTION: Recent evidence suggests that dehydrodolichol diphosphate synthase (DHDDS, MIM*608,172) gene variation can cause neurological diseases. However, the complete clinical and genetic spectrum of DHDDS-related disorders has not been fully elucidated. This study aims to systematically describe the clinical and genetic features of five patients with molecularly confirmed DHDDS variants and to provide an updated review of previously reported cases.
    METHODS: We retrospectively enrolled patients with DHDDS gene variants in the Epilepsy Center of Beijing Tiantan Hospital, Capital Medical University from 2021 to 2023. Clinical, neuroimaging, electrophysiological and genetic data were collected. Whole‑exome sequencing and Sanger validation were performed for variant identification and ACMG‑based classification. PubMed was searched using the term "DHDDS" to identify previously reported cases. The clinical and genetic characteristics of the eligible cases were summarized descriptively.
    RESULTS: Five patients in our hospital with two novel DHDDS variants (c.623G>A, p.G208E and c.697C>A, p.P233T) were reported. A total of 74 patients (3 from our center and 71 from the literature) carrying pathogenic or likely pathogenic variants were collected for the final analysis. The most prevalent variants were c.632G>A (p.R211Q, n = 26, 35.14%), c.110G>A (p.R37H, n = 16, 21.62%), c.109C>T (p.R37C, n = 9, 12.16%), and c.614G>A (p.R205Q, n = 9). The most common clinical manifestations included epilepsy (n = 64, 86.49%), intellectual disability (n = 62, 83.78%), ataxia (n = 50, 67.57%), global developmental delay (n = 50, 67.57%), tremor (n = 48, 64.86%), and myoclonus (n = 44, 59.46%). No significant phenotypic differences were observed among patients carrying different variants.
    CONCLUSION: This study expanded the phenotypic spectrum of diseases related to DHDDS and reported two new variations. For cases of developmental epileptic encephalopathy of unknown cause, progressive myoclonus or complex movement disorders, DHDDS gene screening should be considered.
    Keywords:  Ataxia; DHDDS; Epilepsy; Intellectual disability; Tremor
    DOI:  https://doi.org/10.1016/j.seizure.2026.10.007
  22. J Neuromuscul Dis. 2026 Oct 21. 22143602261463646
    RYR1-related diseases patient-led international research workshop: Novel perspectives, treatments and interventions.
    Pomi Yun, Lourdes Figueroa, Chang Seok Lee, Filip Van Petegem, Nicol C Voermans, Robert T Dirksen, Michael F Goldberg, Līvija Medne, Jinson Paul, Mairéad Ryan, Emily Pedersen, Johanna Lanner, Payam Mohassel.
      RYR1-related diseases (RYR1-RDs) encompass a wide spectrum of disease manifestations with limited available disease-modifying therapies. The RYR1-RD phenotypes include congenital myopathies of different histotypes often with early-onset muscle weakness, feeding difficulties, and respiratory insufficiency of varying severity. RYR1-RDs also include a group of episodic diseases such as exercise intolerance, exertional rhabdomyolysis, periodic paralysis, and malignant hyperthermia susceptibility. The RYR-1 Foundation hosted the second patient-led international research workshop focused on RYR1-RDs which was held on July 23rd-24th, 2025 in Pittsburg, Pennsylvania, USA that included a group of affected individuals, clinicians, and researchers to review the current status of research, and to evaluate high-priority areas for future research to enable development of therapeutics with direct involvement of affected individuals in the design and topics of this workshop. Identified high-priority areas were organized into six sessions: 1) Diagnosis and Genetics of RYR1-RDs, 2) Establishing Clinical Trial Readiness for RYR1-RDs, 3) Novel Insights into RYR1 Pathophysiology, 4) Disease Models and Translational Studies in RYR1-RD, 5) The Therapeutic Development Pipeline, and 6) Physical Therapy and Exercise in RYR1-RDs. Several novel disease models and novel DNA- and RNA-directed therapies were discussed. To establish clinical trial readiness, prospective natural history studies to optimize outcome measures and biomarkers with exploration of imaging modalities and wearable sensors are ongoing. This article provides a cohesive summary of the presentations that encompasses basic research from structural biology and preclinical models to clinical trials, and novel therapeutic development strategies for RYR1-RD as a comprehensive narrative for the neuromuscular and rare disease research audience.
    Keywords:  RYR1-RD; clinical trials; neuromuscular disease; patient-focused workshop; research workshop
    DOI:  https://doi.org/10.1177/22143602261463646
  23. Hypertens Pregnancy. 2026 Dec 31. 45(1): 2734436
    Placental mitochondrial impairment in preeclampsia patients.
    Ramana Vaka, Elizabeth Hinton, Kristin Edwards, Babbette LaMarca.
      Preeclampsia is a pregnancy-specific hypertensive disorder characterized by new-onset hypertension after 20 weeks of gestation, accompanied by end-organ dysfunction with or without proteinuria. Affecting approximately 5-7% of pregnancies worldwide, it remains a leading cause of maternal and fetal morbidity and mortality. Despite decades of research, the underlying pathophysiology of preeclampsia remains incompletely understood. However, increasing evidence implicates placental mitochondrial oxidative stress in its pathogenesis. In this review, we summarize the current literature pertaining to ultrastructural evidence of mitochondrial damage, defects in oxidative phosphorylation and electron transport chain activity, and alterations in reactive oxygen species production, antioxidant defense, and mitochondrial biogenesis. Finally, we discuss translational considerations and highlight how therapeutic strategies targeted at restoring mitochondrial function may represent a promising approach for managing preeclampsia.
    Keywords:  Bioenergetics; mitochondria; placenta; preeclampsia; reactive oxygen species
    DOI:  https://doi.org/10.1080/10641955.2026.2734436
  24. Front Pharmacol. 2026 ;17 1911495
    Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety.
    Zhi-Yun Xiang, Xiu-Hua Yang, Wen-Ying Lan, Xin-Yu Xiao, Qun Huang, Lin-Lin Yang.
       Background: Dysregulated mitochondrial dynamics, including fission, fusion, biogenesis, and mitophagy, underlie the pathogenesis of many diseases. Natural products have the potential for multi-target therapy, but insufficient understanding of their mechanisms of action and pharmacokinetic limitations hinder their clinical translation.
    Objective: This review proposes a regulatory framework covering the four dimensions of biogenesis, morphology, quality control, and defense, aiming to systematically clarify how natural products regulate mitochondrial function and critically evaluate their translational potential. The framework emphasizes that inter-organelle contact platforms, such as mitochondria-endoplasmic reticulum contact sites (MERCs) and mitochondrial-lysosomal contact sites (MLCs), are key sites through which natural products exert regulatory effects.
    Methods: Major scientific databases, including PubMed, Web of Science, and Scopus, were searched, and evidence on mechanisms, pharmacokinetics, and toxicology from preclinical and clinical studies was comprehensively reviewed.
    Results: Natural products can selectively regulate key mitochondrial pathways and regulatory nodes, including the AMPK/SIRT1/PGC-1α axis involved in mitochondrial biogenesis, the DRP1 axis involved in mitochondrial fission, and the PINK1/Parkin pathway involved in mitophagy. Representative metabolites include resveratrol, curcumin, and Coptis chinensis-derived alkaloids. A key finding of this review is that the intestinal microbiota plays an important role in converting low-bioavailability precursors, such as tannins, into systemically active metabolites, such as urolithin A (UA), thus inducing mitophagy. Although these metabolites usually show strong activity in vitro, their low oral bioavailability and rapid metabolism lead to significant pharmacokinetic/pharmacodynamic (PK/PD) mismatch, which remains a major obstacle to their clinical translation.
    Conclusion: Natural products are powerful multidimensional regulators of mitochondrial homeostasis. In order to fully realize their therapeutic potential, strategies must be adopted to overcome PK/PD mismatch, including the development of targeted delivery systems, in-depth analysis of microbiome-metabolite interactions, and the integration of artificial intelligence and CRISPR-based technological innovation to support precision therapy.
    Keywords:  gut microbiota–mitochondria axis; mitochondrial dynamics; mitohormesis; mitophagy; natural products; pharmacokinetics
    DOI:  https://doi.org/10.3389/fphar.2026.1911495
  25. Front Physiol. 2026 ;17 1975105
    Rethinking mitochondrial isolation for the next generation of mitochondrial therapies.
    Ethan A Simpson, Celina Phan, Jason P Acker.
      Mitochondrial isolation is fundamental to the study of mitochondrial biology and is increasingly relevant to emerging therapeutic applications such as mitochondrial transplantation. However, isolation procedures can substantially influence mitochondrial yield, purity, structural integrity, and bioenergetic function, making method selection an important determinant of experimental and translational outcomes. This review examines current mitochondrial isolation strategies, including physical disruption, chemical permeabilization, emerging microfluidic and automated dissociation technologies, and downstream separation approaches such as differential centrifugation, density-gradient centrifugation, filtration, and immunoaffinity enrichment. Each approach offers distinct advantages and limitations depending on the biological source, processing requirements, and intended application. Conventional methods remain widely used because of their accessibility and flexibility, but may introduce operator variability, mechanical stress, contamination, or loss of mitochondrial function. More selective purification strategies can improve sample purity, although often at the cost of additional processing time, technical complexity, and reduced recovery. Emerging technologies, including standardized mechanical dissociation and microfluidic disruption, may provide greater control over mitochondrial release, but require broader validation across tissues and sample volumes. A persistent challenge across isolation workflows is balancing mitochondrial recovery with preservation of organelle integrity and function. Future progress will require standardized, scalable isolation strategies that consistently preserve mitochondrial quality across different biological sources and downstream applications. Continued refinement of these approaches will be essential for advancing mitochondrial research and supporting the development of mitochondrial-based therapies.
    Keywords:  bioprocessing; isolation; mitochondria; oxidative injury; stabilization
    DOI:  https://doi.org/10.3389/fphys.2026.1975105
  26. Exp Neurol. 2026 Oct 18. pii: S0014-4886(26)00446-2. [Epub ahead of print]408 116078
    A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
    Abida Khan, Talha Jawaid, Zia Ur Rehman, Mohammed Kanan Alshammari, Md Afroz Bakht, Faiyaz Shakeel, Mohammed Zawiah, Mohd Imran.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.
    Keywords:  Mitochondrial dysfunction; Mitophagy; Oxidative stress; PINK1/Parkin; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2026.116078
  27. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  28. Orphanet J Rare Dis. 2026 Jul 24. pii: 374. [Epub ahead of print]21(1):
    The new frontier of newborn screening: integrating genomics, metabolomics, and data science for inborn errors of metabolism.
    Muhammad Wasim, Yajun Wang, Guoda Ma.
      Newborn screening (NBS) for inborn errors of metabolism (IEMs) represents one of the most successful public health initiatives of the past century. Originating with the simple bacterial inhibition assay for phenylketonuria, the field was revolutionized by tandem mass spectrometry (MS/MS). Today, we stand at the precipice of a second, more profound revolution driven by the convergence of high-throughput genomics, next-generation metabolomics, and advanced data science. This review articulates this paradigm shift, detailing how MS/MS is being augmented by targeted DNA analysis and how whole genome sequencing and untargeted metabolomics, integrated with artificial intelligence, are expanding the detectable universe of disorders and enabling precision interventions. However, this powerful multi-omic approach raises critical challenges: incomplete penetrance, overdiagnosis, economic burden, psychosocial impacts, algorithm biases, and the genomic data gap that exacerbates health disparities. We critically examine the practical limitations of AI, the lack of evidence for cost-effectiveness, the slow pace of database updates, and the need for short-term reanalysis systems to "rescue" cases left undiagnosed. Global policy variations and data-sharing governance frameworks are also addressed. We conclude that the future of NBS lies not in sequential technology replacement, but in the responsible creation of a sophisticated, multi-omic biomedical information system to transform NBS into a foundational pillar of precision pediatric medicine.
    Keywords:  Inborn errors of metabolism; Metabolomics; Newborn screening; Precision medicine; Tandem mass spectrometry
    DOI:  https://doi.org/10.1186/s13023-026-04513-0
  29. Drug Discov Today. 2026 Oct 20. pii: S1359-6446(26)00244-8. [Epub ahead of print] 104839
    Patient access to cell and gene therapies in Europe: stakeholder perspectives on impeding factors across the medicine lifecycle.
    Christine C van Hattem, Jurriaan Gort, Renske M T Ten Ham, Toine C G Egberts, Lourens T Bloem.
      Cell (including tissue) and gene therapies (CGTs) have the potential to address unmet medical needs, yet few have successfully navigated the medicine lifecycle toward patient access in Europe because of impeding factors with possibly different stakeholder perspectives. Through a scoping review, we identified 991 document-stakeholder-theme combinations across 30 major themes of impeding factors and seven lifecycle categories. Most frequently reported themes were legislation & regulatory framework and capacity, resources, expertise, followed by uncertainty in regulatory & reimbursement assessments, quality requirements, and collaboration & coordination. Several stakeholders and product types were under-represented. We recommend active multistakeholder collaboration in designing legislation and capacity building to sustain patient access.
    Keywords:  ATMPs; Europe; advanced therapy medicinal products; cell therapy; gene therapy; medicine lifecycle; patient access; regulation; reimbursement; tissue engineering
    DOI:  https://doi.org/10.1016/j.drudis.2026.104839
  30. iScience. 2026 Nov 20. 29(11): 117791
    Global epidemiological and genetic burden of rare neurological diseases in children.
    Zhihao Xie, Chengyue Sun, Wei Liang, Xiuli Zhao, Long Miao, Xingbo Liu, Yanyu Lu, Chang Liu, Zihan Yin, Jinliang Li, Zhiying Xie.
      We assessed the global burden of rare childhood neurological diseases from 1990 to 2021 and projected trends to 2050 using Global Burden of Disease data, alongside an analysis of the genetic burden from ClinVar. Four neurological conditions were classified as rare childhood neurological diseases: motor neuron disease, multiple sclerosis, neuroblastoma and other peripheral nervous cell tumors, and other neurological disorders. From 1990 to 2021, the global age-standardized prevalence and disability-adjusted life-year rates of rare childhood neurological diseases increased, with higher burdens among boys and in low-middle sociodemographic index countries. Our customized forecasting model projected that 110.2 thousand children would be affected by 2050, representing an 11.83% increase from 2021. Annual and cumulative increases in newly reported disease-causing genes and pathogenic/likely pathogenic variants associated with monogenic neurological diseases were observed from 1990 to 2024. The increasing and disparate burden of rare childhood neurological diseases highlights the need for targeted prevention.
    Keywords:  ClinVar; GBD; childhood; genetic evidence; global burden; rare neurological diseases
    DOI:  https://doi.org/10.1016/j.isci.2026.117791
  31. Mol Genet Metab. 2026 Oct 18. pii: S1096-7192(26)00580-9. [Epub ahead of print]149(4): 110297
    Biotin-dependent carboxylases and related disorders: Comparative mechanisms and therapeutic advances.
    Shuang Tan, Cunshuo Yu, Xiaoqing Li, Suhong Zhu, You Wang.
      Biotin-dependent carboxylases (BDCs), including pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and the ACC1/ACC2 isoforms of acetyl-CoA carboxylase (ACC), are core enzymes of intermediary metabolism. Inherited deficiencies of several BDCs, together with disorders of biotin utilization such as holocarboxylase synthetase and biotinidase deficiencies, produce a heterogeneous group of metabolic disorders, although the strength of human disease evidence differs markedly among individual enzymes. This review compares the domain architecture and shared two-site catalytic mechanism of these enzymes, including the biotin-carrying swinging arm. It then contrasts the clinical phenotypes and molecular mechanisms of the primary carboxylase deficiencies and the disorders of biotin utilization. Diagnostic approaches and current management are outlined, followed by a critical appraisal of emerging disease-modifying therapies, with propionic acidemia as the most extensively studied translational model spanning gene therapy, mRNA replacement, enzyme replacement, small-molecule candidates, and anaplerotic strategies. We conclude that a shared catalytic principle does not imply shared disease biology, and that treatment strategies must be matched to the metabolic context of each disorder.
    Keywords:  Biotin-dependent carboxylases; Emerging therapies; Inherited metabolic diseases; Multiple carboxylase deficiency; Propionic acidemia
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110297
  32. Calcif Tissue Int. 2026 Oct 20. pii: 165. [Epub ahead of print]117(1):
    Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction.
    Ting Ji, Tengbo Pei, Jian Yang, Ting Wan, Yang Zhang, Xin Ma, Meng He, Tianyan Gu, Rongzeng Lu, Wentao Guo.
      Methylmalonic acid (MMA) is a functional marker of vitamin B12 insufficiency and an emerging metabolic factor associated with skeletal aging and osteoporosis. This review synthesizes epidemiological, experimental, and mechanistic evidence linking the vitamin B12-MMA axis to impaired bone homeostasis. Population studies associate elevated circulating MMA with lower bone mineral density, higher odds of osteoporosis, and lower knee extensor strength, while disturbed vitamin B12 metabolism has also been linked to altered bone turnover. Experimental MMA exposure and models of methylmalonyl-CoA mutase (MMUT) deficiency reveal context-dependent abnormalities in mitochondrial respiration, energy metabolism, redox balance, and quality control. These findings provide a rationale for investigating skeletal effects, but the broader consequences of vitamin B12 deficiency and inherited metabolic defects should be distinguished from direct MMA actions in bone cells. Concurrent homocysteine accumulation and reduced S-adenosylmethionine availability may further impair collagen cross-linking, epigenetic regulation, and skeletal remodeling. These pathways support a metabolic-mitochondrial framework in which functional vitamin B12 deficiency contributes to bone loss through coordinated effects on bioenergetics, redox balance, cell fate, and extracellular matrix quality. MMA may therefore complement vitamin B12, homocysteine, renal function, and conventional bone markers in the assessment of skeletal metabolic risk. Prospective human studies, bone-specific mechanistic experiments, and intervention trials are needed to establish causality, clinically useful thresholds, and the skeletal benefits of correcting vitamin B12 deficiency or targeting mitochondrial dysfunction.
    Keywords:  Methylmalonic acid; Mitochondrial dysfunction; Osteoporosis; Skeletal aging; Vitamin B12 deficiency
    DOI:  https://doi.org/10.1007/s00223-026-01622-7
  33. Med Phys. 2026 Nov;pii: e70686. [Epub ahead of print]53(11):
    Learning global and local representations for generalized category discovery in neurodegenerative diseases.
    Yu Shen, Xiangli Yang, Yixiang Hu, Kai Qiao, Jinjin Hai, Jian Chen, Bin Yan.
       BACKGROUND: Artificial intelligence (AI) has achieved notable success in closed-set classification of neurodegenerative diseases, but its performance degrades significantly in more realistic open-set settings, such as discovering rare or novel disease subtypes from unlabeled data that are not seen during training.
    PURPOSE: This study introduces, to our knowledge, the first framework for generalized category discovery (GCD) in neurodegenerative diseases using MRI. It aims to leverage labeled data from known categories to automatically identify novel categories within unlabeled datasets.
    METHODS: We propose a GCD framework integrating semi-supervised contrastive learning with global-local representation learning to jointly optimize feature learning. Globally, we enforce consistency between weakly augmented views of the same instance by aligning their similarity relationships with other embeddings in a support queue. Locally, we treat neighborhood embeddings from the support queue as positive pairs for cross-instance contrastive learning, enhancing fine-grained discrimination. This dual strategy results in a unified learning objective that is applicable to both labeled and unlabeled data, effectively narrowing the representation gap among semantically similar instances.
    RESULTS: We evaluate our method on a benchmark dataset comprising six neurodegenerative diseases, with over 1500 patient samples. Experimental results demonstrate that our framework consistently outperforms representative state-of-the-art methods. Specifically, our method achieves 66.02% Accuracy and 60.59% Normalized Mutual Information on all categories, and 54.53% Accuracy and 16.67% Normalized Mutual Information on novel categories, surpassing existing state-of-the-art methods.
    CONCLUSIONS: Our framework underscores the model's robustness and its practical value in discovering new neurodegenerative disease conditions, highlighting its potential for advancing open-set diagnostic AI.
    Keywords:  contrastive learning; generalized category discovery; global and local representations; magnetic resonance imaging (MRI); medical image classification; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/mp.70686
  34. Pharmaceut Med. 2026 Oct 23.
    Ataxia Therapeutics: A Comprehensive Overview of the Clinical Development Pipeline.
    Marisa Cappella, Nicoletta Locuratolo, Marco Salvatore, Agata Polizzi, Elena Carbone, Federica Perrone, Guido Bellomo, Nicola Vanacore, Eleonora Lacorte, Paola Piscopo.
      Ataxias are a heterogeneous group of rare neurological disorders characterized by progressive impairment of motor coordination and balance, caused by a broad range of genetic, immune-mediated, and degenerative mechanisms. Despite significant advances in molecular diagnostics and disease characterization, effective disease-targeted treatments remain limited, with omaveloxolone currently representing the only approved therapy for Friedreich's ataxia. In this review, we provide a comprehensive and up-to-date overview of the clinical drug development pipeline for ataxias, based on a systematic analysis of international clinical trial registries up to April 2026. One hundred and fifty-four interventional pharmacological trials investigating 66 therapeutic agents across phases 1-3 were identified. The majority of ongoing clinical efforts focus on symptomatic and supportive therapies, which together constitute more than half of the pipeline and include the most developmentally advanced programs. Neuroprotective therapies represent a substantial portion of trials but have shown mixed efficacy to date. In contrast, disease-targeted approaches, including gene therapies, antisense oligonucleotides, cell-based therapies, and protein replacement strategies, account for a smaller share of the pipeline and remain largely confined to early-phase development. More than half of investigational agents are repurposed compounds, reflecting a pragmatic strategy to accelerate therapeutic progress in rare disorders. Overall, the ataxia therapeutic landscape is expanding but remains fragmented, underscoring the need for improved patient stratification, validated biomarkers, harmonized registries, and international collaboration to enable the successful translation of emerging therapies into clinical practice.
    DOI:  https://doi.org/10.1007/s40290-026-00640-y
  35. Cureus. 2026 Sep;18(9): e116756
    Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.
    Ayesha Malik, Maryam Ferdousi, Shazli Azmi, Rayaz A Malik.
      Corneal confocal microscopy (CCM) is a rapid, non-invasive ophthalmic imaging technique that enables detailed visualization and quantification of small corneal nerve fibres. Although initially developed for the assessment of diabetic neuropathy, its application has broadened substantially, with increasing evidence supporting its value in a range of central neurodegenerative diseases. This narrative review synthesizes current findings on the use of CCM in dementia, multiple sclerosis, stroke, burning mouth syndrome, amyotrophic lateral sclerosis, trigeminal neuralgia, migraine and Parkinson's disease. Across these conditions, CCM consistently identifies measurable alterations in corneal nerve fibre density, length, branching and morphology, as well as changes in corneal immune cell populations. These structural abnormalities frequently correlate with disease severity, functional decline and clinical progression. In some disorders, CCM demonstrates diagnostic performance comparable to or exceeding existing biomarkers, and offers distinct advantages as a non-invasive, repeatable and objective measure that can detect early or subclinical neurodegeneration. Corneal confocal microscopy also shows potential as a prognostic and monitoring tool, particularly in conditions with limited reliable biomarkers. It may help stratify risk, track therapeutic response, and provide surrogate endpoints for clinical trials. Despite these strengths, several limitations remain, including modest sample sizes in some studies, variability in image interpretation, and difficulties differentiating between neurodegenerative conditions with overlapping patterns of nerve loss. Emerging automated analysis methods and artificial intelligence-based algorithms may help address these challenges by improving accuracy, reproducibility, and scalability. Overall, CCM represents a promising technique that bridges ophthalmology and neurology. A growing body of literature supports its utility across multiple neurodegenerative diseases, and further large-scale, longitudinal studies may help establish its role within routine clinical assessment and research.
    Keywords:  corneal confocal microscopy imaging; dementia; medical device technology development and assessment; neurodegeneration; parkinsons disease
    DOI:  https://doi.org/10.7759/cureus.116756
  36. J Inflamm Res. 2026 ;19 641837
    Mitochondria-Macrophage Interactions in Sepsis at Different Immune Stages: Integrating Immunometabolic Reprogramming, Organ Damage, and Therapeutic Strategies.
    Jiaqi Li, Yuting Sun, Meilin He, Xueyi Liao, Qingfang Zou, Shuming Pan.
      Sepsis is a life-threatening disorder caused by dysregulated host responses to infection, characterized by immune dysfunction, metabolic reprogramming, and multi-organ injury. Mitochondria, beyond their role in energy metabolism, act as central signaling hubs that integrate cellular metabolism, innate immunity, and inflammatory responses. Emerging evidence suggests that disrupted mitochondria-macrophage crosstalk forms a self-amplifying loop that drives excessive inflammation and organ dysfunction during sepsis. This review highlights recent advances in understanding how mitochondrial quality control and immunometabolic remodeling regulate macrophage activation and function. We discuss the impact of key metabolic pathways, including glycolysis, oxidative phosphorylation, tricarboxylic acid cycle remodeling, and fatty acid metabolism, on macrophage polarization, as well as the dynamic roles of mitophagy, mitochondrial biogenesis, and mitochondrial dynamics throughout sepsis progression. We further summarize current challenges and potential therapeutic strategies targeting the mitochondria-macrophage axis. Elucidating this regulatory network may provide new insights into precision medicine and the development of targeted therapies for sepsis.
    Keywords:  macrophages; metabolic reprogramming; mitochondria; mitochondrial quality control; multiple organ dysfunction; sepsis
    DOI:  https://doi.org/10.2147/JIR.S641837
  37. J Cell Mol Med. 2026 Oct;pii: e71412. [Epub ahead of print]30(20):
    Iron Homeostasis and Liver Diseases.
    Peng Yang, Zhitian Shi, Qin Huang, Zhihong Tu, Yue Sun, Lin Wang, Yonglong Wei.
      Iron is an essential micronutrient whose ability to cycle between ferric (Fe3+) and ferrous (Fe2+) states makes it crucial for physiological processes, including oxygen transport, DNA synthesis, and oxidative phosphorylation. However, because both deficiency and excess can cause severe pathology, precise regulation is critical. The liver plays a central role in systemic iron metabolism, and growing evidence identifies hepatic iron dyshomeostasis as a key catalyst in diverse liver disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), alcoholic liver disease, liver fibrosis, and hepatocellular carcinoma (HCC). Hepatic iron accumulation promotes liver injury primarily through oxidative stress, mitochondrial dysfunction, and ferroptosis. In this review, we synthesize the multi-layered regulatory landscape of hepatic iron homeostasis, encompassing systemic coordination, cellular fine-tuning, and epigenetic modifications. We thoroughly dissect the pathogenic impact of iron overload and critically evaluate emerging therapeutic strategies aimed at restoring iron balance, such as hepcidin mimetics and ferroptosis modulators. Finally, we discuss current literature gaps-including preclinical model limitations, the lack of standardized non-invasive biomarkers, and drug delivery bottlenecks-providing a clear roadmap for future translational research in iron-related liver pathologies.
    Keywords:  ferroptosis; hepatocellular carcinoma; iron homeostasis; liver fibrosis; metabolic dysfunction‐associated steatotic liver disease
    DOI:  https://doi.org/10.1111/jcmm.71412
  38. Nature. 2026 Oct;658(8137): 858-860
    How tech billionaires are disrupting biomedical science.
    Heidi Ledford.
      
    Keywords:  Diseases; Funding; Institutions
    DOI:  https://doi.org/10.1038/d41586-026-03311-9
  39. Cell Press Blue. 2026 Oct 07. pii: 100129. [Epub ahead of print]
    Context-specific hypermetabolism in humans with mitochondrial defects.
    Evan D Shaulson, Alexander J Sercel, Shannon Rausser, Samantha Leonard, Kathryn Whyte, Faris Zuraikat, Heather Seid, Qiuhan Huang, Alex Junker, Darshana Kapri, Mangesh Kurade, David Shire, Joanna Chen, Caroline Trumpff, Catherine Kelly, Natalia Bobba-Alves, Kris Englestad, Herman Pontzer, Wei Shen, Seth A Creasy, Edward L Melanson, Michael Rosenbaum, Marie-Pierre St-Onge, Dympna Gallagher, Michio Hirano, Martin Picard.
      Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.
    Keywords:  GDF15; doubly labeled water; energy expenditure; fatigue; hypermetabolism; metabolic phenotyping; mitochondrial disease; resting energy expenditure; sickness behavior; whole-room indirect calorimetry
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100129
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