bims-polgdi Biomed News
on POLG disease
Issue of 2026–03–08
forty-nine papers selected by
Luca Bolliger, lxBio
  1. Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
  2. Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
  3. The landscape of mitochondrial transplantation: A bibliometric analysis.
  4. Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.
  5. Mitochondrial complex assembly in epilepsy of primary mitochondrial disease origin.
  6. A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.
  7. Functions of J-domain proteins in mitochondrial protein biogenesis.
  8. Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
  9. [Decreased plasma citrulline is a biochemical marker in newborn screening for MT-ATP6-associated mitochondrial disease: two case reports and a literature review].
  10. Rare diseases: NICE lays out quality standard to improve diagnosis and treatment.
  11. Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
  12. MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
  13. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  14. Establishing a commercial solution for extremely rare genetic diseases.
  15. Function and regulation of the mitochondrial stress response.
  16. Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
  17. Mitochondrial function meets oncology: the multifaceted role of TFAM across cancer types.
  18. Mitochondrial transfer and transplantation in the immune cells: Mechanistic foundations, medical applications, and future prospects.
  19. Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
  20. Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
  21. Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
  22. Targeting mitochondrial quality control: Ginsenoside Rg1 as a therapeutic candidate for neuromuscular diseases.
  23. Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
  24. A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda.
  25. Loss of Splicing Homeostasis as a Hallmark of Aging.
  26. Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.
  27. Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
  28. Systematic Review of Patient Focused Drug Development Meeting Reports for Conditions Affecting Neurodevelopment.
  29. Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
  30. Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
  31. Fueling the Fire: Metabolic Dysfunction and Senescence as Drivers of Lung Aging and Disease.
  32. Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
  33. Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
  34. Socio-economic burden and health-related quality of life in patients with rare diseases during the COVID-19 pandemic: abridged secondary publication.
  35. The Genomics and Genetics of Rare Disease Illuminate Human Biology.
  36. Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
  37. The spatial architecture of neuroimmune interactions in epilepsy.
  38. ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
  39. Advanced three-dimensional in vitro models for Parkinson's disease research.
  40. Disruption of sphingolipid metabolism triggers lung vascular inflammation and aging-like changes under hypoxia through VDAC1-mediated mitochondrial DNA release.
  41. The PBC Ireland patient registry: study protocol for a national platform on primary biliary cholangitis.
  42. Potential of Intranasal Delivery of Human Mesenchymal Stem Cells and Extracellular Vesicles for Stroke Therapy.
  43. Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
  44. Cardioprotection Through Mitochondrial Modulation: A Systematic Review of Pharmacological Interventions in Animal Models of I/R Injury.
  45. Mitochondrial deficits and activation of autophagy in human iPSC-derived midbrain dopaminergic progenitors from patients with Wilson's disease.
  46. Coenzyme Q10 Supplementation in a Child with Biallelic COQ8A Variants: A Case Report.
  47. Association of Mitochondrial DNA Genetic Variants With Depression and Anxiety in Chinese Patients With Systemic Lupus Erythematosus.
  48. Language in rare disease: a call for systemic and empathetic action.
  49. Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
  1. Genet Med. 2026 Jan;pii: S1098-3600(25)00267-9. [Epub ahead of print]28(1): 101620
    Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
    Thiloka Ratnaike, Siddharth Ramanan, Nour Elkhateeb, Ramya Narayanan, Jenny Yang, Eszter Sara Arany, Manya Mirchandani, Rachael Piper, Katherine Schon, M Eren Kule, Christopher Gilmartin, Angela Lochmüller, Emogene Shaw, Rita Horváth, Patrick F Chinnery.
       PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
    METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
    RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
    CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.
    Keywords:  HPO; Mitochondrial disease; Phenotype similarity; Rare disease; UMAP
    DOI:  https://doi.org/10.1016/j.gim.2025.101620
  2. Eur J Neurosci. 2026 Mar;63(5): e70449
    Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
    Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.
      Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.
    Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles
    DOI:  https://doi.org/10.1111/ejn.70449
  3. Cell Transplant. 2026 Jan-Dec;35:35 9636897261427903
    The landscape of mitochondrial transplantation: A bibliometric analysis.
    Xiaojuan Yang, Miaohui Wang, Xuhang Fan, Minheng Zhang, Siyao Chen, Yue Liu, Haixia Fan.
      Recent years have witnessed rapid progress in mitochondrial transplantation (MT) as a novel strategy for restoring mitochondrial function in diverse pathological conditions, including somatic mitochondrial transfer and reproductive mitochondrial replacement therapy. With its expanding applications in regenerative medicine and disease modeling, systematic quantitative evaluation of the global MT research landscape remains limited. To address this gap, we performed a bibliometric analysis of publications indexed in the Web of Science Core Collection from 1996 to 2024, with cross-database validation using Scopus. CiteSpace, VOSviewer, and the R package bibliometrix were applied to assess publication trends, collaboration networks, co-citation patterns, and keyword co-occurrence. In total, 1104 articles and reviews were included. The results revealed rapid growth in MT-related research, with the United States and China as leading contributors. Mitochondrion emerged as the most influential journal, while Yamada Y, Harashima H, and McCully JD were recognized as key authors. High-frequency keywords highlighted major themes including mitochondrial transfer, mesenchymal stem cells, and ischemia-reperfusion injury. Emerging terms such as extracellular vesicles, tunneling nanotubes, and advanced delivery systems, particularly the MITO-Porter platform, reflected current research frontiers. Overall, this study provides a comprehensive overview of global research trends and evolving directions in mitochondrial transplantation.
    Keywords:  MITO-porter; cardiovascular diseases; mitochondrial dysfunction; mitochondrial transplantation; neurodegenerative diseases; stem cells; therapeutic applications
    DOI:  https://doi.org/10.1177/09636897261427903
  4. Acta Neuropathol. 2026 Mar 04. pii: 23. [Epub ahead of print]151(1):
    Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.
    Ngan Le Kim Tran, Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Molly M Watkins, Hanna J Sledge, J Raphael Gibbs, Bryan J Traynor, Clifton L Dalgard, Sonja W Scholz, Dennis W Dickson, Wolfdieter Springer, Owen A Ross.
      Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration.
    Keywords:  Lewy body disease; Mitochondrial haplogroup; Neuropathology; mtDNA
    DOI:  https://doi.org/10.1007/s00401-026-02993-9
  5. Seizure. 2026 Feb 18. pii: S1059-1311(26)00050-6. [Epub ahead of print]
    Mitochondrial complex assembly in epilepsy of primary mitochondrial disease origin.
    Gavin P McStay.
      Primary mitochondrial diseases are caused by mutations in genes required for expression, function or assembly of the mitochondrial oxidative phosphorylation system. The pathology of primary mitochondrial diseases is varied and a subset of these are associated with epilepsy and seizures. Mutations are found in each of the 5 complexes of the oxidative phosphorylation system in both structural subunits and assembly factors along with mitochondrially encoded components of the protein synthesis machinery. This review will highlight the mutations identified in clinical case studies that are associated with epilepsy and seizures and include the studies using cell systems and other model organisms where molecular characterisation of oxidative phosphorylation is more extensive. The molecular causes of epilepsy have not been well characterised in the relevant cells. This review identifies gaps in knowledge and suggestions for future studies to advance the understanding of the molecular pathogenesis of epilepsy that is associated with primary mitochondrial disease.
    Keywords:  Biogenesis; Electron transport chain; Epilepsy; Mitochondria; Oxidative phosphorylation; Seizures
    DOI:  https://doi.org/10.1016/j.seizure.2026.02.016
  6. Mol Neurobiol. 2026 Mar 04. pii: 485. [Epub ahead of print]63(1):
    A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.
    Jing Wu, Cunhui Pan, Ruowei Zhu, Xi Huang, Xiaoting Lou, Li Yang.
      Leber's hereditary optic neuropathy (LHON) is a hereditary neurodegenerative disorder caused by pathogenic mitochondrial DNA (mtDNA) variants. While MT-CO2 defects are implicated in neurodegeneration, their direct association with optic atrophy has not been reported. We identify a heteroplasmic MT-CO2 variant, m.8024G > A (p.Glu147Lys), in a patient with progressive optic atrophy and explore its potential association with mitochondrial dysfunction. A 13-year-old male with progressive unilateral-then-bilateral vision loss underwent comprehensive ophthalmic/neurological evaluation, trio whole-exome sequencing, and mtDNA sequencing. The pathogenicity of the identified variant was assessed in patient-derived fibroblasts using mitochondrial stress tests, ATP/ROS assays, enzymatic profiling, BN-PAGE, mitochondrial membrane potential, mtDNA copy number, ultrastructural microscopy, and immunoblotting. Functional analyses revealed that this variant, which reduces the expression of mtDNA-encoded electron transport chain (ETC) subunits and induces severe Complex IV deficiency, reduced cellular oxygen consumption rate (OCR), impaired ATP synthesis, decreased mtDNA copy number, and elevated reactive oxygen species (ROS) production. Concurrently, mutant cells exhibited enhanced mitophagy with preserved flux, a compensatory response to persistent mitochondrial damage. Unlike canonical optic neuropathy associated with homoplasmic mtDNA mutations, this heteroplasmic variant is linked to mitochondrial dysfunction potentially related to tissue-specific heteroplasmy and altered mitophagic responses. We report a heteroplasmic m.8024G > A mutation in MT-CO2 associated with childhood-onset isolated optic atrophy. Functional analyses in patient fibroblasts show that this variant is associated with MT-CO2 structural perturbation, Complex IV dysfunction, altered mitophagy, and mitochondrial energy failure-supporting its potential pathogenic relevance. This study expands the genotypic and phenotypic spectrum of mitochondrial optic neuropathies and provides mechanistic insights into the pathogenesis of heteroplasmic mtDNA variant-related disease.
    Keywords:  MT-CO2; Mitochondrial complex IV; Optic atrophy; Optic neuropathy
    DOI:  https://doi.org/10.1007/s12035-026-05774-3
  7. Protein Sci. 2026 Apr;35(4): e70516
    Functions of J-domain proteins in mitochondrial protein biogenesis.
    Vitasta Tiku, Georg Bossenz, Janine Kirstein, Thomas Becker.
      Mitochondrial biogenesis and functions depend on the import and assembly of more than 1000 proteins that are made as precursors on cytosolic ribosomes. The majority of these precursor proteins are transported from the ribosome to the translocase of the outer membrane (TOM complex), which constitutes the main entry site for mitochondrial precursors. The transient localization of mitochondrial precursor proteins in the cytosol represents a major burden for cellular proteostasis since these proteins can aggregate and accumulate in different cellular compartments, causing proteotoxic stress. Inside mitochondria, protein translocases sort the precursor proteins into the mitochondrial subcompartments-outer and inner membrane, the intermembrane space and matrix. The imported proteins have to be folded and efficiently assembled into functional protein complexes. Molecular chaperones such as Hsp70 monitor these processes to minimize proteotoxic stress. J-domain proteins stimulate the ATPase activity of Hsp70 and recruit the chaperones to their clients in the biogenesis of mitochondrial proteins. They ensure protein targeting to mitochondria, drive protein import into mitochondria, as well as folding and assembly of mitochondrial proteins. Here, we summarize the emerging view of how J-domain proteins guide mitochondrial precursor proteins from their synthesis in the cytosol until their folding into a mature protein and assembly into protein complexes in mitochondria.
    Keywords:  ER‐SURF; Hsp70; J‐domain protein; TOM complex; mitochondria; protein targeting
    DOI:  https://doi.org/10.1002/pro.70516
  8. Front Cell Dev Biol. 2026 ;14 1745201
    Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
    Yishuo Ji, Ying Wang, Xiaowei Yu, Yi Jin, Kai Zhao, Yue Hu, Zhenglin He.
      Aging and aging-related diseases are increasingly viewed as systemic disorders arising from disrupted inter-organ communication, yet the mechanisms linking local metabolic stress to organism-wide dysfunction remain unclear. The liver occupies a central position in this network, but how hepatic mitochondrial stress is translated into circulating signals that remodel distant tissues is incompletely understood. Here, we synthesize evidence identifying hepatic mitochondria as a systemic signaling hub that integrates metabolic and inflammatory stress and disseminates blood-borne cues during aging. We focus on three major classes of mitochondrial outputs: UPRmt-driven mitokines, including fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15); metabolites generated through mitochondrial metabolic reprogramming; and mitochondrial danger signals such as mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (mtDNA). These signals act through endocrine, metabolic, and immune pathways to reshape mitochondrial function, inflammation, and energy homeostasis across multiple organs. We further discuss how aging shifts hepatic mitochondrial signaling from adaptive to maladaptive states and emphasize that liver-centered regulation operates within bidirectional networks involving the gut, skeletal muscle, and immune system. Finally, we outline translational challenges and potential strategies for modulating hepatic mitochondrial outputs to restore systemic homeostasis in aging and aging-related diseases.
    Keywords:  UPRmt; aging; diseases; hepatic mitochondria; inter-organ communication; mitokines; mtDNA; mtROS
    DOI:  https://doi.org/10.3389/fcell.2026.1745201
  9. Zhongguo Dang Dai Er Ke Za Zhi. 2026 Feb 15. pii: 1008-8830(2026)02-0250-07. [Epub ahead of print]28(2): 250-256
    [Decreased plasma citrulline is a biochemical marker in newborn screening for MT-ATP6-associated mitochondrial disease: two case reports and a literature review].
    Hui-Ming Yan, Ying Quan, Ying Zhou, Luo Jiang, Liang-Yu Zhang, Zheng-Qing Wan, Hui Xi.
      This report describes the potential diagnostic value of decreased plasma citrulline (pCit) levels for the early recognition of MT-ATP6-related mitochondrial disease. Two cases were reported, and relevant literature was reviewed. Case 1: Onset occurred at 3 months of age with an acute presentation that rapidly progressed to metabolic crisis, multiorgan failure, and central respiratory failure, resulting in death in early infancy. Case 2: Onset occurred at 6 months of age with progressive developmental delay. Brain magnetic resonance imaging revealed bilateral symmetric basal ganglia lesions, and Leigh syndrome was diagnosed. Following citrulline supplementation and comprehensive intervention, improvements were observed in intellectual development and metabolic indices. Both patients carried the MT-ATP6 variant m.8993T>G (p.L156R), confirming MT-ATP6-associated mitochondrial disease. This case series indicates that decreased pCit on newborn screening is an early biochemical marker of MT-ATP6-associated mitochondrial disease. Early diagnosis and metabolic intervention are beneficial for prognosis.
    Keywords:  Hypocitrullinemia; MT- ATP6; Mitochondrial disease; Newborn screening; m.8993T>G
    DOI:  https://doi.org/10.7499/j.issn.1008-8830.2505143
  10. BMJ. 2026 Mar 03. 392 s432
    Rare diseases: NICE lays out quality standard to improve diagnosis and treatment.
    Jacqui Wise.
      
    DOI:  https://doi.org/10.1136/bmj.s432
  11. Nat Rev Neurosci. 2026 Mar 04.
    Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
    Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.
      Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.
    DOI:  https://doi.org/10.1038/s41583-026-01031-7
  12. Am J Physiol Cell Physiol. 2026 Mar 04.
    MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
    Mireille Khacho, Yan Burelle.
      Muscle stem cells (MuSCs) are essential for muscle regeneration, but their function declines with aging 1-4, neuromuscular disorders5-8 , and non-genetic muscle-wasting conditions9 . Their regenerative capacity is also influenced by environmental factors, including dietary changes such as high-fat diets and diabetes 10-12, impacting their ability to restore muscle integrity. Understanding the mechanisms that regulate MuSC function is thus crucial for developing strategies to preserve muscle health and improve regenerative potential in both physiological and pathological contexts. Recent advances have unveiled a crucial role for mitochondria in controlling MuSC quiescence, fate decisions, and differentiation into myofibers. Several studies have now shown that disruption of mitochondrial function, through genetic or pharmacological means, leads to dysregulation of MuSC functions and impaired myogenic lineage progression. Mitochondrial abnormalities in MuSCs have also been shown to contribute to the loss of regenerative capacity observed in conditions such as aging, sepsis, in myopathies. Together, this evidence and others have sparked great interest for understanding how these organelles regulate MuSC behavior and exploring the therapeutic potential of mitochondria targeted therapies to improve or maintain muscle regeneration. This review aims to provide a comprehensive overview of the role of mitochondria in regulating MuSC quiescence, fate decisions and myogenesis under both normal and diseased conditions. It summarizes current knowledge, highlights existing gaps, and explores emerging areas related to bioenergetic properties and metabolic signaling, mitochondrial network dynamics, quality control, and inter-organelle cross-talk across different MuSC states. It also discusses potential therapeutic strategies targeting mitochondrial function to enhance MuSC regenerative capacity and counteract muscle degeneration.
    Keywords:  Muscle stem cells; metabolism; mitochondrial dynamics; mitophagy; stem cell fate
    DOI:  https://doi.org/10.1152/ajpcell.00027.2026
  13. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  14. Nat Biotechnol. 2026 Mar 02.
    Establishing a commercial solution for extremely rare genetic diseases.
    Stanley T Crooke, Andrew W Lo.
      
    DOI:  https://doi.org/10.1038/s41587-026-03056-w
  15. Nat Struct Mol Biol. 2026 Mar 05.
    Function and regulation of the mitochondrial stress response.
    Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.
      As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
    DOI:  https://doi.org/10.1038/s41594-026-01769-9
  16. Mitochondrion. 2026 Feb 28. pii: S1567-7249(26)00027-9. [Epub ahead of print]88 102137
    Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
    Wei Wang, Xiang Dong, Chun-Yu Cao, Hong-Bo Li, Ya-Feng Lv.
      Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encoding the mitochondrial helicase Twinkle, disrupt mtDNA maintenance and underlie a subset of PS cases. Here, we generated the first mouse models carrying patient-specific TWNK missense mutations c.814G > A (p.Ala272Thr) and c.1166C > T (p.Ala389Val), both in homozygosity and compound heterozygosity, using CRISPR/Cas9 editing. Mutant mice exhibit profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy, while overall growth remains normal. Molecular assays reveal a significant reduction in mtDNA copy number and ATP content in muscle and brain, accompanied by impaired respiratory-chain function. These phenotypes faithfully recapitulate core features of human PS, establishing a genetically precise in vivo platform to dissect disease mechanisms and to evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.
    Keywords:  Mitochondrial dysfunction; Mouse model; Perrault syndrome; Sensorineural hearing loss; TWNK; mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2026.102137
  17. Apoptosis. 2026 Mar 03. pii: 82. [Epub ahead of print]31(3):
    Mitochondrial function meets oncology: the multifaceted role of TFAM across cancer types.
    Jie Wang, Ruicheng Wu, Fanglin Shao, Zhouting Tuo, Xinrui Li, Koo Han Yoo, Wuran Wei, Zhipeng Wang, Dengxiong Li, Dechao Feng.
      Mitochondrial transcription factor A (TFAM) is indispensable for mitochondrial DNA (mtDNA) maintenance and transcription, governing cellular bioenergetics. Despite its known physiological importance, TFAM plays a complex and often paradoxical role in cancer biology. This study integrates pan-cancer bioinformatics analyses with experimental evidence to comprehensively elucidate TFAM's multifaceted impact on tumorigenesis. We systematically investigated the heterogeneity of TFAM across diverse cancer types, specifically focusing on its regulatory mechanisms in metabolic reprogramming, signal transduction, and immune microenvironment remodeling. Our analysis reveals that TFAM functions as a critical node connecting mitochondrial integrity to tumor progression, balancing tumor-promoting and tumor-suppressive roles depending on the context. Finally, we discuss the challenges of targeting TFAM, such as off-target toxicity, and highlight emerging precision oncology strategies, including mitochondria-targeted delivery systems, that aim to exploit these mitochondrial vulnerabilities.
    Keywords:  Bioinformatics; Mitochondrial function; Pan-cancer analysis; TFAM; Therapeutic strategy
    DOI:  https://doi.org/10.1007/s10495-026-02305-2
  18. Autoimmun Rev. 2026 Feb 28. pii: S1568-9972(26)00025-X. [Epub ahead of print]25(3): 104011
    Mitochondrial transfer and transplantation in the immune cells: Mechanistic foundations, medical applications, and future prospects.
    Xiaofeng Liu, Xinyu Feng, Deping Zhan, Heng Yin.
      Mitochondria exhibit tissue-specific physiological functions and are central to the maintenance of cellular homeostasis. Emerging evidence indicates that intercellular mitochondrial transfer is regulated by multiple determinants and exerts a profound influence on the function of both innate and adaptive immune cells. The underlying mechanisms are highly heterogeneous, involving distinct cellular contexts, microenvironmental cues, and modes of intercellular communication. This review summarizes the major triggers and mechanistic pathways governing mitochondrial transfer in immune cells and immune-related diseases, and discusses the therapeutic potential of this process while highlighting key challenges that currently limit its clinical translation. By integrating recent mechanistic insights and translational perspectives, this review aims to provide a conceptual framework for the development of mitochondrial transfer-based strategies in the treatment of immune-mediated disorders.
    Keywords:  Immune cells; Mitochondrial transfer; Neutrophils; T cells
    DOI:  https://doi.org/10.1016/j.autrev.2026.104011
  19. Mol Genet Metab Rep. 2026 Mar;46 101302
    Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
    Gerardo G Piroli, Rebecca Myers, Lynda Holloway, Andrew Hayek, Ellen Linebaugh, Julie R Jones, Cindy Skinner, Steven A Skinner, Norma Frizzell, Richard Steet.
      Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.
    Keywords:  Complex III; Mitochondria; Mitochondrial transplantation; Respiration; UQCRC1; UQCRC2
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101302
  20. Life Sci Alliance. 2026 May;pii: e202503602. [Epub ahead of print]9(5):
    Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
    Ekaterina O Zorikova, Sabita Chourasia, Irit Rosenhek-Goldian, Sidney R Cohen, Semen V Nesterov, Atan Gross.
      Mitochondria orchestrate energy conversion and cell fate, yet label-free approaches that report both functional and physical states at the single-organelle level are nonexistent. Here, we combine atomic force microscopy (AFM) imaging with single-mitochondrion phenotyping by quantifying stiffness, height, and spontaneous low-frequency height fluctuations at the nanoscale. Across respiratory activators, inhibitors, and uncouplers, the integrated 0- to 20-Hz fluctuation power correlates with mitochondrial membrane potential (ΔΨm) and does not covary with changes in mitochondrial height (a proxy for swelling). In liver mitochondria lacking mitochondrial carrier homolog 2 (MTCH2), a regulator of mitochondrial metabolism, dynamics, and apoptosis, AFM reveals a compact, mechanically stiff, high-fluctuation state consistent with hyperpolarization and distinct from inhibited/uncoupled signatures. Extending the assay to mitochondria isolated from mouse embryonic fibroblasts, AFM data can distinguish between genotypes: loss of the mitochondrial pro-fusion proteins mitofusin 1 or 2 (MFN1 or MFN2) yields stiff, low-fluctuation mitochondria with reduced ΔΨm, whereas MTCH2 loss produces stiff, high-fluctuation, high-ΔΨm mitochondria. These three label-free features provide reproducible single-organelle "fingerprints" that resolve bioenergetic states and molecular defects and complement fluorescence and respirometry.
    DOI:  https://doi.org/10.26508/lsa.202503602
  21. J Neurochem. 2026 Mar;170(3): e70395
    Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
    Yesim Kaya, Kevser Kübra Kırboğa.
      Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.
    Keywords:  3D disease modeling; brain organoids; induced pluripotent stem cells; neurodegenerative diseases
    DOI:  https://doi.org/10.1111/jnc.70395
  22. J Ginseng Res. 2026 Mar;50(2): 100930
    Targeting mitochondrial quality control: Ginsenoside Rg1 as a therapeutic candidate for neuromuscular diseases.
    Xiaoqing Cai, Haixia Lan, Yingying Jiao, Yaoqi Wu, Peidan Yang, Tongkai Chen, Yafang Song.
      Neuromuscular diseases (NMDs) are complex disorders caused by the dysfunction of motor neurons and skeletal muscles. They lead to progressive muscle weakness and atrophy and impose a significant economic burden on patients and society at large. The dysregulation of mitochondrial quality control (MQC), a key cellular process, contributes to the pathogenesis of several NMDs. Interestingly, accumulating evidence demonstrates that ginsenoside Rg1 can regulate MQC by modulating mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitocytosis, thus aiding with the management of several diseases. This review comprehensively summarizes the current understanding of ginsenoside Rg1's effects on mitochondrial function. Furthermore, it proposes that Rg1 may target MQC mechanisms, emerging as an effective active agent for the treatment of NMDs. This review aims to bridge existing knowledge gaps and establish a theoretical foundation for the clinical application of ginsenoside Rg1 in the treatment of NMDs characterized by MQC dysfunction.
    Keywords:  Ginsenoside Rg1; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Neuromuscular diseases
    DOI:  https://doi.org/10.1016/j.jgr.2025.12.003
  23. Mol Biol Cell. 2026 Mar 04. mbcE25110560
    Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
    Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.
      Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.
    DOI:  https://doi.org/10.1091/mbc.E25-11-0560
  24. J Ayurveda Integr Med. 2026 Mar 03. pii: S0975-9476(26)00006-9. [Epub ahead of print]17(2): 101322
    A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda.
    Deepika Jangir, Aditi Joshi, Saketh Ram Thrigulla, Abhimanyu Kumar, Mitali Mukerji.
      Rare diseases, though individually uncommon, collectively affect millions and remain among the most underdiagnosed and poorly managed conditions in conventional healthcare. Ayurveda, with its systems approach and emphasis on Dosha imbalance, offers a complementary lens to interpret such unlisted conditions, known as Anukta Vyadhi. Human Phenotype Ontology (HPO) that catalogs 10,610 phenotypes across 12,678 rare diseases can be used to bridge modern phenotype vocabularies and Ayurvedic classifications. This study explores whether integrating the Anukta framework can enable meaningful assessment of rare diseases in Ayurveda clinical settings. A curated list of 140 Nanatmaja Vikara (NV)-Vata (80), Pitta (40), and Kapha (20) was mapped to HPO terms, preserving the semantic context of Ayurvedic descriptions. Noteworthy, 128 of NV phenotypes mapped to 199 HPO terms. Over 7200 rare diseases had representation of Nanatmaja Vikara. Vata-linked features were the most enriched (4786), followed by Pitta (465) and Kapha (240). 1349 of diseases showed dual Dosha involvement and 360 of all three. Seizures, short stature, and ptosis were most prevalent features of nV; gastroesophageal reflux, fever, and abnormal skin blistering of nP; and obesity, lethargy, and pallor of nK. Detailed case interpretation of Steinert Myotonic Dystrophy, Syndromic Diarrhea and Alstrom Syndrome revealed association with Vata-Kapha, Vata-Pitta, and Tridosha features respectively. This integration of Anukta framework with structured ontologies provides a practical pathway for understanding rare diseases for management in Ayurveda clinics and integrative decision-making when biomedical options are limited.
    Keywords:  Anukta Vyadhi; Ayurgenomics; Human phenotype ontology; Nanatamja Vikara; Personalized medicine; Rare diseases
    DOI:  https://doi.org/10.1016/j.jaim.2026.101322
  25. Mol Cell Biol. 2026 Mar 02. 1-19
    Loss of Splicing Homeostasis as a Hallmark of Aging.
    Stefano Donega, Myriam Gorospe, Lorna W Harries, Luigi Ferrucci.
      Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.
    Keywords:  Splicing; adaptive gene expression programs; aging; proteomic diversity; senescence
    DOI:  https://doi.org/10.1080/10985549.2026.2627235
  26. J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 89-95
    Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.
    Daria Hoang, Alan Pestronk, Jafar Kafaie.
       ABSTRACT: We report a pediatric case of severe isolated mitochondrial myopathy because of the rare m.3251A>G variant of the MT-TL1 gene. A 7-year-old boy presented to the hospital with acute-on-chronic weakness and respiratory insufficiency. Initial laboratory tests were notable for elevated lactate, aldolase, and lactate dehydrogenase. Despite a negative autoimmune panel, he was presumed to have myositis and treated with steroids and intravenous immunoglobulin. He continued to deteriorate, eventually requiring intubation and ventilation. Muscle biopsy revealed numerous ragged red fibers, abnormal intracellular lipid droplets with no lymphocytic inflammation, and increased succinate dehydrogenase reactivity, reflecting mitochondrial proliferation in many fibers. Steroids were discontinued, and he was started on a mitochondrial cocktail of cofactors with clinical improvement. Genetic testing identified the m.3251A>G variant, confirming primary mitochondrial disorder. This case expands the known phenotype of the m.3251A>G mutation. We also discuss clinical and histopathological differences between mitochondrial and inflammatory myopathies.
    Keywords:  MELAS; histopathology; immune myopathy; mitochondrial myopathy; muscle biopsy
    DOI:  https://doi.org/10.1097/CND.0000000000000547
  27. NPJ Aging. 2026 Mar 05.
    Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
    Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.
      The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.
    DOI:  https://doi.org/10.1038/s41514-026-00351-3
  28. Ther Innov Regul Sci. 2026 Mar 05.
    Systematic Review of Patient Focused Drug Development Meeting Reports for Conditions Affecting Neurodevelopment.
    Cristan Farmer, Victoria Kim, Tanvi Das, Seth Cutler, Heidi Wallis, Audrey Thurm.
       BACKGROUND: Researchers of rare diseases affecting neurodevelopment struggle with concept and outcome assessment identification issues that are uniquely associated with developmental concepts but common across conditions. However, the potential to capitalize on the collective commonness of rare disease in order to achieve the large samples often required to create and validate clinical outcome assessments is insufficiently tapped. Identifying synergies in concepts of interest across conditions affecting neurodevelopment may accelerate clinical outcome assessment development for prioritized concepts. We conducted the first systematic review of patient focused drug development (PFDD) meeting reports, to identify concepts prioritized by patients and caregivers across conditions.
    METHODS: Sixteen reports on rare conditions affecting neurodevelopment were identified. The responses to two survey items, "top three most troublesome symptoms" and "top three ideal treatment targets," were coded into general concepts and the endorsement rates were aggregated across the conditions.
    RESULTS: Full consensus about any individual troublesome symptom or treatment target was rare for any condition. Three conditions had no concept that exceeded 30% endorsement. However, for 11 of the 16 conditions, at least 30% of the respondents endorsed the developmental concepts of Communication or Cognitive/Developmental as a most troublesome symptom and as an ideal treatment target.
    CONCLUSIONS: This empirical support for the shared prioritization of developmental concepts across heterogeneous conditions is an important first step in unifying clinical outcome assessment development efforts to promote clinical trial readiness in rare disease.
    Keywords:  Clinical meaningfulness; Lived experience; Patient focused drug development; Public participation; Rare disease
    DOI:  https://doi.org/10.1007/s43441-026-00925-z
  29. Autophagy Rep. 2026 ;5(1): 2635914
    Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.
      Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.
    Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2635914
  30. Biomed Pharmacother. 2026 Mar 02. pii: S0753-3322(26)00159-9. [Epub ahead of print]197 119127
    Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
    Yanxing Hu, Huyan Chen, Chenyun Ding, Shengbo Zhang, Qing Chen, Hongying Sun, Qiaozhen Yang.
      Mitochondrial metabolism and innate immune signaling are increasingly recognized as intersecting pathways in chronic inflammatory disease. Here, we identify a metabolically driven mechanism linking the TCA cycle imbalance to mucosal inflammation in oral lichen planus (OLP). Multi-omics analysis revealed that fumarate hydratase (FH) is upregulated in OLP tissues and cells, leading to significant fumarate depletion. This metabolic shift induces mitochondrial dysfunction, characterized by enhanced oxidative phosphorylation, proton leak, and TFAM downregulation. These changes destabilize the mitochondrial genome, promote mtDNA leakage into the cytosol, and activate the cGAS-STING pathway, resulting in TBK1-IRF3- NF-κB -driven inflammatory responses. Genetic knockdown of FH or pharmacological supplementation with monomethyl fumarate (MMF) restored mitochondrial homeostasis, prevented mtDNA release, and attenuated immune activation. Furthermore, depletion of mtDNA using 2',3'-dideoxycytidine (ddC) validated the essential role of mtDNA in sustaining cGAS-STING dependent inflammation. Co-treatment with fumarate further suppressed cytosolic mtDNA and enhanced repression of innate signaling. These findings uncover a functional FH-fumarate-mtDNA-cGAS-STING axis in OLP and reveal fumarate as a key metabolic modulator of mitochondrial immune surveillance. Our work provides conceptual and therapeutic insight into the role of mitochondrial metabolism in non-infectious mucosal inflammation.
    Keywords:  Citric acid cycle; DNA; Fumarate hydratase; Inflammation; Lichen planus; Mitochondrial; Mitochondrial diseases; Oral
    DOI:  https://doi.org/10.1016/j.biopha.2026.119127
  31. Physiol Rev. 2026 Mar 06.
    Fueling the Fire: Metabolic Dysfunction and Senescence as Drivers of Lung Aging and Disease.
    Corrine R Kliment, Aditi U Gurkar, Nayra Cárdenes, Richard Ramonell, Toren Finkel, Melanie Königshoff.
      With a rapidly expanding human population at advanced ages and age as the main driver for chronic diseases, we face the challenge of understanding tissue aging and devising new therapeutic interventions. Cellular senescence is an important hallmark of all aging tissues and has emerged as a potential key driver of chronic lung diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and asthma. This comprehensive review recapitulates current knowledge of pathways and processes involved in cellular senescence with emphasis on the role of mitochondrial dysfunction and the "4 Ms" (morphology, mitophagy, metabolism, and metabolites). We review our current knowledge of healthy lung aging, discuss which pathomechanisms in chronic lung disease are characterized by senescence, and summarize current target therapeutics and their impact on lung disease. Within this exponentially growing field, we propose emerging concepts and current gaps in knowledge which need to be addressed to develop better opportunities for therapeutic strategies and future investigations.
    Keywords:  Aging; Lung; Metabolism; Mitochondria; senescence
    DOI:  https://doi.org/10.1152/physrev.00024.2025
  32. Acta Histochem. 2026 Feb 28. pii: S0065-1281(26)00016-4. [Epub ahead of print]128(2): 152331
    Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
    Aswathy P Nair, Aishwarya Janaki P, Janani Gopalarethinam, Abishek Kumar B, Balachandar Vellingiri, Mohana Devi Subramaniam.
      Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.
    Keywords:  Leber’s Hereditary Optic Neuropathy; Mitochondria transfer; Mitochondrial disease; Stem cells; Tunneling Nanotubes
    DOI:  https://doi.org/10.1016/j.acthis.2026.152331
  33. Neuromolecular Med. 2026 Mar 07. pii: 15. [Epub ahead of print]28(1):
    Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
    Gaurav Singh, Simranpreet Kaur, Khadga Raj Aran.
      Parkinson's disease (PD), is slowly advancing disease condition of the nervous system, which leads to interruption of normal motor function, resulting in symptoms such as tremor, muscle rigidity, bradykinesia, and postural instability. PD is commonly also accompanied by motor impairment, associated with broad non-motor symptoms, of which sensory prob 21qwlems are including behavioural and sleeping disorders and autonomic dysfunctions. The disease is characterised by slow degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc), and pathological misfolded α-synuclein (α-syn) deposition protein. Mitochondrial Rho GTPase (Miro1) is one of the major regulators of neuronal energy transport, mitochondrial motility, and communication in the central nervous system (CNS). It also regulates the quality of mitochondria in their interaction with regulatory proteins, PTEN-induced kinase 1 (PINK1), Parkin, and Leucine-rich repeat kinase2 (LRRK2). Studies stated that there are a few PD-related genes that are correlated with Miro1, which influences its activity. The dysregulation or genetic mutations of Miro1 disrupt the mitochondrial activities, including the transport, mitophagy, and calcium (Ca2+) homeostasis, particularly among dopaminergic neurons. These imbalances augment oxidative stress, mitochondrial dysfunction, and α-syn aggregation, which eventually regulate neuron exposure and are a risk factor in the development of PD. This review highlights the role of Miro1 in the development and pathophysiology of PD, with particular emphasis on recent experimental and clinical findings. It also focuses on the therapeutic prospect of Miro1-targeted approaches as new emerging interventions to reduce the development of the disease.
    Keywords:  Calcium homeostasis; Miro1; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12017-026-08917-w
  34. Hong Kong Med J. 2026 Feb;32 Suppl 1(1): 24-28
    Socio-economic burden and health-related quality of life in patients with rare diseases during the COVID-19 pandemic: abridged secondary publication.
    C C Y Chung, W H S Wong, S L Lee, B H Y Chung.
      
  35. Annu Rev Genomics Hum Genet. 2026 Mar 04.
    The Genomics and Genetics of Rare Disease Illuminate Human Biology.
    James R Lupski, Richard A Gibbs.
      Richard Gibbs interviews James (Jim) Lupski about his training in New York and work in Houston to elucidate the role of complex genomic rearrangements in human genetic diseases. The challenges and excitement of developing human personalized genomics and the advantages of clinical translation of genome methods for both patients and researchers are discussed.
    DOI:  https://doi.org/10.1146/annurev-genom-020525-014546
  36. Front Pharmacol. 2026 ;17 1748360
    Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
    Marcos Roberto de Oliveira.
      Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich's ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type-specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.
    Keywords:  dimethyl fumarate; mitochondria; mitochondrial biogenesis; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1748360
  37. Front Immunol. 2026 ;17 1742927
    The spatial architecture of neuroimmune interactions in epilepsy.
    Dianwu Chu, Wuhao Zhang, Xing Zhou, Hang Yin, Jian Yin.
      Epilepsy is increasingly recognized as a disorder not only of neuronal dysfunction but also of immune dysregulation within the central nervous system (CNS). Accumulating evidence points to a critical role for the immune microenvironment in shaping epileptogenesis-the process that underlies the development and progression of epilepsy. In this Review, we examine the spatial dynamics of neuroimmune interactions, highlighting how local inflammatory niches emerge and evolve across brain compartments such as the parenchyma and perivascular space. We describe how the spatial organization and activation of resident glial cells, alongside the infiltration of peripheral immune cells facilitated by blood-brain barrier (BBB) disruption, contribute to region-specific patterns of neuroinflammation. Critically, we emphasize that understanding "where" these neuroimmune interactions occur-their precise spatial organization within distinct cellular microenvironments-is as fundamental as identifying "what" immune cells are involved or "how" they function. Particular focus is given to the localized actions of immune mediators, including regulatory T cells and pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, and their influence on neuronal excitability. We also discuss the spatiotemporal heterogeneity of immune signatures across different epilepsy syndromes, drawing from both experimental models and clinical observations. Finally, we explore emerging therapeutic strategies that target spatially defined immune responses and consider the potential of spatial biomarkers and advanced tissue-mapping technologies to refine disease classification and guide precision therapies. By positioning the spatial immune landscape as a central feature of epileptogenesis, we propose a framework for developing effective, potentially curative interventions for epilepsy.
    Keywords:  astrocyte; epilepsy; immune microenvironment; microglia; neuroinflammation; spatial transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2026.1742927
  38. Redox Biol. 2026 Mar 03. pii: S2213-2317(26)00107-2. [Epub ahead of print]92 104109
    ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
    Yosuke Nagai, Keiichiro Matoba, Rimei Nishimura.
      Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) serve as central molecular switches that couple cytoskeletal dynamics with redox regulation and mitochondrial quality control. Dysregulated ROCK signaling promotes mitochondrial fragmentation, oxidative stress, and metabolic inflexibility, thereby linking nutrient overload to multi-organ dysfunction in diabetes, obesity, and cardiometabolic disease. Recent advances have identified ROCK1 as a key regulator of mitochondrial dynamics and bioenergetics: ROCK1 directly phosphorylates the fission protein Drp1 and suppresses the AMPK-PGC-1α pathway, resulting in impaired fatty acid oxidation, decreased mitochondrial biogenesis, and enhanced oxidative injury. Pharmacological or genetic inhibition of ROCK restores mitochondrial structure, energy metabolism, and redox balance across the heart, kidney, and liver, underscoring its therapeutic relevance. In contrast, ROCK2 plays more complementary roles in immune regulation and fibrotic remodeling, as evidenced by the clinical success of selective ROCK2 inhibition. In addition, metabolic drugs such as statins and GLP-1 receptor agonists can indirectly attenuate ROCK activity, suggesting feasible translational strategies for cardiometabolic disease. Despite these advances, isoform-specific mechanisms remain incompletely defined, and selective ROCK1 inhibitors have not yet been developed. Future studies should focus on clarifying ROCK1-specific signaling in mitochondrial homeostasis, developing tissue-targeted inhibitors, and combining ROCK modulation with metabolic or antioxidant therapies. A further understanding of the ROCK-mitochondria axis will enable the design of precise interventions to restore redox equilibrium and prevent progression of metabolic and cardiovascular disorders.
    Keywords:  Cardiometabolic diseases; Metabolic remodeling; Mitochondrial dynamics; ROCK1; Redox signaling
    DOI:  https://doi.org/10.1016/j.redox.2026.104109
  39. Neural Regen Res. 2026 Feb 28.
    Advanced three-dimensional in vitro models for Parkinson's disease research.
    Anabela Moreira, James B Phillips, António J Salgado.
       ABSTRACT: As one of the most common neurodegenerative disorders, Parkinson's disease is a chronic, progressive, and debilitating condition that affects millions of people worldwide. Despite the continuously improved understanding of disease pathogenesis and the identification of numerous potential therapeutic targets, Parkinson's disease management currently relies exclusively on symptomatic treatments that are incapable of halting or slowing down disease progression. The lack of preclinical models that are representative of human biology and physiology is one of the main factors attributed to the limited clinical translation of new therapies. With the advent of induced pluripotent stem cells and gene editing technology, complex and highly customizable in vitro models can be developed to mimic individual pathological characteristics and target specific patient groups, paving the way for personalized medicine approaches. This review summarizes recent developments in advanced in vitro 3D models of Parkinson's disease, with a focus on human cellular models of neurodegeneration that make use of spheroids, organoids, scaffold-based, and microfluidic platforms. Such intricate structures have allowed the recapitulation of key features of Parkinson's disease in vitro, including dopaminergic neuron degeneration, α-synuclein pathology, mitochondrial dysfunction, glial activation, and blood-brain barrier disruption, thus constituting valuable assets in pharmacological and toxicological investigation. While in vitro models cannot yet completely replace animal experimentation in preclinical research, they represent an important step forward in reducing the number of animals used and obtaining human and patient-specific cellular responses, which may contribute to the successful translation of new disease-modifying therapies.
    Keywords:  ; 3D models; Parkinson’s disease; dopaminergic neurons; human pluripotent stem cells; midbrain organoids; neurodegeneration; personalized medicine; α-synuclein
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00356
  40. Apoptosis. 2026 Mar 03. pii: 83. [Epub ahead of print]31(3):
    Disruption of sphingolipid metabolism triggers lung vascular inflammation and aging-like changes under hypoxia through VDAC1-mediated mitochondrial DNA release.
    Jin Xu, YiLing Ge, Bin Zhang, SiYuan He, QingLin Cao, PeiJie Li, YingRui Bu, YunGang Bai, Lin Zhang, GuoDong Tan, Jin Ma, ManJiang Xie.
      The lung, a key organ for oxygen exchange, is particularly susceptible to high-altitude hypoxic stress. Hypoxia induces vascular impairment, which is characterized by vascular inflammatory responses and aging-like changes. Lipid metabolism has been shown to be closely associated with cellular homeostasis and membrane balance. However, the alterations in pulmonary lipid metabolism in response to high-altitude hypoxia are not fully characterized. In this study, model mice were subjected to a hypobaric chamber at an altitude of 5500 m for 3 days, and pulmonary microvascular endothelial cells (PMVECs) were cultured under 1% oxygen for 18 h to simulate the effects of acute severe hypoxia. High-altitude hypoxia significantly disrupted lung sphingolipid metabolism, accompanied by inflammation and aging-like changes in mice. Moreover, C24-Ceramide (Cer) and its synthase (CERS2) were significantly increased in PMVECs. C24-Cer was identified to bind to voltage-dependent anion channel 1 (VDAC1) (a mitochondrial outer membrane protein), which promoted mitochondrial DNA (mtDNA) release and subsequently induced the inflammation and aging-like changes by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway. Inhibition of C24-Cer or VDAC1 oligomerization by si-Cers2 or VBIT-4 could significantly reduce mtDNA release and alleviate inflammation and aging-like changes in the PMVECs and lung tissue under hypoxia. Our present work provides a novel and potential therapeutic target for high-altitude hypoxia-related vascular diseases.
    Keywords:  High-altitude hypoxia; Mitochondrial dysfunction; Pulmonary inflammation; Sphingolipids; cGAS-STING pathway
    DOI:  https://doi.org/10.1007/s10495-026-02296-0
  41. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261427491
    The PBC Ireland patient registry: study protocol for a national platform on primary biliary cholangitis.
    Gerry Nesbitt, Alexandra Curley.
       Background: Primary Biliary Cholangitis (PBC) is a chronic, progressive liver disease. This paper outlines how a PBC patient registry was developed to address the gaps in evidence, care and policy affecting PBC patients in Ireland.
    Objectives: The PBC patient registry is designed to collect patient-reported data regarding medical history, pruritus, fatigue and quality of life of PBC patients living in Ireland. This data can be used to identify care and treatment gaps and ensure that the PBC patient voice is included in new treatment decisions and healthcare policy. This real-world data will support further scientific and clinical research, drive patient-led advocacy efforts and facilitate collaboration with the liver disease communities globally.
    Design: A patient-led, observational, registry-based study of PBC patients in Ireland.
    Methods and analysis: Participants must have a PBC diagnosis and be 18 years of age or older. PROMs (patient-reported outcome measures) were administered through a secure web-based system. After providing electronic informed consent, participants completed online data collection forms. These included demographic information, medical history, standard of care and validated PROMs for fatigue, pruritus and quality of life. This was followed by an anonymous survey to collect usability and comprehensiveness metadata.
    Ethics: The protocol was approved by TIER IRB Services, protocol ID: 5250715 (July 18th, 2025), which determined the study to be exempt as an observational, minimal-risk, non-interventional research activity involving anonymised patient-reported data.
    Discussion: At the time of publication, 52 participants were registered in the patient registry, of which 40 completed all data collection forms. The results of the post-completion survey suggest high satisfaction across the domains of usability, comprehension, relevance, privacy/confidentiality and overall experience. The PBC patient registry shows that web-based PROMs can be used to collect real-world evidence from patients. Participants reported that the system was easy to use and comprehensive, confirming the usability and effectiveness of this approach. It also provides a starting point to identify healthcare and treatment gaps and facilitates the inclusion of PBC patients' voices in national and international health policy decisions that affect them.
    Trial Registration: Not applicable.
    Keywords:  autoimmune liver disease; patient registry; patient-reported outcome measures; primary biliary cholangitis; rare liver disease; real-world patient data
    DOI:  https://doi.org/10.1177/26330040261427491
  42. Acta Biomater. 2026 Feb 26. pii: S1742-7061(26)00133-9. [Epub ahead of print]
    Potential of Intranasal Delivery of Human Mesenchymal Stem Cells and Extracellular Vesicles for Stroke Therapy.
    Arshia Arbabian, Tristan Driscoll, Yan Li, Samuel C Grant.
      Cerebral ischemic stroke, caused by interrupted cerebral blood flow, remains a leading cause of mortality and long-term disability worldwide. Current FDA-approved therapies-intravenous tissue-type plasminogen activator (tPA) and mechanical thrombectomy-are constrained by narrow time windows (4.5-24 h) and limited accessibility. Mesenchymal stem cells (MSCs) have emerged as promising candidates for neurorestoration, yet their therapeutic efficacy is hindered by poor blood-brain barrier (BBB) penetration and systemic entrapment. Increasing evidence indicates that MSCs exert their therapeutic effects primarily through paracrine mechanisms mediated by extracellular vesicles (EVs), which regulate inflammation, apoptosis, neurogenesis, and angiogenesis. However, translation of EV-based therapies from bench to bedside remains limited, largely due to inefficient delivery and the invasiveness of existing routes. Intranasal (IN) administration offers a minimally invasive approach to bypass the BBB and achieve direct, repeated delivery to the brain. This review synthesizes the mechanistic foundations, preclinical progress, and translational potential of intranasal delivery of MSCs and their EVs for ischemic stroke therapy. We highlight comparative analyses of biodistribution, cellular targets, and functional outcomes across administration routes, emphasizing how route optimization governs therapeutic efficacy. Collectively, these insights establish intranasal delivery as a practical platform for next-generation, cell-free regenerative therapies targeting ischemic brain injury. STATEMENT OF SIGNIFICANCE: Despite extensive investigation of stem-cell-based interventions for ischemic stroke, the influence of administration route on therapeutic outcomes remains poorly defined. This review integrates preclinical and early-phase clinical findings to delineate how delivery pathways shape biodistribution, mechanistic engagement, and neurorepair efficacy of human mesenchymal stem cells (hMSC) and their derived extracellular vesicles (EV). By contrasting conventional intravenous and intra-arterial approaches with the emerging intranasal route, this article emphasizes a non-invasive strategy capable of bypassing the blood-brain barrier, supporting multidose regimens, and sustaining localized repair. Beyond summarizing outcomes, this work clarifies mechanistic drivers-angiogenesis, neurogenesis, and immunomodulation-that can be fine-tuned through delivery design. The synthesis provides a framework for rationally optimizing cell-free hMSC-EV therapeutics and underscores the translational promise of intranasal delivery for clinical stroke management.
    Keywords:  biodistribution; extracellular vesicles; human mesenchymal stem cells; intranasal delivery; stroke therapy
    DOI:  https://doi.org/10.1016/j.actbio.2026.02.049
  43. Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627
    Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
    Akriti Prashar, Rosa Puertollano.
      Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102627
  44. Cardiovasc Drugs Ther. 2026 Mar 04.
    Cardioprotection Through Mitochondrial Modulation: A Systematic Review of Pharmacological Interventions in Animal Models of I/R Injury.
    Trissha Ybanez, Joshua Ingles, Eugene Du Toit, Jason Peart.
       PURPOSE: Myocardial reperfusion following ischaemia paradoxically exacerbates mitochondrial and thus cardiac dysfunction. Although various treatment strategies have been utilised to prevent irreversible myocardial injury, translation to positive clinical trial outcomes has been unsuccessful. This systematic review aimed to evaluate pharmacological interventions in animal models of ischaemia-reperfusion (I/R), with emphasis on cardiac and cell death outcomes and direct assessment of mitochondrial bioenergetics.
    METHODS: Search terms were entered into PubMed, Scopus, Embase and Web of Science. Screening, data extraction and quality assessment of papers were conducted according to the inclusion and exclusion criteria selected for this study. Eighteen papers from a total of 1571 studies were included. These studies investigated 15 drugs of interest in animals subjected to either in vivo or ex vivo I/R. Mitochondrial function parameters were assessed by measuring either mitochondrial respiration and/or enzyme activity, with 4 of these also assessing electron transport chain protein expression.
    RESULTS: Pharmaceuticals preserved mitochondrial respiratory capacity by directly targeting the electron transport chain complexes or indirectly via proteins involved in canonical cardioprotective pathways. This led to improved post-ischaemic cardiac function and reductions in markers of cellular injury and myocardial infarction.
    CONCLUSION: Multi-targeted manipulation of components of mitochondrial signalling and function evidently reduces I/R injury. Quality assessment of most papers revealed an unclear risk of bias due to inadequate reporting of study parameters. Clear and consistent reporting of study outcomes, specifically mitochondrial bioenergetics across all experimental stages, is essential to enhance the translational potential of mitoprotective compounds in the clinical treatment of I/R.
    Keywords:  Cardiac ischaemia; Cardioprotection; Mitochondria; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1007/s10557-026-07851-0
  45. Stem Cell Res. 2026 Feb 24. pii: S1873-5061(26)00042-5. [Epub ahead of print]92 103946
    Mitochondrial deficits and activation of autophagy in human iPSC-derived midbrain dopaminergic progenitors from patients with Wilson's disease.
    Shu-Hong Wang, Xiao-Zhong Jing, Xiao-Ping Wang.
      Wilson's disease (WD) is a disorder of copper metabolism that can cause severe neurological manifestations, including parkinsonism. This suggests that nigrostriatal dopaminergic system dysfunction may contribute to neurological WD. However, pathological changes in the central nervous system associated with WD remain poorly understood due to limited patient samples and the absence of animal models with robust neurological phenotypes. In our previous research, we established an induced pluripotent stem cell (iPSC) line from a WD patient carrying the R778L mutation. Here, we successfully differentiated iPSCs from both WD patients and healthy controls into midbrain dopaminergic progenitor cells (WD-mDAPCs and HC-mDAPCs, respectively). WD-mDAPCs exhibited cell-type-specific mitochondrial vulnerability, indicating that mitochondrial dysfunction may play an important role in WD neuropathogenesis. Furthermore, an increased number of autophagosomes was detected in WD-mDAPCs. Thus, we have established a novel cellular model for investigating neural abnormalities in WD. Therapeutic strategies targeting mitochondrial protection and autophagy activation may alleviate copper-induced neurological impairment in WD.
    Keywords:  Autophagyactivation; Midbraindopaminergicprogenitorcells; Mitochondrialdysfunction; Wilson’sdisease
    DOI:  https://doi.org/10.1016/j.scr.2026.103946
  46. Case Rep Neurol. 2026 Jan-Dec;18(1):18(1): 121-127
    Coenzyme Q10 Supplementation in a Child with Biallelic COQ8A Variants: A Case Report.
    Hirotaka Motoi, Risa Watanabe, Ayano Shirai, Yusuke Sakata, Yukiko Kuroda, Yoshihiro Watanabe, Shuichi Ito.
       Introduction: Pathogenic variants in COQ8A cause a rare form of primary coenzyme Q10 (CoQ10) deficiency that can lead to childhood-onset cerebellar ataxia and developmental delay. However, reports of pediatric cases remain limited, and evidence regarding therapeutic response to CoQ10 supplementation in children is still scarce.
    Case Presentation: We report a 7-year-old boy with compound heterozygous COQ8A variants who presented with progressive cerebellar ataxia and intellectual disability. Oral CoQ10 supplementation was initiated at a dose of 10 mg/kg/day after institutional ethics approval. During 1 year of treatment, the Scale for the Assessment and Rating of Ataxia (SARA) score improved from 17 to 9, and serum CoQ10 concentration increased from 622 to 9.100 ng/mL. Mild cognitive improvement was also observed, with the intelligence quotient increasing from 53 to 64. Brain MRI demonstrated radiological stabilization of cerebellar atrophy. No adverse effects related to CoQ10 supplementation were observed throughout the treatment period.
    Conclusion: This case demonstrates the clinical benefit and safety of CoQ10 supplementation in pediatric-onset COQ8A-related ataxia. Early genetic diagnosis and timely initiation of CoQ10 therapy may lead to meaningful neurological improvement and stabilization of disease progression in affected children.
    Keywords:  COQ8A; Cerebellar ataxia; Coenzyme Q10 deficiency; Mitochondrial disorder
    DOI:  https://doi.org/10.1159/000550495
  47. Int J Rheum Dis. 2026 Mar;29(3): e70595
    Association of Mitochondrial DNA Genetic Variants With Depression and Anxiety in Chinese Patients With Systemic Lupus Erythematosus.
    Qiqun Zong, Yue Li, Yuxin Wang, Yaping Feng, Yingying Yu, Mingyi Zhang, Yuqin Tang, Liangyu Cui, Lin Cai, Ying Xu, Hongyu Sun, Xingyu Gong, Yuqi Liu, Shuang Liu, Yangfan Chen, Wenfei Li, Haifeng Pan, Faming Pan, Hong Su, Yanfeng Zou.
       OBJECTIVE: To explore the association of mitochondrial DNA (mtDNA) genetic variants, including single nucleotide variants (SNVs), insertions and deletions (InDels), and copy number variations (CNVs), with depression and anxiety in Chinese patients with systemic lupus erythematosus (SLE).
    METHODS: A two-stage study of 530 patients with SLE was conducted to explore the association between mtDNA genetic variants (SNVs and InDels) and depression and anxiety. A total of 499 patients with SLE were recruited to explore the association between mtDNA CNVs and depression and anxiety. Meanwhile, the patients were followed up for 12 weeks to observe the improvement of depression and anxiety. The levels of reactive oxygen species (ROS), adenosine triphosphate (ATP), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were detected.
    RESULTS: Two mtDNA SNVs (C16291T, A16399G) in the displacement loop (D-loop) region were associated with depression in patients with SLE (PBH = 0.003, PBH = 0.007). Two mtDNA SNVs (T9950C, T16140C) in the cytochrome c oxidase subunit III (COX3) gene and D-loop region were associated with anxiety in patients with SLE (PBH = 0.001; PBH = 0.003). Associations of mtDNA CNVs with depression and anxiety in SLE were observed in several subgroups (Padj < 0.05). T9950C and T16140C variants were related to the improvement of anxiety in SLE (PBH < 0.05). An inverse U-shaped non-linear association was observed between mtDNA CNVs and the improvement of anxiety in the body mass index (BMI) ≥ 24 subgroup of SLE (Pnon-linear = 0.038). The levels of ROS (p = 0.040) and IL-6 (p = 0.039) were increased and ATP level (p = 0.034) was decreased in the COX3 gene variation group.
    CONCLUSION: mtDNA genetic variants may be associated with depression and anxiety in Chinese patients with SLE. This study provides a new idea for improving depression and anxiety in SLE.
    Keywords:  anxiety; depression; genetic variation; mitochondrial DNA; systemic lupus erythematosus
    DOI:  https://doi.org/10.1111/1756-185x.70595
  48. Lancet. 2026 Feb 26. pii: S0140-6736(26)00359-4. [Epub ahead of print]
    Language in rare disease: a call for systemic and empathetic action.
    Gareth Baynam, Kym M Boycott, Kirsten Johnson, Lucy Mckay.
      
    DOI:  https://doi.org/10.1016/S0140-6736(26)00359-4
  49. Neuroscience. 2026 Mar 03. pii: S0306-4522(26)00156-9. [Epub ahead of print]
    Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
    Enis Guso, Alessia Lupoli, Emanuele Olivieri, Alessia Bottoni, Maira Gironi, Davide M Missarelli, Ahmed T Toosy, Elena Rossi, Roberto Furlan.
      Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.
    Keywords:  Cell metabolism; Epigenetic remodelling; Innate immune memory; Ischemic stroke; Neurodegeneration; Neuroimmunology; Neuroinflammation; Trained immunity
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.047
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