bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–02–08
eighty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  2. Mitochondrial superoxide signals shield the nucleus to delay ageing.
  3. Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.
  4. Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
  5. Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
  6. LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones.
  7. Mitochondrial SLC6A6 supports taurine transport.
  8. PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
  9. A dynamic displacement mechanism drives protein import into mitochondria.
  10. Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
  11. Expanding the cognitive spectrum of mitochondrial diseases.
  12. LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.
  13. Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.
  14. Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
  15. MTFP1 preserves β-cell cristae structure and bioenergetics to ensure insulin release and glucose homeostasis.
  16. Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
  17. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  18. Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.
  19. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
  20. Diagnostic challenges in mitochondrial encephalomyopathy with m.10158T>C mutation: a case report and literature review.
  21. Cell-intrinsic vulnerability and immune activation cooperate to drive degeneration in a mitochondrial complex I deficiency model of optic neuropathy.
  22. Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
  23. Suppression of interferon signaling via small-molecule modulation of TFAM.
  24. Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
  25. Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
  26. HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity.
  27. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  28. The mitochondria-targeted peptide HDAP2 reduces mitochondrial loss and retinal ganglion cell degeneration after optic nerve injury.
  29. Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
  30. Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
  31. A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
  32. An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
  33. Pharmacological Depletion of Retinal Mononuclear Phagocytes Is Neuroprotective in a Mouse Model of Mitochondrial Optic Neuropathy.
  34. Mitochondrial specialization and signaling shape neuronal function.
  35. Advancing Neuropediatric Rare Disease Diagnosis Through Clinical Genome Sequencing.
  36. Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
  37. Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
  38. Phenotype-first patient matching with SimPheny identifies diagnostic candidates beyond curated gene associations.
  39. Mitochondria at the membrane provide a route to inflammatory cell death.
  40. Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
  41. Fibroblast Transcriptomics in Molecular Diagnostics of a Comprehensive Dystonia Cohort.
  42. Screening strategy using a filamentous fungus model to repurpose drugs for mitochondrial complex I deficiencies.
  43. Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
  44. Chlamydial membrane vesicles deliver the beta barrel outer membrane protein OmpA to mitochondria to inhibit apoptosis.
  45. Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP+ Model of Parkinson's Disease.
  46. Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
  47. Targeted Mitochondrial ECSIT Overexpression Attenuates MASH by Increasing OTUD3 Expression.
  48. Dying oligodendrocytes persist without mitochondria.
  49. Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
  50. In vitro model of human subcutaneous adipocyte spheroids for studying mitochondrial dysfunction and mitochondria activating compounds.
  51. Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
  52. The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
  53. Mechanisms of microRNA trafficking to mitochondria in the heart.
  54. Transient protein structure guides surface diffusion pathways for electron transport in membrane supercomplexes.
  55. Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.
  56. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  57. Imaging mitochondrial hydrogen sulfide in multicellular spheroids using a near-infrared iridium(III) complex.
  58. Epilepsy Phenotype and EEG Finding of Rhythmic High-Amplitude Delta With Superimposed Spikes (RHADS) in Succinate Dehydrogenase Deficiency.
  59. Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.
  60. Mitochondrial Transplantation Therapy for Ischemic Stroke: Progress and Challenges.
  61. Maximizing Access to Cell and Gene Therapy for Patients with Rare Diseases.
  62. Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury.
  63. Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency.
  64. Mitochondria targeting by a nonionic and emissive push-pull type chromophore or its polymer conjugate.
  65. Mitochondrial disorders with renal involvement and kidney transplantation require genotypic and phenotypic characterisation.
  66. The past, present, and future of RNA biochemistry and mitochondrial research.
  67. Diagnostic yield of genome sequencing in children with progressive movement disorders.
  68. Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.
  69. Identification and verification of hub genes related to mitochondrial dysfunction in epilepsy based on bioinformatics analysis.
  70. Biliary elimination of cholesterol can be modulated by hepatocyte mitochondrial Aquaporin-8 in mice.
  71. Bridging gaps in mitochondrial disease diagnosis: the role of advanced biomarker discovery.
  72. Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
  73. Introgressed mitochondrial fragments from archaic hominins alter nuclear genome function in modern humans.
  74. Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
  75. Energetic stress in combination with impaired fatty acid oxidation induces sequestration of CoA and adaptation of CoA metabolism.
  76. Detection and localization of single-nucleotide mutations in synthetic oligonucleotides by ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry.
  77. Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
  78. Brain organoids as models of extracellular vesicle-mediated human neural communication.
  79. Mitochondrial dysfunction in MASH: Focusing on chronic inflammation and intercellular communication.
  80. A recently evolved domain of the human ING1 epigenetic regulator targets mitochondria and induces senescence.
  81. An in vivo and in vitro spatiotemporal profile of human midbrain development.
  1. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  2. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide signals shield the nucleus to delay ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01461-8
  3. J Lipid Res. 2026 Jan 28. pii: S0022-2275(26)00013-1. [Epub ahead of print] 100987
    Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.
    Eliana Barriocanal-Casado, Sylwia A Stopka, Alba Pesini, Juan J Aristizabal-Henao, Srada Karmacharya, Devon Van Cura, Ryan Zhang, Kelsey R Nickerson, Kashni Grover, Oksana Zavidij, Sarah R Wessel, Niven R Narain, Vijay Modur, Stephane Gesta, Michael A Kiebish, Catarina M Quinzii.
      Primary Coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder caused by mutations in genes involved in CoQ biosynthesis (e.g., COQ4) that result in impaired mitochondrial respiration, oxidative stress, and dysfunction across multiple organ systems due to decreased mitochondrial levels of CoQ10. Although oral CoQ10 supplementation has been examined for standard of care, poor absorption and inadequate tissue and intracellular distribution have resulted in a lack of clinically significant efficacy. BPM31510 is a lipid nanoparticle formulation of oxidized CoQ10 designed to improve bioavailability and targeted uptake into the mitochondria. In the current study, we assessed the efficacy of BPM31510 to increase CoQ levels in Coq4F147C mice, a novel genetic knock-in model of primary CoQ deficiency. CoQ9, the main form of CoQ in mice, and CoQ10 were significantly decreased in brain, kidney, heart, and muscle of Coq4F147C mice compared to Coq4+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MSI demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4F147C mice. These results demonstrate that BPM31510 successfully concentrates pharmacologically active CoQ10 in target tissues that are not reachable with oral therapy, in a genetic model of primary CoQ deficiency. We enabled the visualization of sub-organ CoQ10 localization to specifically demonstrate CoQ10 restoration. This study establishes proof-of-concept for spatial quinomics, a new methodology that combines spatial metabolomics with quinomics to evaluate next-generation CoQ10-based therapeutics for mitochondrial disorders.
    Keywords:  CoQ10 deficiency; MALDI; MSI; mass spectrometry; mitochondrial disease; quinomics
    DOI:  https://doi.org/10.1016/j.jlr.2026.100987
  4. Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]
    Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
    Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.
      Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.
    Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation
    DOI:  https://doi.org/10.1093/brain/awag037
  5. Mol Genet Metab. 2025 Dec 11. pii: S1096-7192(25)00696-1. [Epub ahead of print]147(3): 109704
    Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
    Martina Messina, Rebecca Ganetzky, Carlos R Ferreira, Nenad Blau, Shamima Rahman.
      Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).
    Keywords:  Biomarkers; ICIMD; IEMbase; Inherited metabolic disorders; Signs and symptoms
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109704
  6. Redox Biol. 2026 Jan 28. pii: S2213-2317(26)00059-5. [Epub ahead of print]90 104061
    LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones.
    Tae Young Kim, Eun-Hae Jang, Yun-Hee Bae, Eun-Mi Hur, Byoung Dae Lee.
      Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2-the most common genetic contributor to both familial and sporadic PD-as a regulator of cytochrome c oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. In vivo, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2-COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.
    Keywords:  COX; COX19; Copper chaperone; LRRK2; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.redox.2026.104061
  7. Nat Metab. 2026 Feb 06.
    Mitochondrial SLC6A6 supports taurine transport.
    Katsuhisa Inoue.
      
    DOI:  https://doi.org/10.1038/s42255-026-01471-6
  8. Autophagy. 2026 Feb 04. 1-19
    PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
    Chih-Wei Chen, Ying-Jung Chen, Xiaojing Cuili, Yi-Han Chen, Zee-Fen Chang.
      PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD to generate phosphatidic acid (PA) from cardiolipin on the OMM of damaged mitochondria after depolarization. This lipid signal is essential for positioning MFN2 nearby PINK1 for phosphorylation of Ub conjugates on MFN2, thus enabling the subsequent amplification of PRKN binding to mitochondria. We provide further evidence that mitochondria-endoplasmic reticulum (Mito-ER) tethering prohibits the proximity of MFN2 with PINK1 and PRKN amplification on mitochondria. Importantly, the loss of NME3-regulated PA signal causes Mito-ER tethering. Overall, our findings suggest that NME3 cooperates with PLD6 to generate PA as a critical step in Mito-ER untethering, allowing MFN2 access to PINK1 for p-S65-poly-Ub-dependent feedforward activation of PRKN.Abbreviation ACTB: actin beta; BDNF brain derived neurotrophic factor; CL: cardiolipin; CRISPR: clustered regularly interspaced short palindromic repeats; DAG: diacylglycerol; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; FRET: Förster resonance energy transfer; IF: immunofluorescence; KO: knockout; KD: knockdown; LPIN1: lipin 1; MERCS: mitochondria-endoplasmic reticulum contact sites; MFN2: mitofusin 2; Mito: mitochondria; OMM: outer mitochondrial membrane; p-Ub: phosphorylated ubiquitin; PA: phosphatidic acid; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; PLD6/MitoPLD: phospholipase D family member 6; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: retinoic acid; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; TEM: transmission electron microscopy; TN-NME3: TOMM20-NΔ-NME3; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I; Ub: ubiquitin; VDAC: voltage dependent anion channel; WB: western blot.
    Keywords:  MFN2; NME3; PINK1; PRKN; mitophagy; phosphatidic acid
    DOI:  https://doi.org/10.1080/15548627.2026.2623981
  9. bioRxiv. 2026 Jan 14. pii: 2026.01.14.699430. [Epub ahead of print]
    A dynamic displacement mechanism drives protein import into mitochondria.
    Iva Sucec, Undina Guillerm, Jakob Schneider, Iniyan Ganesan, Niklas Webling, Anna Kapitonova, Conny Steiert, Frank Schmelter, Antoine Feignier, Rajkumar Singh, Laura F Fielden, Julia Dung, Doron Rapaport, Beate Bersch, Karin B Busch, Francois Dehez, Nils Wiedemann, Paul Schanda.
      Most mitochondrial proteins are produced in the cytosol and imported through the translocase of the outer mitochondrial membrane (TOM) to reach their final destination. Although this protein entry gate has been structurally characterized, it remains unclear how precursor proteins are handed off from the cytosolic receptor domains to the translocation pore. Here we show that the cytosolic domain of Tom22 - traditionally viewed as the central TOM receptor - acts not as a structured scaffold but as a largely disordered, flexible segment that plays an active role in precursor transfer. Atomic-level structural techniques and in vivo experiments identified a conserved short linear motif that forms a transient α-helical element within this disordered domain. By binding to the canonical precursor protein binding sites of the receptors Tom20 and Tom70, this critical α-helical segment acts as a precursor protein displacement element (PPDE). This competitive interaction facilitates the release of preproteins directly above the import pore, and thereby drives translocation across the outer mitochondrial membrane. These findings reveal that flexibility, rather than rigid structure, underlies the central transfer step of mitochondrial outer-membrane protein translocation. Our results point to a versatile mechanism for ligand displacement in chaperone, receptor, and transport systems that must balance selective binding with efficient release.
    DOI:  https://doi.org/10.64898/2026.01.14.699430
  10. bioRxiv. 2026 Jan 23. pii: 2026.01.22.701145. [Epub ahead of print]
    Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
    Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.
      As highly dynamic organelles, mitochondria play an essential role in neuronal survival and synaptic function. Excitotoxicity is as a critical factor that promotes mitochondrial dysfunction after traumatic brain injury (TBI). Intercellular mitochondrial transfer and exogenous mitochondrial transplantation are emerging concepts to understand mitochondrial trafficking in response to mitochondrial dysfunction; however, robust in vivo evidence remains limited on the extent of these processes in the central nervous system (CNS). There is a significant knowledge gap in our understanding of mitochondrial transfer mechanisms under both normal physiological conditions and after experimental TBI. Mouse lines expressing mitochondrial green-fluorescent dendra-2 (mtD2) and GFP (mtGFP) targeted to inner and outer mitochondrial membranes, respectively, were used to study astrocyte-specific (Aldh1l1-CreER; mtD2 f/f - AmtD2 and Aldh1l1-CreER; mtGFP f/f - AmtGFP) and neuron-specific (CamK2aCre; mtD2 f/f - NmtD2 and CamK2aCre; mtGFP f/f - NmtGFP) mitochondrial dynamics and bioenergetics in acute TBI and excitotoxicity. At 24 hrs following TBI, neurons in the NmtD2 mouse brain exhibited rapid and significant alterations in mitochondrial morphology, including changes in total mitochondrial volume, volume distribution, and sphericity. Synaptic neuronal (SN) mitochondria display robust deficits in mitochondrial bioenergetics and complex protein levels while non-synaptic neuronal (NSN) mitochondria show State III bioenergetics and complex proteins at control levels. These findings are accompanied by a marked increase in astrocyte-derived mitochondria (AmtGFP) transfer to neurons at 24 hrs post-injury, compared to control animals, but no increase in transfer to neuronal synapses. While TBI also altered astrocytic mitochondrial morphology in the cortex, astrocytic mitochondrial bioenergetics remained preserved. Single-cell RNA-seq analysis of astrocytes revealed significant transcriptional reprogramming following TBI, characterized by the upregulation of genes associated with mitochondrial homeostasis and the machinery for organelle trafficking. In vitro co-cultures of primary cortical astrocytes and neurons demonstrated that astrocytes can transfer mitochondria to neurons via direct contact and that NMDA-mediated excitotoxicity further enhanced this astrocyte-to-neuron mitochondrial transfer. Furthermore, astrocytic-derived extracellular vesicles containing mitochondria (EV-mito) deliver mitochondria to neurons and EV-mediated mitochondrial transfer significantly ameliorated NMDA-induced mitochondrial dysfunction in primary cortical neurons. Together, these findings show that astrocytes take on a TBI-related phenotype that facilitates dynamic changes in mitochondrial networks and mitochondrial trafficking to neurons. Astrocytic transfer of respiratory-competent mitochondria support is an intrinsic neuroprotective response to injury that supports mitochondrial function in neuronal soma, dendrites, and axons but not at the neuronal synapse. Finally, we show therapeutic potential of exogenous mitochondrial transfer, particularly via EV-mito, for treating neurological disorders associated with excitotoxicity, such as TBI.
    DOI:  https://doi.org/10.64898/2026.01.22.701145
  11. Neurol Sci. 2026 Feb 04. 47(3): 228
    Expanding the cognitive spectrum of mitochondrial diseases.
    Anna Rita Giovagnoli, Costanza Lamperti, Ioana Raluca Mihai, Alessia Catania.
      
    Keywords:  Attention; Memory; Mitochondrial disease; Social cognition; Theory of mind
    DOI:  https://doi.org/10.1007/s10072-026-08827-6
  12. bioRxiv. 2026 Jan 13. pii: 2026.01.12.699049. [Epub ahead of print]
    LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.
    Md Shariful Islam, Valentin Cóppola-Segovia, Alessandra Musso, Darren J Moore.
      Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing a Roc GTPase domain and a serine/threonine-directed protein kinase domain, with PD-linked mutations known to enhance LRRK2 kinase activity and neuronal toxicity. Our previous studies identified the Golgi protein, ADP-Ribosylation Factor GTPase-Activating Protein 1 (ArfGAP1), as a novel modifier of LRRK2-induced cellular toxicity, where it can serve as a GAP-like protein and a robust kinase substrate of LRRK2. Here, we further explore the phosphorylation of ArfGAP1 by LRRK2 and its functional consequences. LRRK2 mediates the robust phosphorylation of ArfGAP1 within its lipid-sensing ALPS2 motif at residues Ser284, Thr291 and Thr292. We mutated these three phosphorylation sites, either alone or combined, to create hydrophobic phospho-null or charged phospho-mimicking versions of ArfGAP1. We find that modulating ArfGAP1 phosphorylation impairs its normal capacity to induce Golgi fragmentation upon overexpression in neural cells. Blocking phosphorylation impairs ArfGAP1-induced neurite outgrowth inhibition in primary neurons and protects against the neurotoxic effects of PD-linked G2019S LRRK2. ArfGAP1 interactome analysis in neural cells identifies 114 putative interacting proteins with a proportion of these unexpectedly localized to mitochondria, including the outer membrane proteins Voltage-Dependent Anion Channel (VDAC) 1-3. An ArfGAP1 triple phospho-mimic displays an increased interaction with mitochondrial VDACs owing to the redistribution of ArfGAP1 from the cis -Golgi to the cytoplasm. Promoting ArfGAP1 phosphorylation also blocks the formation of Golgi-derived vesicles following mild ER stress. Our data provides evidence for a complex functional interaction between LRRK2 and ArfGAP1 that serves to regulate ArfGAP1 subcellular localization, protein interactions, activity and neuronal toxicity via LRRK2-mediated phosphorylation of its membrane-binding ALPS2 motif. Our findings support additional validation of ArfGAP1 as a putative therapeutic target for modulating LRRK2 -linked PD.
    DOI:  https://doi.org/10.64898/2026.01.12.699049
  13. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00073-0. [Epub ahead of print]
    Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.
    Yingqi Xu, Junyu Li, Shanshan Ma, Ting Yang, Ziyue Shen, Mingtao Li, Qiaoying Huang.
      Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.
    Keywords:  Parkinson's disease; Rab27; dopaminergic neurons; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.053
  14. FASEB Bioadv. 2026 Feb;8(2): e70088
    Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
    Takanaga Shirai, Hideto Hanakita, Kohei Takeda, Yu Kitaoka, Kaori Ishikawa, Kazuto Nakada, Tohru Takemasa.
      Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG)(+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14-day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild-type (WT) and PolG(+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype-specific differences in muscle atrophy were observed. However, PolG(+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress-related responses are involved in mitochondrial adaptations during denervation-induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG(+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.
    Keywords:  atrophy; mitochondria; mtDNA; oxidative stress; polymerase gamma; skeletal muscle
    DOI:  https://doi.org/10.1096/fba.2025-00072
  15. bioRxiv. 2026 Feb 03. pii: 2026.01.12.697845. [Epub ahead of print]
    MTFP1 preserves β-cell cristae structure and bioenergetics to ensure insulin release and glucose homeostasis.
    Sunehera Sarwat, Rosa Alen, Zhiyi Wu, Chuyue Zhang, Michael Paszek, MingMing Yang, Giada Ostinelli, Alina Mihalovits, Bell Baker, Timothy Wai, Guy A Rutter, Tristan A Rodriguez, Aida Martinez-Sanchez.
      Pancreatic β-cells are uniquely dependent on mitochondrial metabolism to couple glucose sensing to insulin secretion, a process impaired in diabetes. Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane protein that plays pleiotropic, tissue-specific roles in mitochondrial function and dynamics. Our previous work has identified Mtfp1 mRNA as a target for miR-125b, a microRNA that negatively regulates insulin secretion from β-cells. Nevertheless, the function of MTFP1 in these cells remained unexplored. Here, we show that MTFP1 is essential for normal glucose-stimulated insulin secretion (GSIS) in mouse and human cell lines and islets, and that mice with β-cell-specific elimination of MTFP1 develop glucose intolerance. Whereas β-cell survival and mitochondrial content were unaffected, oxidative phosphorylation and ATP production were sharply lowered. These changes were accompanied by disruption of mitochondrial cristae structure and a reduced contact surface with the endoplasmic reticulum, providing a mechanistic basis for defective stimulus-secretion coupling. Conversely, MTFP1 overexpression in mouse and human islets sufficed to improve mitochondrial respiration and GSIS. Finally, MTFP1 downregulation blocked the positive effects of miR-125b elimination in GSIS and mitochondrial respiration, unveiling MTFP1 as a downstream effector of miR-125b. Together, our findings identify MTFP1 as a critical regulator of β-cell mitochondrial architecture and function, necessary for efficient insulin secretion and glucose homeostasis, and a potential therapeutic target to enhance β-cell bioenergetic resilience in diabetes.
    DOI:  https://doi.org/10.64898/2026.01.12.697845
  16. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
    Peng X Chen, Leyuan Zhang, Xueying Wu, Zhiqiang Liang, Xusheng Hao, Qingyuan Zhu, Ying Liu, Jinrou Zheng, Qian Zhang, Qinmeng Yang, Fan Zhou, Chunbao Zhou, Ye Tian.
      The nuclear envelope (NE) is essential for cellular homeostasis, yet its integrity declines with age, accelerating functional deterioration. Here we report a mitochondria-to-NE signalling pathway that safeguards NE integrity through redox-dependent lipid metabolism. In Caenorhabditis elegans, reducing mitochondrial ETC activity preserves NE morphology during ageing. This effect requires developmental mitochondrial superoxide, which downregulates SBP-1 (SREBP orthologue) and suppresses unsaturated fatty acid biosynthesis. The resulting reduction in unsaturated fatty acid levels limits lipid peroxidation, thereby preserving NE structure. Interventions targeting lipid peroxidation preserve NE integrity, extend lifespan in worms and ameliorate senescence-associated phenotypes in human fibroblasts and monkey cells mimicking Hutchinson-Gilford progeria syndrome disease. Our findings reveal a previously unrecognized role for mitochondrial superoxide as a protective developmental signal that programs long-term NE integrity. This work establishes lipid peroxidation control as a conserved strategy to delay nuclear ageing and highlights redox-lipid cross-talk as a therapeutic axis for healthy ageing.
    DOI:  https://doi.org/10.1038/s42255-026-01452-9
  17. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.13.699287
  18. bioRxiv. 2026 Jan 21. pii: 2026.01.20.700642. [Epub ahead of print]
    Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration.
    Kriti Shukla, Zhi Zhang, Kendra S Plafker, Satoshi Matsuzaki, Casandra Salinas-Salinas, Yvonne Thomason, Samah Houmam, Dylan Barber, Anna Fakye, Kenneth M Humphries, Scott M Plafker, Jialing Lin, Heather C Rice.
      Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimer's disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we found that mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain function. We identified a novel interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial phosphatase. We determined that APP and PGAM5 co-localize at mitochondria-ER contact sites (MERCS), and we confirm an endogenous interaction using proximity ligation assays in mouse brain slices. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear respiratory factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane to regulate the expression of mitochondrial respiratory chain complexes and enzymes. Consistent with this, we found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nnqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Together, these findings suggest that APP supports mitochondrial function by modulating PGAM5-Keap1-Nrf2 signaling, providing a mechanistic link between loss of APP function and impaired mitochondrial respiration.
    DOI:  https://doi.org/10.64898/2026.01.20.700642
  19. Nat Metab. 2026 Feb 06.
    SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
    Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.
      Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01455-6
  20. Front Integr Neurosci. 2025 ;19 1709380
    Diagnostic challenges in mitochondrial encephalomyopathy with m.10158T>C mutation: a case report and literature review.
    Zhuqing Luan, Zhigang Liang.
      Mitochondrial encephalomyopathy is a complex disorder with heterogeneous clinical manifestations that often complicate its clinical diagnosis. We report the first documented case of a 52-year-old woman harboring a novel and rare genotypic combination: the m.10158T>C point mutation together with a 12.8-kb large-scale mtDNA deletion. After a protracted diagnostic course involving multiple prior misdiagnoses, the definitive diagnosis was ultimately established through integrated genetic, histopathological, and neuroimaging evaluation. This case underscores both the diagnostic challenges in mitochondrial disorders and the critical need for systematic differentiation from common neurological mimics such as encephalitis and stroke.
    Keywords:  case report; mitochondrial DNA; mitochondrial encephalomyopathy; point mutation; stroke; stroke-like episodes
    DOI:  https://doi.org/10.3389/fnint.2025.1709380
  21. J Neuroinflammation. 2026 Feb 06.
    Cell-intrinsic vulnerability and immune activation cooperate to drive degeneration in a mitochondrial complex I deficiency model of optic neuropathy.
    Daniela Santamaría-Muñoz, Raenier V Reyes, Miranda R Krueger, Andrea García-Llorca, Brennan Marsh-Armstrong, Xin Duan, Yang Hu, Derek S Welsbie, Nicholas Marsh-Armstrong, Elisenda Sanz, Albert Quintana, Sergi Simó, Anna La Torre.
      
    DOI:  https://doi.org/10.1186/s12974-026-03707-4
  22. bioRxiv. 2026 Jan 25. pii: 2026.01.25.701366. [Epub ahead of print]
    Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
    Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.
      Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol γ), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol γ displays from modest to limited unwinding activity. This led us to dissect Pol γ strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol γ carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol γ can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol γ complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol γ elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol γ strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity.
    Graphical abstract:
    DOI:  https://doi.org/10.64898/2026.01.25.701366
  23. Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14
    Suppression of interferon signaling via small-molecule modulation of TFAM.
    Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.
      The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.
    Keywords:  TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule
    DOI:  https://doi.org/10.7554/eLife.108742
  24. Mol Genet Metab. 2026 Jan 27. pii: S1096-7192(26)00036-3. [Epub ahead of print]147(3): 109753
    Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
    Alessandra Maresca, Monica Moresco, Giulia Amore, Chiara La Morgia, Maria Lucia Valentino, Giada Capirossi, Giulia Sacchetti, Valerio Carelli, Christian Vedeler, Laurence A Bindoff, Kristin N Varhaug.
      Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.
    Keywords:  Blood biomarkers; Cell free mitochondrial DNA; Inflammation; Mitochondrial diseases; Neurodegeneration; Neurofilaments light chain
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109753
  25. Cell Death Dis. 2026 Feb 02. 17(1): 195
    Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
    Yena Cho, Jessica Winarto, Dae-Geun Song, Dong Hee Na, Kyo Bin Kang, Su-Nam Kim, Yong Kee Kim.
      Mitochondria are essential for cellular homeostasis, supplying key metabolites and energy. While post-translational modifications regulate mitochondrial enzymes, their roles remain less explored compared to those in the nucleus and cytoplasm. Here, we demonstrate that reversible arginine methylation governs the activity of several mitochondrial enzymes, with a particular focus on isocitrate dehydrogenase 2 (IDH2). We identify coactivator-associated arginine methyltransferase 1 (CARM1) as a mitochondrial enzyme that asymmetrically dimethylates IDH2 at R188, leading to enzymatic inhibition while enhancing protein stability. This modification is dynamically reversed by the lysine demethylases KDM3A and KDM4A, which restore IDH2 activity. Notably, despite its reduced stability, demethylated IDH2 promotes α-ketoglutarate production, enhancing mitochondrial membrane potential and oxygen consumption. These findings highlight the critical role of reversible arginine methylation in fine-tuning mitochondrial enzyme function and maintaining mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41419-026-08444-3
  26. Cell Biol Toxicol. 2026 Feb 05.
    HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity.
    Chanhaeng Lee, Dong Yeol Kim, Sang-Min Kim, Inn-Oc Han.
      Parkinson's disease (PD) is characterized by dopaminergic neuronal loss, often associated with mitochondrial dysfunction and impaired mitophagy. Here, we investigated the role of HUWE1, an E3 ubiquitin ligase, in regulating mitophagy and neuronal survival in a cellular PD model. HUWE1 promoted mitophagy, whereas its depletion sensitized SH-SY5Y cells to 6-hydroxydopamine (6-OHDA)- and 1-methyl-4-phenylpyridinium (MPP⁺)-induced cytotoxicity and mitochondrial dysfunction. Notably, both toxins downregulated HUWE1, suggesting that loss of HUWE1 contributes to dopaminergic vulnerability. Conversely, HUWE1 overexpression preserved mitochondrial integrity and enhanced mitophagy under neurotoxic stress. Importantly, BL-918, a ULK1 activator that promotes AMBRA1 recruitment, facilitated HUWE1-mediated mitophagy in SH-SY5Y cells. BL-918 treatment significantly attenuated 6-OHDA- and MPP⁺-induced neurotoxicity and protected mitochondrial function via HUWE1 activation. Collectively, these findings identify HUWE1 as a key mechanistic regulator of mitophagy linked to dopaminergic neuronal vulnerability, and provide a conceptual framework for future investigations examining its role in PD-relevant model systems.
    Keywords:  Dopaminergic neurons; HUWE1; Mitophagy; Parkinson’s disease; SH-SY5Y cells
    DOI:  https://doi.org/10.1007/s10565-026-10146-7
  27. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  28. Neuroscience. 2026 Feb 01. pii: S0306-4522(26)00083-7. [Epub ahead of print]
    The mitochondria-targeted peptide HDAP2 reduces mitochondrial loss and retinal ganglion cell degeneration after optic nerve injury.
    Margaret A MacNeil, Sara Arain, Widnie Mentor, Virginia Garcia-Marin, Alexander Birk.
      Mitochondrial dysfunction is a critical early driver of retinal ganglion cell (RGC) loss in optic nerve injury. We evaluated whether HDAP2, a mitochondria-targeted aromatic peptide designed to support mitochondrial membrane integrity, could preserve neuronal structure after optic nerve crush (ONC) in C57BL/6 mice (both sexes, n = 31). Systemically administered HDAP2 penetrated the blood-retinal barrier and localized to RGCs and mitochondrial-rich retinal layers. Daily treatment significantly improved RGC survival compared to saline-treated ONC animals. RGC densities increased across central, midperipheral, and peripheral regions. Transmission electron microscopy revealed that HDAP2 substantially reduced mitochondrial loss within crushed optic nerve axons. Mitochondrial density in HDAP2-treated nerves approached levels observed in uninjured controls and was nearly 3-fold higher than untreated ONC nerves. Mitochondrial morphology was similar across groups, indicating that HDAP2 prevents mitochondrial loss rather than rescuing damaged organelles. HDAP2-treated nerves also exhibited a numerically higher density of structurally intact axons, consistent with reduced ultrastructural degeneration. These findings demonstrate that HDAP2 limits mitochondrial loss and attenuates neuronal degeneration after ONC. Together, the results support HDAP2 as a promising therapeutic candidate for protecting CNS projection neurons by maintaining mitochondrial stability after axonal injury.
    Keywords:  Cell-penetrating peptides; Glaucoma; Mitochondrial dysfunction; Neuroprotection; Optic nerve crush; Retinal ganglion cells
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.01.045
  29. Amino Acids. 2026 Feb 01. 58(1): 8
    Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
    Abdilatif Aynaashe, Petri Kursula.
      Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.
    Keywords:  ALS; Axonal transport dysfunction; CMT; Mitochondrial dysfunction; Molecular mechanism; Neurodegeneration; Protein aggregation; RNA transport and metabolism; Stress response dysfunction
    DOI:  https://doi.org/10.1007/s00726-026-03500-w
  30. Cell Rep. 2026 Jan 28. pii: S2211-1247(25)01684-5. [Epub ahead of print]45(2): 116912
    Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
    Mariam Karim, Keisuke Yaku, Jun-Dal Kim, Akira Okekawa, Tsutomu Wada, Hitoshi Uchida, Amane Mizutani, Tran Canh Tung Nguyen, Yoshiharu Kawaguchi, Yoshimi Nakagawa, Toshiyasu Sasaoka, Yasuhito Yahara, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD+ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD+ biosynthesis pathway, drastically reduced NAD+ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD+ levels were restored to normal in middle-aged NADS-knockout mice, whereas muscle function remained compromised. Gene expression analysis showed that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS-knockout mice and aged wild-type mice. We also found that the α-ketoglutarate-JMJD3 axis downregulates Has2 expression. Then, impaired hyaluronic acid signaling dampened muscle stem cells, leading to decreased locomotor activity. These results suggest that maintaining NAD+ levels during early life is important for promoting healthy aging in skeletal muscle.
    Keywords:  CP: metabolism; DOHaD theory; NAD(+); aging; histone methylation; hyaluronic acid; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.116912
  31. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699897. [Epub ahead of print]
    A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
    Shanon T Nizard, Yiyang Chen, Madhavika N Serasinghe, Ruben Fernandez-Rodriguez, Kamrin D Shultz, Jesminara Khatun, Anthony Mendoza, Juan F Henao-Martinez, Jesse D Gelles, Stella G Bayiokos, J Andrew Duty, Shane Meehan, Mihaela Skobe, Jerry Edward Chipuk.
      Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to meet cellular demands. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated, mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616 (DRP1-S616Ⓟ), which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Building upon this foundation, we developed a human recombinant monoclonal antibody with high specificity for DRP1-S616Ⓟ, referred to as 3G11. Using diverse biochemical platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels which correlates with mitochondrial hyperfusion; while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF V600E disease. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications.
    DOI:  https://doi.org/10.64898/2026.01.16.699897
  32. Neuroophthalmology. 2026 ;50(1): 96-100
    An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
    Pascal Reynier, Patrizia Amati-Bonneau, Valérie Desquiret-Dumas, Marc Ferré, Naïg Gueguen, Solenn Plouzennec, Mathieu Michel, Arnaud Chevrollier, Antoine Pegat, Christophe Orssaud.
      Biallelic pathogenic variants in the SLC25A46 gene are responsible for various neurological syndromes, including Charcot-Marie-Tooth disease type 6B, pontocerebellar hypoplasia type 1E, Leigh syndrome, progressive myoclonic ataxia and Parkinson's disease, most of them being associated with optic atrophy. We here report the case of a 26-year-old female patient with a slowly progressive and apparently isolated form of optic neuropathy due to the NM_138773.4:c.[327-2A > T];[410A > G] compound heterozygous variants in this gene. The presence of a subclinical peripheral neuropathy revealed by electroneuromyography confirmed the responsibility of these SLC25A46 variants. The absence of functional and structural mitochondrial abnormalities in the patient's fibroblasts was consistent with the mild neurological phenotype. This case report suggests that SLC25A46 gene merit consideration during genetic testing for both syndromic and isolated optic neuropathies.
    Keywords:  OCT; Optic neuropathy; SLC25A46 gene; histological analysis; peripheral neuropathy
    DOI:  https://doi.org/10.1080/01658107.2025.2581675
  33. Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 6
    Pharmacological Depletion of Retinal Mononuclear Phagocytes Is Neuroprotective in a Mouse Model of Mitochondrial Optic Neuropathy.
    Avital L Okrent Smolar, Rahul Viswanath, Howard M Bomze, Ying Hao, Sandra S Stinnett, Sidney M Gospe.
       Purpose: The Vglut2-Cre;ndufs4loxP/loxP mouse strain with retinal ganglion cell (RGC)-specific mitochondrial complex I dysfunction develops severe RGC degeneration by postnatal day 90 (P90), with accompanying retinal mononuclear phagocyte (MNP) accumulation. We have reported that continuous exposure to hypoxia partially rescues RGC death in these mice, with minimal effect on MNP abundance. We hypothesized that pharmacological depletion of MNPs with the colony-stimulating factor-1 receptor inhibitor pexidartinib would enhance RGC neuroprotection by hypoxia.
    Methods: Iba1+ retinal MNP depletion was assessed in C57Bl/6J mice fed control or pexidartinib-infused chow beginning at P25. Subsequently, Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were raised under normoxia or hypoxia and fed control or pexidartinib chow from P25 to P90. The neuroprotective effect of pexidartinib and hypoxia alone and in combination was assessed by quantifying RGC soma and axon survival in retinal flat mounts and optic nerve cross-sections.
    Results: Pexidartinib completely depleted retinal MNPs within 1 week of treatment. Untreated Vglut2-Cre;ndufs4loxP/loxP mice exhibited the expected approximately 50% reduction of RGC soma and axon survival at P90 (P < 0.0001 for both). Hypoxia or pexidartinib monotherapy each reduced RGC degeneration by more than one-half, whereas their combination resulted in complete RGC neuroprotection (P < 0.01 for all 3 treatments). Normal myelination patterns were restored in mice receiving dual therapy.
    Conclusions: Pexidartinib effectively depletes retinal MNPs and is neuroprotective in the setting of severe RGC mitochondrial dysfunction. This therapeutic effect is additive to that of hypoxia. Combating retinal neuro-inflammation may therefore be a useful adjunct therapy in mitochondrial optic neuropathies like Leber hereditary optic neuropathy (LHON).
    DOI:  https://doi.org/10.1167/iovs.67.2.6
  34. Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]
    Mitochondrial specialization and signaling shape neuronal function.
    Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.
      Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.
    Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport
    DOI:  https://doi.org/10.1016/j.tins.2025.12.006
  35. Pediatr Neurol. 2026 Jan 14. pii: S0887-8994(26)00017-2. [Epub ahead of print]177 28-45
    Advancing Neuropediatric Rare Disease Diagnosis Through Clinical Genome Sequencing.
    Fabio Sirchia, Silvia Kalantari, Diana Carli, Mariia Zadorozhna, Francesco Bassanese, Erin Thorpe Venti, Ryan J Taft, Akanchha Kesari, Lorena Sorasio, Vincenzo Antona, Andrea Guala, Agnese Feresin, Anna Basile, Francesco Licciardi, Jessica Garau, Paolo Gasparini, Enrico Grosso, Alessandro Mussa, Giovanni Battista Ferrero, Alfredo Brusco, Elisa Giorgio.
       BACKGROUND: Many patients with rare genetic diseases remain undiagnosed or receive a molecular diagnosis only after years. In this study, we want to evaluate the usefulness of clinical genome sequencing (cGS) in a cohort of complex neuropediatric patients with undiagnosed rare genetic diseases.
    METHODS: Between 2018 and 2022, our Medical Genetics Units in Torino, Trieste and Pavia partnered with the iHope program, a philanthropic initiative by Illumina Inc., with the aim of offering family-based cGS within the Italian National Health Service (Servizio Sanitario Nazionale) diagnostic process. A multidisciplinary team of pediatricians, clinical geneticists, and molecular biologists selected 64 cases. Inclusion criteria consisted of suspicion of an ultra-rare monogenic disease and at least one negative result from a first-tier genetic test.
    RESULTS: A definitive molecular diagnosis was achieved in 57.8% of the patients. All patients and families underwent clinical re-evaluation to assess the diagnostic relevance of the laboratory findings, which led us to reclassify 10 variants of unknown significance as responsible for the probands' phenotypes. Diagnoses impacted patients' management, enabling palliative care referrals, avoiding unnecessary invasive tests, and guiding follow-up treatments.
    CONCLUSIONS: Our study confirms that the use of cGS in a rare disease setting increased the diagnostic yield even in complex cases where other methods had previously failed. We speculate that introducing cGS as first-tier test within the Italian Servizio Sanitario Nazionale might offer both diagnostic and economic advantages.
    Keywords:  Diagnostic utility; Genome sequencing; Mendelian conditions; Molecular diagnoses; Rare diseases; Undiagnosed diseases
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.01.004
  36. ACS Sens. 2026 Feb 03. XXX
    Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
    Katie G Vineall, Alexia Andrikopoulos, Michael J Sun, Anna Yan, Ethan R Hartanto, Danielle L Schmitt.
      Phosphatase and tensin homologue-induced kinase 1 (PINK1) is a serine/threonine kinase that plays roles in mitophagy, cell death, and regulation of cellular bioenergetics. Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity. Therefore, we sought to develop a novel PINK1 kinase activity reporter to characterize PINK1 activity. Taking advantage of the separation of phase-based activity reporter of kinase (SPARK) design, we developed a phase separation-based PINK1 biosensor (PINK1-SPARK). With PINK1-SPARK, we observe real-time PINK1 activity in single cells treated with mitochondria-depolarizing agents or pharmacological activators. We then developed a HaloTag-based PINK1-SPARK for multiplexed imaging of PINK1 activity with live-cell markers of mitochondrial damage. Thus, PINK1-SPARK is a new tool that enables temporal measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function.
    Keywords:  PINK1; biosensor; fluorescence; kinase activity reporter; mitophagy
    DOI:  https://doi.org/10.1021/acssensors.5c03859
  37. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00007-3. [Epub ahead of print]88 102117
    Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
    Daniel R Cuesta-Aguirre, Ana Onieva, M Pilar Aluja, Cristina Santos.
      Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing (MPS) data from ten additional European tissues. Heteroplasmy was tissue-specific, with skeletal muscle, kidney, and liver showing the highest levels, while the intestines, skin, and cerebellum had the lowest. Blood uniquely displayed more heteroplasmies in coding than non-coding regions. Several conserved positions not previously described as hotspots showed high frequencies. These results establish the first comprehensive tissue-specific heteroplasmic profile of the complete mitochondrial genome in a European population, improving the interpretation of mtDNA variation in forensic and biomedical contexts.
    Keywords:  Heteroplasmic profile; Heteroplasmy; Massively Parallel Sequencing (MPS); Mitochondrial DNA (mtDNA); Point heteroplasmy
    DOI:  https://doi.org/10.1016/j.mito.2026.102117
  38. medRxiv. 2026 Jan 17. pii: 2026.01.15.26344236. [Epub ahead of print]
    Phenotype-first patient matching with SimPheny identifies diagnostic candidates beyond curated gene associations.
    Undiagnosed Diseases Network
      Diagnostic tools for rare diseases typically rely on curated gene-phenotype associations and static disease models, limiting their effectiveness in cases with atypical presentations or previously uncharacterized disorders. To address these limitations, we present SimPheny, a phenotype-first algorithm for gene prioritization that operates independently of documented gene-phenotype associations. SimPheny identifies phenotypically similar diagnosed patients by comparing an undiagnosed patient's disease presentation to a reference cohort of diagnosed cases, and returns gene hypotheses by matching the undiagnosed patient's candidate gene list to the causative genes of similar patients using a statistical scoring model. Evaluated in diagnosed probands from the Undiagnosed Diseases Network (UDN) with the true diagnostic gene blinded, SimPheny consistently ranked the diagnostic gene among the top five candidates, outperforming existing tools, particularly for genes with limited gene-phenotype association data. When applied to previously unsolved UDN cases, clinical review confirmed that SimPheny's high-confidence causative gene predictions were diagnostic in nearly half of the analyzed cases. As the size of the diagnosed reference cohort increases, SimPheny's diagnostic reach expands without sacrificing ranking performance. By leveraging real patient data rather than curated models, SimPheny provides a generalizable, scalable framework for improving diagnostic yield in rare disease cohorts.
    DOI:  https://doi.org/10.64898/2026.01.15.26344236
  39. Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00550-9. [Epub ahead of print]38(2): 260-262
    Mitochondria at the membrane provide a route to inflammatory cell death.
    Zezhao Chen, Daichao Xu.
      In a recent issue of Cell, Wang et al. identify "mitoxyperilysis," a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.019
  40. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00010-3. [Epub ahead of print]88 102120
    Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
    Eunbin Jee, Maisha Medha, Hwayoung Baek, Jonghan Kim, Yuho Kim.
      Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.
    Keywords:  Cardiomyopathy; Frataxin; Iron overload; Lysosome; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102120
  41. Ann Neurol. 2026 Feb 02.
    Fibroblast Transcriptomics in Molecular Diagnostics of a Comprehensive Dystonia Cohort.
    Alice Saparov, Ivana Dzinovic, Theresa Brunet, Vicente A Yépez, Florian Hölzlwimmer, Elisabetta Indelicato, Birgit Assmann, Susann Badmann, Diana Ballhausen, Steffen Berweck, Felix Brechtmann, Melanie Brugger, Kevork Derderian, Felix Distelmaier, Philip Harrer, Denisa Harvanova, Petra Havrankova, Ann-Kathrin Jaroszynski, Miriam Kolnikova, Robert Kopajtich, Anne Koy, Magdalena Krygier, Lukas Kunc, Katarina Kusikova, Oliver Maier, Maria Mazurkiewicz-Bełdzińska, Christian Mertes, Ava Oberlack, Timo Roser, Alexandra Sitzberger, Ugo Sorrentino, Antonia M Stehr, Katharina Vill, Matias Wagner, Holger Prokisch, Sylvia Boesch, Jan Necpal, Robert Jech, Juliane Winkelmann, Elisabeth Graf, Julien Gagneur, Matej Skorvanek, Michael Zech.
       OBJECTIVE: Genomic sequencing leaves >50% of dystonia-affected individuals without a diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) data from 167 patients with dystonia across a range of ages and presentations.
    METHODS: We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. The recruited patients had early-onset dystonia in 85.0%, non-focal dystonia in 92.2%, and coexisting features in 76.0%. Thirty-six patient samples with pre-identified variants (36/167, 21.6%) and 131 samples with no previously prioritized diagnostic candidates from genomic sequencing (131/167, 78.4%) were evaluated.
    RESULTS: We found that >80% of dystonia-associated genes were detected by fibroblast RNA-seq. Expression and splicing aberration analyses produced a manageable number of significant RNA defects affecting dystonia-associated genes. The approach was especially successful in validating pathogenic effects of loss-of-function variants, with disease-relevant RNA-underexpression detected for 66.7% (10/15). Studying aberrant expression and splicing in the context of other pre-identified variant types yielded relevant results in 28.6% (6/21 samples). We obtained a 6.9% (9/131) diagnostic uplift for patients without prior candidates, all of whom exhibited combined dystonia with autosomal recessive inheritance. The new diagnoses from RNA-seq and genomic reanalysis were based on previously neglected splice-region (3/9) and deep(er) intronic (6/9) variants. For the observed events, integration of new machine-learning scores predicted corresponding aberrant gene expression in the brain.
    INTERPRETATION: Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and offered a modest yield in patients without prior candidate variants. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78171
  42. Life Sci. 2026 Feb 03. pii: S0024-3205(26)00059-7. [Epub ahead of print] 124251
    Screening strategy using a filamentous fungus model to repurpose drugs for mitochondrial complex I deficiencies.
    Carole H Sellem, Nolwenn Bounaix, Mathilde Logerais, Aurélie Renaud, Marc Alexandre d'Elia, Jeremy Richard, Claire Almyre, Guillaume Becker, Jordan Rivron, Anaïs Hoarau, Naïg Gueguen, Valérie Desquiret-Dumas, Aurore Inisan, Sophie Belal, Adélie Mellinger, François Godard, Véronique Paquis-Flucklinger, Olivier R Baris, Stéphane Azoulay, Agnès Delahodde, Déborah Tribouillard-Tanvier, Nathalie Bonnefoy, Vincent Procaccio.
       AIM: This study aimed to repurpose FDA-approved drugs for the treatment of mitochondrial complex I diseases.
    MATERIALS AND METHODS: The NUO-51 protein of the filamentous fungus Podospora anserina is the homolog of the human key catalytic subunit of complex I, NDUFV1. By introducing a pathogenic mutation into P. anserina NUO-51 we created a novel model of complex I deficiency targeting the NDUFV1 subunit. The thermosensitive phenotype of the fungal mutant enabled us to screen a library of nearly one thousand FDA-approved molecules. We have implemented various techniques such as growth analysis, oxygen consumption measurements, complex I activity assays and western blotting on Podospora, Caenorhabditis elegans and human on equivalent NDUFV1 mutant models, treated or untreated with the most effective drugs found during the screen.
    KEY FINDINGS: We isolated a series of compounds able to rescue the growth defect of the Podospora nuo-51 mutant, including ligands of serotonin receptors or transporters. Among the selected drugs, alverine citrate (ALV) and dapoxetine hydrochloride (DAP) emerged as the most active drugs. Both drugs enhanced respiration and complex I activity, not only in the Podospora mutant, but also in Caenorhabditis elegans worms deficient for the NDUFV1 ortholog and in fibroblast from patient carrying NDUFV1 mutations.
    SIGNIFICANCE: Together, our work demonstrates the usefulness of Podospora anserina as fungal model for identifying promising therapeutic candidates for complex I diseases, paving the way for future clinical trials.
    Keywords:  Complex I; Disease models; Drug repositioning; Mitochondrial diseases; Oxidative phosphorylation; Serotonin receptor ligands
    DOI:  https://doi.org/10.1016/j.lfs.2026.124251
  43. bioRxiv. 2026 Jan 12. pii: 2026.01.12.698694. [Epub ahead of print]
    Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
    Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig Malloy, Stanislaw Deja, Shawn C Burgess, Matthew Mitsche, Jay D Horton.
      Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.
    DOI:  https://doi.org/10.64898/2026.01.12.698694
  44. PLoS Pathog. 2026 Feb 02. 22(2): e1013247
    Chlamydial membrane vesicles deliver the beta barrel outer membrane protein OmpA to mitochondria to inhibit apoptosis.
    Andreea Mesesan, Henry Oehler, Collins Waguia Kontchou, Aladin Haimovici, Martin Helmstädter, Oliver Kretz, Oliver Schilling, Stefan Tholen, John Atanga, Irina Nazarenko, Ulf Matti, Jonas Ries, Ian E Gentle, Georg Häcker.
      Chlamydiae are obligate intracellular bacteria that inhibit mitochondrial apoptosis to maintain integrity of the host cell. We have previously reported that a chlamydial outer membrane β-barrel protein, OmpA, can during ectopic expression inhibit mitochondrial apoptosis through direct interaction with the BCL-2-family effectors BAX and BAK. We here show that OmpA from Chlamydia trachomatis (Ctr) uses membrane vesicles for its delivery to the outer mitochondrial membrane during Ctr infection. Using a number of imaging and fractionation techniques, we show that OmpA during infection reaches mitochondria and is inserted into mitochondrial membranes. Chlamydia derived vesicles (CDV) from Ctr-infected cells contained OmpA as well as other outer membrane proteins and LPS. When added to uninfected cells, CDVs fused with mitochondrial membranes, causing the interaction of OmpA with BAK and the cytosolic retro-translocation of BAX. CDV addition to uninfected cells also protected the cells against apoptosis. We previously showed that OmpA works in co-ordination with VDAC2 to block apoptosis and here propose a structural model of this BAK inhibition by OmpA that reenacts the inhibition of BAK by VDAC2. The results provide evidence that OmpA from Chlamydia, as well as the structurally similar ortholog from the related Simkania, specifically exploits its relationship to mitochondrial porins to protect the infected cell against apoptosis and to enable intracellular growth of the bacteria in human cells.
    DOI:  https://doi.org/10.1371/journal.ppat.1013247
  45. J Neurochem. 2026 Feb;170(2): e70363
    Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP+ Model of Parkinson's Disease.
    Hyun-Seung Lee, Sun-Ah Kang, Jae-Won Eom, Min Seong Kim, Ji-Soo Kim, Yang-Hee Kim.
      Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient primary mouse astrocytes, human iPSC-derived midbrain dopaminergic neurons, and Rho0 CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn2+) homeostasis and lysosomal integrity. We identify intracellular zinc as a critical mediator linking mitochondrial dysfunction to lysosomal membrane permeabilization (LMP) and neuronal death. Inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP+) elevated reactive oxygen species (ROS) and intracellular zinc, jointly driving LMP. Blocking either ROS or zinc markedly attenuated lysosomal damage and cell death, demonstrating that both act upstream of LMP. To define zinc regulation, we examined metallothionein-3 (MT-3), a brain-enriched zinc-binding protein. MT-3-deficient astrocytes were more vulnerable to MPP+ and zinc overload (ZnCl2) but paradoxically resistant to hydrogen peroxide (H2O2), suggesting that MT-3 buffers cytosolic zinc during mitochondrial injury or extracellular zinc influx yet can release bound zinc under oxidative conditions. Using Rho0 cells, we show that MPP+ toxicity depends on mitochondrial ROS, as loss of mitochondrial function nearly abolished cell death. However, Rho0 cells were highly sensitive to ZnCl2 and H2O2 and exhibited markedly reduced lysosomal abundance, indicating limited capacity to sequester zinc and increased susceptibility to zinc-mediated injury. These findings support a coordinated system in which lysosomes and zinc-binding proteins maintain zinc homeostasis. When cytosolic zinc rises, its accumulation within lysosomes induces LMP and accelerates cell death. Collectively, our results identify intracellular zinc as an upstream trigger of lysosomal dysfunction and neurodegeneration. Zinc-mediated LMP provides a mechanistic link between mitochondrial injury, impaired autophagic flux, and α-synuclein pathology in PD. Enhancing zinc homeostasis and lysosomal resilience may offer promising therapeutic strategies.
    Keywords:  Parkinson's disease; lysosomal membrane permeabilization (LMP); mitochondria; reactive oxygen species (ROS); zinc
    DOI:  https://doi.org/10.1111/jnc.70363
  46. Ageing Res Rev. 2026 Feb 03. pii: S1568-1637(26)00043-7. [Epub ahead of print] 103051
    Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
    Jingge Xu, Xingyi Li, Zhiyu Zhang, Jiahui Wu, Haiyang Yu, Yuzheng Wu, Dan Wang, Ruixia Bao, Tao Wang, Yi Zhang, Qian Chen.
      As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.
    Keywords:  Ageing kidney; Mitochondrial donor cells; Mitochondrial homeostasis; Mitochondrial transfer; Pharmacological therapeutics
    DOI:  https://doi.org/10.1016/j.arr.2026.103051
  47. Adv Sci (Weinh). 2026 Feb 04. e18974
    Targeted Mitochondrial ECSIT Overexpression Attenuates MASH by Increasing OTUD3 Expression.
    Yuqing Jiang, Tingting Tong, Pengxi Shi, Xiaofan Chen, Chenhao Wang, Qingyuan Weng, Sihan Chen, Linli Que, Qi Chen, Yuehua Li, Qiang Zhu, Jiantao Li.
      Mitochondrial dysfunction plays a key role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). As is known to play a key role in mitochondria, ECSIT, in relation to oxidized mitochondrial DNA is still unclear. This study examines mitochondrial ECSIT expression in MASH mouse models. Mitochondria-targeted ECSIT transgenic (ECSITMTG) mice and wild-type (WT) controls are fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks or a methionine- and choline-deficient (MCD) diet for 8 weeks. Results demonstrate that mitochondrial ECSIT overexpression alleviates diet-induced MASH phenotypes. Mechanistically, we demonstrate that mitochondrial ECSIT promotes the localization of the deubiquitinase OTUD3 to mitochondria. OTUD3 then stabilizes SIRT3 via deubiquitination, thereby inhibiting mtDNA oxidation and alleviating steatosis-induced metabolic disorders. Overall, these findings indicate that mitochondrial ECSIT protects against MASH progression by stabilizing SIRT3, suggesting its potential as a therapeutic target.
    Keywords:  ECSIT; MASH; OTUD3; SIRT3; ox‐mtDNA
    DOI:  https://doi.org/10.1002/advs.202518974
  48. bioRxiv. 2026 Jan 22. pii: 2026.01.19.699752. [Epub ahead of print]
    Dying oligodendrocytes persist without mitochondria.
    Xhoela Bame, S Zoela Gilani, Yasmine Kamen, Robert A Hill.
      Myelin is an insulating, multi-layered membrane that supports axonal integrity and neural communication. Different stressors impair myelinating oligodendrocytes, leading to demyelination, inflammation, and neurodegeneration. The intracellular processes underlying oligodendrocyte degeneration and death are unclear. Here, using optically targeted DNA damage that causes single-cell demyelination, we reveal that injured mature oligodendrocytes lose mitochondria within days and persist without them for weeks to months before cell death. This differs from other oligodendrocyte lineage cells, which exhibit acute mitochondrial changes followed by rapid cell death. Conditional deletion of the mitochondrial-related gene, Fis1 , in mature oligodendrocytes, similarly causes acute loss of mitochondria and prolonged cell death. The unique cell death is characterized by nuclear changes, intracellular stress, and markers of disease-associated oligodendrocytes. Thus, mitochondrial loss may be an early marker of oligodendrocyte pathology, and mitochondrial quality control is required for oligodendrocyte and myelin homeostasis.
    DOI:  https://doi.org/10.64898/2026.01.19.699752
  49. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]
    Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
    Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.
      Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.
    DOI:  https://doi.org/10.64898/2026.01.13.699119
  50. iScience. 2026 Feb 20. 29(2): 114480
    In vitro model of human subcutaneous adipocyte spheroids for studying mitochondrial dysfunction and mitochondria activating compounds.
    Anita Wagner, Juulia H Lautaoja-Kivipelto, Kalle Pehkonen, Antti Hassinen, Minna Kuusela, Lisa Röttger, Elena Herbers, Anna Ioannidou, Sophia Mädler, Ina Rothenaigner, Soumya Srinivasan, Sini Laasonen, M Tanvir Rahman, Pinja Elomaa, Saija Kortetjärvi, Anneli Olsson, Olavi Ukkola, Kamyar Hadian, Matthias Mann, Hilkka Peltoniemi, Kirsi H Pietiläinen, Martin Klingenspor, Kirsi A Virtanen, Carolina E Hagberg, Eija Pirinen.
      Mitochondrial abnormalities drive subcutaneous white adipose tissue dysfunction in obesity, yet in vitro models to study adipocyte mitochondria remain limited. Here, we establish a human subcutaneous adipocyte spheroid model to characterize mitochondrial metabolism under obesity-relevant conditions and drug exposure. Human preadipocyte spheroids were differentiated in ultra-low attachment plates for 3 weeks using thiazolidinedione-free medium. Matrigel embedding was incorporated into the protocol as it promoted mitochondrial network and respiration compared to scaffold-free conditions. Differentiated spheroids showed increased lipid accumulation, adipogenic gene expression, mitochondrial respiration, adiponectin secretion, and hormonal responsiveness. Lipid mixture administration during differentiation induced metabolic disturbances, including mitochondrial respiration failure, alongside increased mitochondrial biogenesis. Post-differentiation treatment with rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, improved mitochondrial bioenergetics and adiponectin secretion in lipid mixture-administered adipocyte spheroids. Our model enables precise measurement of adipocyte mitochondria metabolism, providing a platform for mitochondria-focused research and drug discovery in obesity.
    Keywords:  Adipocyte; Human metabolism; Lipid; Mitochondria; Obesity; Spheroid
    DOI:  https://doi.org/10.1016/j.isci.2025.114480
  51. AACE Endocrinol Diabetes. 2026 Jan-Feb;13(1):13(1): 102-106
    Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
    Jing Li, Xiaodi Wang, Yanmei Guo, Wenwen Wang, Shujuan Wu, Jingmin Sun.
       Background/Objective: We describe a 5-year-old boy with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome presenting with epilepsy, refractory hyperlactatemia, and profound hypoparathyroidism accompanied by Fahr syndrome-like brain calcifications. This case expands the known phenotypic spectrum of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome by demonstrating concurrent parathyroid dysfunction and basal ganglia calcifications. The objective of this report is to characterize this unique neuroendocrine presentation and highlight diagnostic considerations for similar cases.
    Case Presentation: A previously healthy 5-year-old boy presented with 2 days of vomiting, diarrhea, and 1 generalized tonic-clonic seizure. Examination revealed lethargy, positive Chvostek sign, and positive Trousseau sign. Laboratory results showed plasma-free calcium 0.98 mmol/L (reference range, 1.15-1.33), lactate 6.0 mmol/L (reference, 0.7-2.1), and parathyroid hormone 6.62 pg/mL (reference, 12-65). Brain imaging demonstrated symmetrical basal ganglia calcifications. Treatment included levetiracetam, calcium and vitamin D supplementation. Genetic testing confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with m.3243A>G mutation. Follow-up showed persistent hyperlactatemia (peak 8.4 mmol/L) and worsening hypoparathyroidism (parathyroid hormone <3 pg/mL).
    Discussion: The severity and persistence of parathyroid hormone suppression in this case contrasts with typical mitochondrial disorder presentations. The concurrence of Fahr-type calcifications and profound hypoparathyroidism suggests potential mitochondrial dysfunction in calcium-regulating tissues.
    Conclusion: This case illustrates a severe neuroendocrine phenotype of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome. Unexplained hypoparathyroidism with basal ganglia calcifications should prompt consideration of mitochondrial disorders, even without classic stroke-like episodes.
    Keywords:  Fahr syndrome; MELAS syndrome; hypoparathyroidism; mitochondrial disorders; neuroendocrine disorders; pediatric endocrinology
    DOI:  https://doi.org/10.1016/j.aed.2025.09.007
  52. Case Rep Genet. 2026 ;2026 6492770
    The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
    Gabriele D'Amato, Mattia Gentile, Rossella Carella, Antonio Giannini, Maria Felicia Faienza, Albina Tummolo.
       Background: Mitochondrial DNA depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder presenting in early infancy with encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Patient-derived cells typically exhibit impaired mitochondrial oxidative phosphorylation and a marked reduction in mitochondrial DNA (mtDNA) copy number.
    Case Report: We report the case of a male preterm neonate born at 31 + 3 weeks of gestation following a pregnancy marked by severe polyhydramnios. At birth, his weight was 1400 g. Physical examination revealed dysmorphic features, redundant and lax skin, and generalized muscular hypotonia. Laboratory investigations showed marked lactic acidosis associated with lactic aciduria, ketonuria, and urinary biomarkers indicating activation of preoxidative phosphorylation biochemical pathways to sustain ATP production. Echocardiography demonstrated mild, early-onset hypertrophic cardiomyopathy. The Exome Analysis Clinical and Biochemical Markers: The exome analysis, performed within the first week of life, highlighted a pathogenic variant in homozygous state of FBXL4 gene (c.1648_1649delGA), which led to the diagnosis of MTDPS13. In this clinical contest, a ketogenic diet (KD) was started with a daily caloric intake of 120 kcal/kg and an initial ketogenic ratio of 1:1. These intakes were administered both with a parenteral nutrition and continuous nasogastric tube feeding and were gradually increased and adapted on a day-by-day basis according to lactic acidosis, growth increase, and common metabolic parameters such as glucose, electrolytes, creatinine, and blood urea nitrogen. After 3 days of this treatment approach, a significant reduction in lactate levels and improvement in acid-base balance and growth trend were observed along with clinical and cardiovascular parameters. At discharge from neonatal intensive care unit, the KD was continued at home and during follow-up. The infant showed stability in the clinical and biochemical markers.
    Conclusions: This is the first documented report of the use of a KD in a preterm neonate with this mitochondrial disorder during the early days of life. Prompt genetic confirmation and early initiation of KD may enable a more targeted and effective management of MTDPS within the neonatal intensive care setting.
    DOI:  https://doi.org/10.1155/crig/6492770
  53. Curr Opin Physiol. 2025 Sep;pii: 100848. [Epub ahead of print]45
    Mechanisms of microRNA trafficking to mitochondria in the heart.
    Diego Quiroga, Rachel Daniel, Samarjit Das.
      MicroRNAs (miRNAs) are essential post-transcriptional regulators of gene expression, and accumulating evidence supports their presence and function within mitochondria. These mitochondrial microRNAs (MitomiRs) modulate key processes such as oxidative phosphorylation, ATP production, calcium homeostasis, and reactive oxygen species balance in cardiac tissue. Despite growing recognition of their importance, the mechanisms governing miRNA trafficking to mitochondria remain incompletely understood. This review explores the current knowledge on miRNA biogenesis, mitochondrial import pathways - including the roles of Argonaute 2 (AGO2), the Translocase of the Outer/Inner Mitochondrial Membrane (TOM/TIM) complexes, and Polynucleotide Phosphorylase (PNPase) - and the regulatory impact of specific MitomiRs, such as miR-181c, miR-210, miR-378, let-7b, and miR-1. Understanding how these molecules influence mitochondrial function provides insight into their therapeutic potential in cardiovascular disease.
    DOI:  https://doi.org/10.1016/j.cophys.2025.100848
  54. Nat Commun. 2026 Feb 05.
    Transient protein structure guides surface diffusion pathways for electron transport in membrane supercomplexes.
    Chun Kit Chan, Jonathan Nguyen, Corey F Hryc, Chitrak Gupta, Kevin Redding, William Dowhan, Matthew L Baker, Alberto Perez, Eugenia Mileykovskaya, Abhishek Singharoy.
      The exact biological role of mitochondrial supercomplexes remains debated, particularly their role in guiding redox proteins across membranes during energy conversion. We integrate multiscale modeling and single particle cryo-electron microscopy (cryo-EM) to examine electron transfer in mitochondrial supercomplexes composed of complexes III and IV (CIII and CIV). Using bioinformatic and entropy-based methods, we generated structural ensembles capturing conformations of CIII's disordered QCR6 hinge within the yeast CIII2CIV2 supercomplex. Molecular and Brownian Dynamics simulations reveal that these negatively charged hinge states electrostatically couple with redox proteins, promoting their binding and directional diffusion across the membrane on millisecond timescales. Rather than hindering transfer, disorder lowers the diffusion barrier. Anionic lipids reinforce this recognition by retaining a membrane pool of redox proteins when hinge length is critical. Cryo-EM models of ΔQCR6 show large rearrangements, yet maintain a robust electrostatic environment enabling surface-mediated transfer despite reduced charge. Overall, electron carriers confined on bioenergetic membranes follow a refolding-guided diffusion mechanism that enhances supercomplex energy conversion efficiency by nearly 30%.
    DOI:  https://doi.org/10.1038/s41467-025-67110-y
  55. Annu Rev Biophys. 2026 Feb 05.
    Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.
    Shashank Ranjan Srivastava, Aadish Rawat, Radhakrishnan Mahalakshmi.
      Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane carry out bidirectional flux of metabolites and ions and serve as the first line of communication between the cytosol and mitochondria. They are now recognized as indispensable for mitochondrial function and cellular homeostasis, mitochondria-endoplasmic reticulum communication, lipid and cholesterol biogenesis, Ca2+ homeostasis, and mitochondria-mediated apoptosis. The unique structural features of VDACs are also important in redox regulation. VDAC dysregulation by interaction with amyloid-β, α-synuclein, Tau, or tubulin can lead to neurodegeneration. Here, we provide insights into the structures, isoform-specific molecular functions, cellular interactome, variations, and unique regulatory elements of VDACs and their direct implications in widespread burdens like cancer and neurodegeneration in humans. We discuss how deducing isoform-specific structure-function studies of VDACs has the potential for successful development of next-generation diagnostics-guided therapeutics.
    DOI:  https://doi.org/10.1146/annurev-biophys-061124-102155
  56. Cell Metab. 2026 Feb 03. pii: S1550-4131(26)00003-3. [Epub ahead of print]38(2): 257-259
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      Huang et al.1 show a J-shaped relationship between vigorous activity and cognitive decline, with maximal benefit ∼1,000-1,300 MET-min/week and harm with excessive exercise. Using UK Biobank data, mechanistic models, and an RCT, they implicate lactate-driven mitochondria-derived vesicles that reach the hippocampus, disrupt synapses, and impair cognition.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.003
  57. Spectrochim Acta A Mol Biomol Spectrosc. 2026 Jan 21. pii: S1386-1425(26)00067-3. [Epub ahead of print]352 127496
    Imaging mitochondrial hydrogen sulfide in multicellular spheroids using a near-infrared iridium(III) complex.
    Zhifeng Mao, Liuqi Ye, Fahui Hu, Xiaolei Wu, Daniel Shiu-Hin Chan, Chun-Yuen Wong, Jin-Biao Liu, Chung-Hang Leung, Wanhe Wang.
      Abnormal levels of hydrogen sulfide (H2S) have been linked to multiple diseases, including neurological disorders, cardiovascular diseases, and cancers. Mitochondria play a central role in H2S metabolism, and dysregulation of H2S within mitochondria is emerging as a key factor in mitochondrial dysfunction. To explore the role of mitochondrial H2S in live cells, a near-infrared (NIR) iridium(III) complex-based luminescence probe was constructed for the selective and sensitive detection of endogenous mitochondrial H2S. Complex 1 exhibits a distinct luminescent response to H2S. Upon exposure to H2S, the nitro group in complex 1 is reduced to an amine group for triggering a 1,6-elimination reaction, resulting in luminescence quenching. The probe exhibits high-performance detection with low detection limit of 0.96 μM and exceptional specificity in aqueous buffer. Confocal imaging in living HeLa cells confirmed the probe's ability to detect both exogenous and endogenous H2S. Additionally, the probe specifically localizes to mitochondria, enabling effective bioimaging of mitochondrial H2S in multicellular spheroids (MCSs). Notably, this study presents the first luminescence probe for mitochondrial H2S based on a NIR iridium(III) complex. These findings demonstrate that complex 1 is a promising tool for exploring the biological functions and pathological roles of subcellular H2S in diseases.
    DOI:  https://doi.org/10.1016/j.saa.2026.127496
  58. JIMD Rep. 2026 Mar;67(2): e70072
    Epilepsy Phenotype and EEG Finding of Rhythmic High-Amplitude Delta With Superimposed Spikes (RHADS) in Succinate Dehydrogenase Deficiency.
    Aaron B Bowen, Chiadika Nwanze, Cesar Alves, Lance Rodan, Anna Lecticia Pinto, Melissa A Walker, Irina Anselm, Phillip L Pearl.
      Succinate dehydrogenase (SDH) serves a dual function as complex II of the electron transport chain and an enzyme of the tricarboxylic acid cycle. Pathogenic variants in subunits of SDH result in diverse clinical presentations, including typically autosomal recessive neurodegenerative disorders. Biallelic variants in the SDHA subunit most often cause Leigh syndrome. However, epilepsy phenotypes of these patients are ill-defined and there is only one prior report of epilepsy in a patient with SDHA deficiency. Here we report the seizure and EEG phenotypes of three autosomal recessive SDHA patients with refractory epilepsy, two of whom are siblings. These patients exhibit multiple seizure types and a variety of EEG findings, including a patient with rhythmic high-amplitude delta with superimposed spikes (RHADS), a finding closely associated with polymerase gamma (POLG)-related disorders.
    Keywords:  Leigh syndrome; RHADS; complex II deficiency; epilepsy; succinate dehydrogenase deficiency
    DOI:  https://doi.org/10.1002/jmd2.70072
  59. bioRxiv. 2026 Jan 19. pii: 2026.01.15.699680. [Epub ahead of print]
    Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.
    Linda Alex, Paula J Klutho, Lihui Song, Manuel Gutiérrez-Aguilar, Christopher P Baines.
      Genetic inhibition of cyclophilin D (CypD) delays the opening of the mitochondrial permeability transition pore (MPTP) and therefore reduces necrotic cell death. Elucidation of factors that impact CypD activity is therefore key to understanding the regulation of MPTP opening. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine kinase that has been shown to modulate MPTP and cell death, potentially through phosphorylation of CypD. Therefore, we hypothesized that the mitochondrial fraction of GSK3β directly phosphorylates CypD and promotes opening of MPTP. Overexpression of full length GSK3β in mouse embryonic fibroblasts sensitized the MPTP and exacerbated oxidative stress-induced necrosis. In contrast, genetic inhibition of GSK3β protected against oxidant-induced cytotoxicity but did not affect the MPTP. Recombinant GSK3β could directly bind to and phosphorylate recombinant CypD. Mass spectrometry revealed several putative GSK3β phosphorylation sites on CypD. However, mutation of these sites did not affect the peptidyl prolyl isomerase activity of CypD and reconstitution of these phosphomutants in CypD-deficient cells increased MPTP sensitivity and oxidative-induced cell death to the same extent as wild-type CypD. Further, targeted overexpression of either wild-type or kinase-inactive GSK3β in the mitochondrial matrix did not impact MPTP or cell death. Moreover, while proteinase-K digestion of cardiac mitochondria showed a significant amount of GSK3β in the mitochondria, it was not localized to the matrix. Finally, overexpression of GSK3β was still able to increase MPTP sensitivity and oxidative stress-induced death in CypD-null cells. Taken together, these data indicate that, while GSK3β can modulate MPTP, this appears to be independent of GSK3β's interaction with, or phosphorylation of CypD.
    DOI:  https://doi.org/10.64898/2026.01.15.699680
  60. Cell Mol Neurobiol. 2026 Feb 06.
    Mitochondrial Transplantation Therapy for Ischemic Stroke: Progress and Challenges.
    Zhi-Hong Zhao, Xue-Ling Yang, Zi-Wei Lu, Tao Li, Li-Li Zhao, Ye Li, Mei-Juan Dang, Gui-Lian Zhang, Kun Chen, Hong Fan.
      
    Keywords:  Ischemic stroke; Mitochondrial damage; Mitochondrial quality and quantity control system; Mitochondrial transplantation; Mitochondrial uptake and internalization
    DOI:  https://doi.org/10.1007/s10571-026-01682-1
  61. Hum Gene Ther. 2026 Feb 04. 10430342261422716
    Maximizing Access to Cell and Gene Therapy for Patients with Rare Diseases.
    Terence R Flotte, Guangping Gao.
      
    DOI:  https://doi.org/10.1177/10430342261422716
  62. J Control Release. 2026 Feb 03. pii: S0168-3659(26)00083-0. [Epub ahead of print]392 114682
    Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury.
    Mitsue Hibino, Yukari Muramatsu, Hideyoshi Harashima, Yuma Yamada.
      Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q10 (CoQ10) exhibits mitochondrial protective effects and is considered a promising therapeutic candidate. However, it has difficulty targeting liver mitochondria because of its high hydrophobicity and low bioavailability. To address the therapeutic limitations of CoQ10 caused by poor mitochondrial bioavailability, this study aimed to establish a rational design to systematically evaluate how particle size and lipid composition influence the therapeutic efficacy of CoQ10-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ10-loaded mitochondrial-targeted nanocarriers (CoQ10-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ10-LP, which mimics liposomes used in clinical applications, were prepared using a microfluidic device. These nanocarriers were administered to AILI model mice at early stages of disease, and their hepatic and mitochondrial accumulation, therapeutic impact on serum biomarkers, histological damage, and CoQ10 delivery efficiency were evaluated systematically. The 50-nm CoQ10-MITO-Porter showed the highest hepatoprotective efficacy, indicated by marked attenuation of serum alanine aminotransferase levels and reduced hepatic necrosis. The effect decreased with increasing particle size and was minimal for CoQ10-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ10in early-phase AILI. These findings are expected to serve as a foundation for the development of mitochondria-targeted nanomedicines that alleviate early-phase hepatic damage and may extend to other mitochondrial-related diseases.
    Keywords:  Antioxidant drug; Lipid nanoparticle; Liver targeting; Microfluidics; Mitochondria targeting; Poorly water-soluble drug
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114682
  63. JIMD Rep. 2026 Mar;67(2): e70071
    Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency.
    Sharmila Kiss, Richard J Leventer, Cormac Duff, Emma Macdonald-Laurs, Olivia-Paris Quinn, Fahaz Nazer, Michelle Cao, Abisha Srikumar, Jenzen Dalina, Mary Eggington, Joy Yaplito- Lee.
      Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1, encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the γ-aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including γ-hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10-month-old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left-sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right > left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography-mass spectrometry revealed markedly elevated 4-hydroxybutyric acid and 4,5-dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous ALDH5A1 variants: c.278G>T p.(Cys93Phe) and c.612G>A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9 years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.
    DOI:  https://doi.org/10.1002/jmd2.70071
  64. Chem Commun (Camb). 2026 Feb 05.
    Mitochondria targeting by a nonionic and emissive push-pull type chromophore or its polymer conjugate.
    Atish Nag, Priya Rajdev, Supan Roy, Likesh Kumar, Khushi Verma, Siddhartha S Jana, Suhrit Ghosh.
      Intracellular organelle targeting, especially of mitochondria, is of significant importance for drug delivery to improve therapeutic efficiency and overcome the endosomal trap. While mitochondria targeting has been achieved by mostly cationic systems, this communication reports a rare phenomenon of mitochondria targeting by water-soluble non-ionic polymers (representative substrate of interest), featuring an oligo-oxyethylene appended polymethyl-methacrylate backbone, and terminated with an amine-substituted single naphthalene-monoamide (NMI) derivative (a push-pull type chromophore). The push-pull type charge-neutral NMI chromophore facilitates both cellular uptake and crossing the mitochondrial membrane barrier, while its green emission allows for simultaneous fluorescence imaging. Considering the outstanding mitochondria targeting, cell compatibility, simultaneous imaging and wide-ranging covalent-conjugation possibilities, this simple yet versatile chromophore brings new opportunities in intracellular mitochondria targeted delivery.
    DOI:  https://doi.org/10.1039/d5cc06572k
  65. Pediatr Nephrol. 2026 Feb 05.
    Mitochondrial disorders with renal involvement and kidney transplantation require genotypic and phenotypic characterisation.
    Josef Finsterer.
      
    DOI:  https://doi.org/10.1007/s00467-026-07178-w
  66. Trends Biochem Sci. 2026 Feb;pii: S0968-0004(25)00294-4. [Epub ahead of print]51(2): 95-97
    The past, present, and future of RNA biochemistry and mitochondrial research.
    Ling-Ling Chen, Alicia J Kowaltowski.
      
    DOI:  https://doi.org/10.1016/j.tibs.2025.12.002
  67. Brain. 2026 Feb 05. pii: awag050. [Epub ahead of print]
    Diagnostic yield of genome sequencing in children with progressive movement disorders.
    Luca Schierbaum, Enrique Gonzalez Saez-Diez, Amy Tam, Joshua Rong, Umar Zubair, Katerina Bernardi, Kathryn Yang, Vicente Quiroz, Zainab Zaman, Afshin Saffari, Siofra Carty, Habibah A P Agianda, Sanda Alexandrescu, Florian Eichler, Abigail Sveden, Maya Chopra, Daniel G Calame, Matt C Danzi, Stephan Zuchner, Darius Ebrahimi-Fakhari.
      Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM, and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.
    Keywords:  childhood-onset movement disorders; diagnostic yield; dystonia; long-read sequencing; spasticity; whole genome sequencing
    DOI:  https://doi.org/10.1093/brain/awag050
  68. Cell Rep Med. 2026 Feb 03. pii: S2666-3791(26)00002-9. [Epub ahead of print] 102585
    Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.
    Qi Liu, Borui Xue, Yongfeng Zhang, Mingze Qin, Ziqing Zhu, Zhenguo Wang, Hongyu Li, Shuanshuan Fan, Meijia Su, Shengyou Li, Shijie Yang, Anhui Qin, Teng Ma, Xue Gao, Huiling Sun, Yiming Hao, Lingli Guo, Shihao Nie, Jiaqi Wang, Zhuojing Luo, Jinghui Huang, Bing Xia.
      Peripheral nerve injury causes muscle atrophy due to slow axonal regeneration, highlighting an unmet therapeutic need. Although neuromuscular interactions are classically viewed as unidirectionally nerve dominated, we show that acutely denervated muscle (adMu) regulates nerve regeneration via a retrograde signaling pathway. adMu initiates a trans-tissue regulatory mechanism through extracellular vesicles (EVsadMu) that orchestrate neural energy homeostasis to accelerate regeneration. Functional profiling identifies IDH2 and CS as key metabolic enzymes within EVsadMu. Neurons treated with EVsadMu exhibit a 1.39-fold increase in NADPH/NADP+ ratio via IDH2, along with a 1.18- and 1.27-fold increase in NADH/NAD+ and FADH2/FAD ratios via CS, fueling the tricarboxylic acid (TCA) cycle to enhance mitochondrial bioenergetics. This restores redox balance and energy supply, driving axonal regeneration. In sciatic nerve injury models, EVadMu-microneedle conduits significantly promote energy metabolism and functional recovery. Together, our findings position adMu as a metabolic signaling center enabling retrograde regulation for nerve regeneration, offering potential for clinical translation.
    Keywords:  acute denervation; extracellular vesicles; mitochondrial metabolism; muscle; peripheral nerve injury
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102585
  69. BMC Neurol. 2026 Feb 02.
    Identification and verification of hub genes related to mitochondrial dysfunction in epilepsy based on bioinformatics analysis.
    Yunyun Lu, Yanyan Zhang, Faqiang Li, Feng Chen, Shuaishuai Wang, Ziguang Zhao.
      
    Keywords:  Bioinformatics analysis; Diagnostic model; Epilepsy; Mitochondrial energy metabolism pathways; Mitochondrial energy metabolism-related genes
    DOI:  https://doi.org/10.1186/s12883-026-04638-6
  70. Sci Rep. 2026 Feb 06.
    Biliary elimination of cholesterol can be modulated by hepatocyte mitochondrial Aquaporin-8 in mice.
    María Celeste Capitani, Alejo M Capiglioni, Raúl A Marinelli, Julieta Marrone.
      
    Keywords:  ABCG5; Adenovirus; Biliary cholesterol excretion; Hydrogen peroxide; Mitochondrial aquaporin-8
    DOI:  https://doi.org/10.1038/s41598-026-39058-6
  71. J Mol Med (Berl). 2026 Jan 31. 104(1): 36
    Bridging gaps in mitochondrial disease diagnosis: the role of advanced biomarker discovery.
    Tendai Makwikwi, Maryke Schoonen, Izelle Smuts, Francois H van der Westhuizen.
      
    DOI:  https://doi.org/10.1007/s00109-026-02646-0
  72. Aging Cell. 2026 Feb;25(2): e70405
    Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
    Rita Ibrahim, Christin Froschauer, Susanne Broschk, David R Sannino, Adam J Dobson.
      The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is a leading example, which can extend healthy lifespan in a range of animals, but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess 'mito-nuclear' epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as a gatekeeper.
    DOI:  https://doi.org/10.1111/acel.70405
  73. Sci Adv. 2026 Feb 06. 12(6): eaea0706
    Introgressed mitochondrial fragments from archaic hominins alter nuclear genome function in modern humans.
    Qiong Zhu, Jinning Zhang, Weichen Zhou, Shen-Ao Liang, Shengmiao Wang, Xinyu Cai, Fuyuan Li, Jin Li, Guojie Zhang, Huijuan Feng, Qiaomei Fu, Joshua M Akey, Feng Zhang, Li Jin, Shuhua Xu, Hong-Xiang Zheng, Lu Chen.
      Archaic introgression introduced functionally relevant variants into modern humans, yet small-scale insertions remain understudied. Here, we leverage 2519 modern human genomes and four high-coverage archaic hominin genomes to systematically characterize nuclear mitochondrial DNA segments (NUMTs). We uncover 483 polymorphic NUMTs across globally diverse human populations and 10 in archaic genomes. By combining overlap with Neanderthal-derived and Denisovan-derived haplotypes, phylogenetic analyses, insertion time estimates, and haplotype colocalization, we identify five NUMTs introduced into modern humans via archaic hominin introgression. Functional analyses reveal that introgressed NUMTs can modulate gene expression, including allele-specific up-regulation of the immune-related gene RASGRP3, and reshape three-dimensional chromatin structure at loci such as SCD5 and HNRNPD. These findings highlight an underappreciated mechanism by which archaic mitochondrial fragments shape nuclear genome function and evolution. Our study reframes NUMTs not as passive genomic fossils but as dynamic elements influencing modern human diversity and adaptation.
    DOI:  https://doi.org/10.1126/sciadv.aea0706
  74. JCI Insight. 2026 Jan 29. pii: e195170. [Epub ahead of print]
    Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
    Natalia W Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol-features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.
    Keywords:  Autoimmune diseases; Autoimmunity; Immunology; Lupus; NK cells
    DOI:  https://doi.org/10.1172/jci.insight.195170
  75. FEBS J. 2026 Feb 07.
    Energetic stress in combination with impaired fatty acid oxidation induces sequestration of CoA and adaptation of CoA metabolism.
    Ligia Akemi Kiyuna, Christoff Odendaal, Madhulika Singh, Albert Gerding, Miriam Langelaar-Makkinje, Marianne van der Zwaag, Asmara Drachman, Vladimíra Cetkovská, Gaby Liem Foeng Kioen, Anne-Claire M F Martines, Nicolette C A Huijkman, Hein Schepers, Bart van de Sluis, Dirk-Jan Reijngoud, Ody C M Sibon, Amy C Harms, Thomas Hankemeier, Barbara M Bakker.
      Coenzyme A (CoA) is a vital cofactor involved in 8-10% of all metabolic reactions in human cells. Different inherited enzyme deficiencies in which the oxidation of acyl-CoAs is hampered have been hypothesised to share a phenotype characterised by toxic accumulation of acyl-CoA and a concomitant decline in free CoA (CoASH) levels, whereby CoASH becomes limiting for other metabolic reactions. This is referred to as CoASH sequestration. There is, however, limited experimental evidence for this hypothesis. Using a combination of approaches, we test this hypothesis in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common deficiency of mitochondrial fatty acid oxidation (mFAO), under energetic stress. Both in vitro MCAD-knockout (KO) HepG2 cells and a kinetic model of mFAO showed decreased CoASH, elevated medium-chain acyl-CoA, and decreased long-chain acyl-CoA levels. MCAD-KO mice exposed to fasting and cold as energetic stressors had a significantly increased total CoA pool and increased expression of CoA biosynthetic enzymes in the liver, indicative of an upregulated CoA biosynthesis. Expression of carnitine acyltransferases and acyl-CoA thioesterases, enzymes that liberate CoASH from acyl-CoAs, was also upregulated, suggesting an adaptive response of CoA metabolism to decreased CoASH. Finally, computational model simulations showed that a combination of elevated total CoA and thioesterase activity led to normalisation of both CoASH and medium-chain acyl-CoA levels. Together, the results provide the first evidence for the CoA sequestration hypothesis in MCADD. The observed adaptation of CoA metabolism under energetic stress may act as a compensatory response that counteracts CoASH depletion and accumulation of toxic medium-chain acyl-CoAs.
    Keywords:  CASTOR; CoA metabolism; MCAD deficiency; inborn errors of metabolism; systems medicine
    DOI:  https://doi.org/10.1111/febs.70442
  76. J Pharm Biomed Anal. 2026 Jan 30. pii: S0731-7085(26)00052-X. [Epub ahead of print]273 117384
    Detection and localization of single-nucleotide mutations in synthetic oligonucleotides by ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry.
    Mohamed A Gab-Allah, Hyojin Hwang, Mingyu Kim, Ngoc-Trinh Tran, Bong Jik Kim, Minyoung Kim, Jin Hee Han, Yehree Kim, Byung Yoon Choi, Jeongkwon Kim.
      Accurate detection of point mutations in mitochondrial DNA (mtDNA) is crucial for diagnosing various mitochondrial disorders. In this study, we developed an ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry (UHPLC-HRMS/MS) method for the direct, label-free identification and localization of single-nucleotide mutations using synthetic 20- and 49-mer oligonucleotides as model fragments representing the pathogenic mtDNA point mutation (mt.3243 A>G). Three mobile phase systems, including ammonium bicarbonate (ABC), triethylamine/hexafluoroisopropanol (TEA/HFIP), and tributylamine/HFIP (TBA/HFIP), were systematically evaluated to assess their effects on oligonucleotide retention behavior and duplex stability under denaturing and non-denaturing conditions. The ABC buffer provided optimal performance for maintaining partial duplex integrity, while TEA/HFIP offered superior ionization efficiency for single-stranded analysis. Deconvoluted mass spectra revealed accurate monoisotopic mass differences between wild-type and mutant oligonucleotides, including ∼ + 16 Da for the sense strand (A>G), ∼ -15 Da for the antisense strand (T > C), and ∼ + 1 Da for the duplex, enabling confident mutation discrimination at the intact molecular level. High-resolution MS achieved excellent mass accuracy within ±3 ppm, and high-energy collision dissociation (HCD) MS/MS enabled sequence-specific fragmentation that localized the mutation site with high confidence when compared with theoretical fragments. Overall, this study establishes a reliable analytical framework for mutation detection in oligonucleotide models and highlights the potential of UHPLC-HRMS/MS as a complementary tool for targeted mtDNA fragment analysis.
    Keywords:  Clinical applications; High resolution-mass spectrometry; Ion-pairing agents; Mitochondrial DNA; Oligonucleotides; Point mutation
    DOI:  https://doi.org/10.1016/j.jpba.2026.117384
  77. J Neurochem. 2026 Feb;170(2): e70365
    Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
    Yubo Wang, Stuart A Lipton.
      Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.
    Keywords:  GWAS; S‐nitrosylation; neurodegenerative disease
    DOI:  https://doi.org/10.1111/jnc.70365
  78. Neural Regen Res. 2026 Jan 27.
    Brain organoids as models of extracellular vesicle-mediated human neural communication.
    Giuliana La Rosa, Erika Pascale, Maria Roberta Iazzetta, Edoardo Sozzi, Annalisa Fico, Elvira Immacolata Parrotta, Alessandro Fiorenzano.
       ABSTRACT: Cellular communication orchestrates human brain development through complex interactions involving adhesion molecules, signaling ligands, extracellular matrix, and extracellular vesicles. While intrinsic genetic programs governing neural differentiation are well characterized, the roles of extrinsic, non-cell-autonomous signaling, particularly extracellularmediated communication, remain poorly understood. Here, we review recent advances in three-dimensional brain organoids derived from human pluripotent stem cells as physiologically relevant models that recapitulate key aspects of human neurodevelopment, enabling detailed study of extracellular vesicle-mediated intracellular signaling. We highlight how organoid systems facilitate the investigation of extracellular vesicle cargo dynamics and their influence on neural cell fate, migration, and circuit assembly, as well as their involvement in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. These insights show the potential of brain organoids to unravel complex cellular interactions and inform biomarkers discovery and therapeutic strategies for neurological diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyloid-β; brain organoid; cell-cell communication; extracellular vesicle; neurodegeneration; neurodevelopment; pluripotent stem cell; α-synuclein
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01806
  79. Biochem Biophys Res Commun. 2026 Jan 28. pii: S0006-291X(26)00120-8. [Epub ahead of print]804 153356
    Mitochondrial dysfunction in MASH: Focusing on chronic inflammation and intercellular communication.
    Wanyi Luo, Muxin Yu, Chuwei Zheng, Xiaowen Li, Xiaotian Ma, Guocheng Zeng, Jinming Zhang, Xia Ji, Liyan Sun.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition closely linked to metabolic dysregulation. In its progressive stage, metabolic dysfunction-associated steatohepatitis (MASH), hepatocytes face pathological insults including lipotoxicity and inflammatory cell infiltration. Sustained exposure to these stressors severely disrupts hepatocyte mitochondrial homeostasis, culminating in mitochondrial dysfunction. Crucially, mitochondrial dysfunction is intimately associated with chronic inflammation. After injury, mitochondria produce large amounts of mitochondrial reactive oxygen species (mtROS) or release mitochondrial damage-associated molecules that act as signaling molecules to recruit and activate inflammatory cells, such as neutrophils. Activated neutrophils release neutrophil extracellular traps (NETs), which exacerbate liver inflammation, driving MASH progression towards liver cancer. Despite advances in the understanding of MASLD pathophysiology, challenges remain in identifying relation between mitochondrial dysfunction and intrahepatic inflammation. Intercellular communication, primarily mediated by extracellular vesicles (EVs), plays a pivotal role in this pathology. EVs transport diverse bioactive cargo from donor to recipient cells, modulating various pathophysiological processes. This review synthesizes current literature on mitochondrial dysfunction and chronic inflammation in MASH/MASLD, examines the critical role of intrahepatic intercellular communication, particularly via EVs, and highlights targeting mitochondria as a promising therapeutic strategy for MASH.
    Keywords:  EVs; Intercellular communication; MASH; Mitochondrial dysfunction; NETs; Neutrophil
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153356
  80. Cell Mol Life Sci. 2026 Jan 30. 83(1): 91
    A recently evolved domain of the human ING1 epigenetic regulator targets mitochondria and induces senescence.
    Jessica Bertschmann, Grace Liu, Mahbod Djamshidi, Katy Heshmatazad, Yury Romanov, Jasleen Dhaliwahl, Hamed Hojjat, Yang Yang, A P Jason de Koning, Karl Riabowol, Alexander Hill.
      
    Keywords:  Epigenetic; Evolution; ING1a; Mitochondria; Senescence
    DOI:  https://doi.org/10.1007/s00018-025-06076-y
  81. Nat Commun. 2026 Feb 03. 17(1): 1354
    An in vivo and in vitro spatiotemporal profile of human midbrain development.
    Dimitri Budinger, Pau Puigdevall, George T Hall, Charlotte Roth, Theodoros Xenakis, Elena Marrosu, Julie Jerber, Alessandro Di Domenico, Francesca Picco, Helena Kilpinen, Sergi Castellano, Manju A Kurian, Serena Barral.
      The dopaminergic system has key roles in human physiology and is implicated in a broad range of neurological and neuropsychiatric conditions that are increasingly investigated using induced pluripotent stem cell-derived midbrain models. To determine similarities of such models to human systems, here we undertake single-cell and spatial profiling of first and second trimester fetal midbrain and compare it to in vitro midbrain models. Histological examination reveals that, by the second trimester, fetal midbrain tissue exhibits structural complexity comparable to that of adults. At the molecular level, single-cell profiling uncovers differences in cellular composition across models, with brain organoids most closely resembling late first trimester tissue - an observation supported by meta-integration of existing midbrain datasets. By reconstructing developmental trajectories of neuronal and astrocytic lineages, we map gene expression dynamics associated with maturation. Importantly, integration of spatial transcriptomics provides critical context for aligning organoid models, revealing that their spatial organization and intercellular signaling resemble the architecture and microenvironment of the second trimester midbrain. Ultimately, we leverage our findings to study Dopamine Transporter Deficiency Syndrome progression in patient-derived midbrain organoids, validating their relevance. Understanding the extent of human tissue recapitulation in midbrain laboratory models is essential to justify their use as biological proxies.
    DOI:  https://doi.org/10.1038/s41467-025-67779-1
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