bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–03–01
eighty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Cooperative Architecture of Mitochondrial Proteome Homeostasis.
  2. 4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity.
  3. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
  4. Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
  5. Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
  6. The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.
  7. Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.
  8. Novel Biallelic LIG3 Mutations Causing Lethal Phenotype With Immunodeficiency.
  9. Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
  10. Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.
  11. Mainstreaming genomic testing for mitochondrial disease in Australia.
  12. Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
  13. PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
  14. Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.
  15. Regulation of mitophagy by Fis1 and Fascin1-organized actin.
  16. The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
  17. Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.
  18. Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.
  19. Muscle biopsy and mitochondrial disease criteria as diagnostic tools for paediatric patients presenting with neuromuscular phenotypes: highlighting the role of secondary mitochondrial dysfunction.
  20. Energizing the Injured Heart With Allogenic Mitochondrial Organelle Complex.
  21. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  22. Aspartate availability drives differential engagement of the malate-aspartate shuttle.
  23. Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease.
  24. Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.
  25. The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.
  26. Hypertrophic cardiomyopathy as a novel phenotypic feature of NSUN3-related mitochondrial disease: a case report with review of the literature.
  27. Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.
  28. A case report of combined oxidative phosphorylation deficiency 35 (COXPD35) in Palestine caused by novel compound heterozygous TRIT1 variants.
  29. Decoding the dark genome reveals its organisation into modular disease networks.
  30. Aging-associated mitochondrial circular RNAs.
  31. OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.
  32. Receptor-Mitochondria Crosstalk in the Kynurenine Metabolic Pathway: Integrating Metabolomics and Clinical Mass Spectrometry.
  33. Protein-induced membrane strain drives supercomplex formation.
  34. Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
  35. mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
  36. Phosphatidylserine Decarboxylase Regulates Retinal Ganglion Cell Neurite Outgrowth with Altered Somal Membrane Fluidics and Mitochondrial Morphology.
  37. Comparative Analysis of Methodological Aspects of the Study of Extracellular Vesicles and Extracellular Mitochondria: From Isolation to Internalization.
  38. Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
  39. Specific SLC25 carriers regulate mitochondrial protein synthesis.
  40. Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.
  41. Reversible phosphorylation influences energetic cellular metabolism by modulating mitochondrial gene expression.
  42. Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
  43. Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
  44. Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.
  45. Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
  46. Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.
  47. Excessive Ca 2+ -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury.
  48. Mitochondrial genome editing tools: prospects in animal breeding.
  49. Rescue of mitochondrial power outages with γPNA-based miR-122 inhibitor.
  50. Characterization of Conformational Dynamics and Structural Plasticity of the Catalytic Domain of Human Mitochondrial YME1L Protease.
  51. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  52. Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.
  53. Regional nonsense constraint offers biological and clinical insights into genetic disease.
  54. Nutrient State, Aging, and Diet Modulate SAM50-Dependent Mitochondrial Remodeling and Systemic Metabolic Signatures.
  55. Endoplasmic Reticulum-Mitochondria Calcium Drives Salivary Bioenergetics.
  56. Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
  57. Hot Mitochondria and the Second Law of Thermodynamics.
  58. Molecular analysis of mitochondrial complex I in the levodopa short duration response in Parkinson's disease.
  59. Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury.
  60. Mitochondrial Resilience in Glaucoma: Targeting NAD+ Metabolism and Oxidative Stress in Retinal Ganglion Cell Degeneration with Nicotinamide Riboside and Berberine: Preliminary Clinical Evidence.
  61. Mesenchymal Stromal Cells and Extracellular Vesicles: A Novel Therapeutic Paradigm for Mitochondrial Dysfunctions.
  62. An extracellular vesicle-mediated mitochondrial transfer network critical for testosterone synthesis.
  63. Cell-Penetrating Botulinum Neurotoxin Type A Proteins Alleviate Skeletal Muscle Hypertrophy with Associated Alterations of Mitochondrial Homeostasis.
  64. Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
  65. Discoidin Domain Receptor 1 Translocation to the Mitochondria Promotes Oxidative Stress and Apoptosis in Acute Kidney Injury.
  66. Targeted Reduction of Excessive Mitochondrial Superoxide by Mitoquinone Rescues Cognitive Impairment Without Affecting Spontaneous Recurrent Seizures in a Mouse Model of Temporal Lobe Epilepsy.
  67. Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
  68. Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease.
  69. MEDAG functions as an A-kinase-anchoring protein in adipocytes.
  70. Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.
  71. Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation.
  72. Risk of sudden cardiac death due to inorganic pyrophosphate A2 deficiency in a Pakistani infant: Diagnostic and management challenges in low-resource settings.
  73. Large-scale proteomics across neurological disorders uncovers biomarker panel and targets in multiple sclerosis.
  74. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase.
  75. Progressive encephalopathy associated with novel compound heterozygous NAXE mutations in a Chinese patient: case report and literature review.
  76. Strategic targeting of mitochondria in ischemic heart disease: mechanisms and emerging therapies.
  77. First-of-a-kind stem-cell therapies set for approval in Japan.
  78. Mitochondrial insertions/deletions (INDELs) burden in Parkinson's disease: an analysis from a Brazilian cohort.
  79. Epigenetic Clocks, Resilience, and Multi-Omics Ageing: A Review and the EpiAge-R Conceptual Framework.
  80. Broad lessons from negative trials in rare diseases.
  81. Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.
  82. TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.
  1. medRxiv. 2026 Feb 09. pii: 2026.02.06.26345691. [Epub ahead of print]
    Cooperative Architecture of Mitochondrial Proteome Homeostasis.
    Patrick Forny, Merima Forny, Andrew J Smith, Andrew Y Sung, Kaixian Liu, David J Pagliarini.
      Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal diverse protein activities undergirding this regulation, including MDH2's regulation of MT-ND3 transcription via FASTKD1 binding and CLPP's processing of the mitoribosomal assembly factor MALSU1, which we establish as a disease gene. Through entropy analysis, we reveal unexpectedly heterogeneous protein-level variability across complexes and use complexome profiling to identify new complex-specific membership, including C15orf61's association with complex V. We further observe substantial mtDNA copy number variation, notably upon disruption of the disease-related cobalamin biosynthesis protein MMADHC. Together, we establish new protein functions and provide a multilayered view into mitochondrial proteome regulation.
    Highlights: Multiomic signatures across perturbations reveal extensive post-transcriptional regulationThe TCA cycle enzyme MDH2 binds FASTKD1 to modulate MT-ND3 transcript levelsMALSU1 is a CLPP protease substrate whose deficiency causes a mitochondrial diseaseC15orf61 binds ATP synthase and negatively regulates its higher order assemblyMMADHC inversely affects mtDNA levels potentially mediated through LONP1.
    DOI:  https://doi.org/10.64898/2026.02.06.26345691
  2. bioRxiv. 2026 Feb 12. pii: 2026.02.10.705117. [Epub ahead of print]
    4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity.
    Owen S Skinner, Maria Miranda, Fangcong Dong, Tessa Struhl, Melissa A Walker, Grigorij Schleifer, Matthew T Henke, Jon Clardy, Michio Hirano, Darryl C De Vivo, Eric A Schon, Kristin Engelstad, Stephanie E Siegmund, Catherine Laprise, Christine Des Rosiers, Vamsi K Mootha, Rohit Sharma.
      Management of patients with mitochondrial respiratory chain diseases is challenging, in part because of our incomplete understanding of pathogenesis and a lack of biomarkers. Unknown metabolites account for >90% of detected features in modern metabolomics experiments and hold immense untapped promise for new basic and biomedical research. We recently used mass spectrometry-based metabolomics to identify and validate 19 circulating blood-based biomarkers for patients with the mitochondrial DNA (mtDNA) m.3243A>G pathogenic variant, which is the most frequent cause of the mitochondrial disorder MELAS ( m itochondrial e ncephalomyopathy, lactic a cidosis, and s troke-like episodes). However, the most significantly changing biomarker corresponded to an "unknown" metabolite. Here, we combine cheminformatics with analytical chemistry and identify that feature as 4,5-dihydroxyhexanoic acid (4,5-DHHA), a metabolite previously associated with inherited defects of gamma-aminobutyric acid (GABA) catabolism, but with no prior links to mitochondrial respiratory chain disorders. We validate this finding in an independent MELAS cohort and further show that 4,5-DHHA levels correlate with disease severity and are elevated in patients with other forms of mitochondrial disease and sepsis. Furthermore, brain 4,5-DHHA levels were elevated in two genetic mouse models of mitochondrial disease. In vitro and tissue culture experiments indicate that 4,5-DHHA is generated when the GABA catabolite succinic semialdehyde reacts with an intermediate of the pyruvate dehydrogenase reaction and is sensitive to mitochondrial complex I function. Our work identifies 4,5-DHHA as a robust plasma and urine marker of mitochondrial dysfunction in humans and reveals new connections between the respiratory chain and GABA metabolism.
    Significance Statement: Inborn errors of the mitochondrial respiratory chain cause severe, progressive diseases, yet effective treatments and biomarkers remain limited. Modern metabolomics detects thousands of molecules in biofluids, but the vast majority are unidentified. In this study, we investigate the most significantly altered blood metabolite in patients with the most common mitochondrial disease - MELAS ( m itochondrial e ncephalomyopathy, lactic a cidosis, and s troke-like episodes) - and identify it as an 4,5-dihydroxyhexanoic acid (4,5-DHHA). We show that 4,5-DHHA is reproducibly elevated and correlates with severity. Levels are increased across multiple mitochondrial disorders as well as in sepsis and rise when respiratory chain function is impaired. These findings establish 4,5-DHHA as a promising biomarker of mitochondrial dysfunction and reveal a link to dysregulated GABA metabolism.
    DOI:  https://doi.org/10.64898/2026.02.10.705117
  3. Nat Struct Mol Biol. 2026 Feb 27.
    Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
    Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.
      Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.
    DOI:  https://doi.org/10.1038/s41594-026-01756-0
  4. Biomolecules. 2026 Feb 14. pii: 302. [Epub ahead of print]16(2):
    Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
    Fanny Fontaine, Romain Pénicaud, Stéphane Allouche.
      Coenzyme Q10 (CoQ10) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ10 participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ10 deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ10 biosynthesis. These defects lead to reduced CoQ10 levels and impaired mitochondrial functions. Clinically, primary CoQ10 deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ10, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ10 biology, biosynthesis, and the clinical spectrum of primary CoQ10 deficiencies, and we discuss emerging mechanisms linking CoQ10 depletion to mitochondrial dysfunctions and human diseases.
    Keywords:  coenzyme Q10; metabolism; mitochondrial disorders; mitophagy; oxidative phosphorylation; oxidative stress; primary coenzyme Q10 deficiency
    DOI:  https://doi.org/10.3390/biom16020302
  5. Res Sq. 2026 Feb 17. pii: rs.3.rs-8815446. [Epub ahead of print]
    Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
    Keri-Lyn Kozul, Ali AlAsmari, Essa Alharby, Reem Zakzouk, Youmian Yan, Aziza Mushiba, Anwar Alhamad, Emily Harrelson, Maya Ayach, Kevin Cho, Heba Zahid, Francisca De Luna Vitorino, Richard Searfoss, Xingyu Liu, Mohammed A Saleh, Muhammad Latif, Lianjie Wei, Ali Aldawood, Laila Alsuhaibani, Mohammed Abdulhafith Bafail, Thiago Menezes, Manar Samman, Hannah Pletcher, Ibrahim Sandokji, Walaa Borhan, Tessa Lochetto, Abrar Alamri, Wedad Mudayfin, Mazin Syed, Leah Shriver, Benjamin Garcia, Eissa Faqeih, Gary Patti, Natalie Niemi, Naif Almontashiri.
      The mitochondrial phosphatase PPTC7 has emerged as a potent regulator of metabolism and mitophagy as its global knockout leads to perinatal lethality in mice. However, no known Mendelian diseases have been linked to PPTC7 deficiency, rendering its role in human pathophysiology unclear. Here, we identify two independent homozygous variants in PPTC7 : a missense variant, p.D158N, and a duplication variant (c.*57dup) within the 3` untranslated region (UTR). These variants were detected in three patients from two unrelated families presenting with a primary mitochondrial disease characterized by hypomyelinating leukodystrophy, recurrent metabolic and lactic acidosis, and anemia with immune dysregulation. Patient samples, including plasma and primary fibroblasts, showed robust metabolic and mitochondrial dysfunction, with substantial phenotypic overlap with Pptc7 knockout murine fibroblast models. PPTC7 patient fibroblasts carrying the p.D158N variant and CRISPR-knocked in cells to model the 3`UTR variant showed hallmarks of excessive BNIP3- and NIX-mediated mitophagy, including aberrant mitochondrial morphology, diminished mitochondrial protein expression, and increased mt-Keima flux. Critically, increased mitophagy in these cellular models was rescued by exogenous PPTC7 expression, confirming dysfunction derives from loss of this mitochondrial phosphatase. Mechanistically, we found that the p.D158N variant, affecting a highly conserved residue, disrupts metal binding to compromise both the enzymatic phosphatase function of PPTC7 as well as its negative regulation of BNIP3 and NIX. Collectively, these data provide the first known cases with a recessive inborn error of mitophagy due to PPTC7 deficiency and underscore the importance of this mitochondrial phosphatase in maintaining metabolic health and balanced mitophagy.
    DOI:  https://doi.org/10.21203/rs.3.rs-8815446/v1
  6. Protein Sci. 2026 Mar;35(3): e70506
    The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.
    J Tabitha Hees, Angelika B Harbauer.
      Neurons depend on tightly regulated spatial proteostasis to maintain function across their extended morphology. The endoplasmic reticulum (ER), traditionally known for its function in protein synthesis, folding, and trafficking, has long been recognized as a central platform for directing proteins to organelles of the secretory and endocytic pathways. In contrast, its involvement in the targeting of mitochondrial proteins, which are not directly connected to classical trafficking routes, remains less well understood and has only recently gained attention. Growing evidence implicates the ER in post-translational delivery of mitochondrial precursors through mechanisms that integrate local translation, chaperone activity, and dynamic organelle contact sites. ER-mitochondria contacts form dynamic platforms for precursor translation, stabilization and transfer, as exemplified by pathways such as ER-SURF. Endolysosomes add an additional layer of regulation by influencing both ER function and mitochondrial proteostasis. However, how these processes are mechanistically coordinated, particularly in neurons with their complex architecture, remains incompletely understood. In this review, we synthesize the current understanding on ER-mediated mitochondrial protein targeting, highlight the role of membrane contact sites between ER, mitochondria and endolysosomes, and discuss how chaperone networks and signaling pathways shape mitochondrial precursor handling. We further explore how disruption of these systems might contribute to neurodegeneration, positioning organelle crosstalk as a critical determinant of mitochondrial proteostasis and neuronal health.
    Keywords:  ER‐SURF; endoplasmic reticulum; mitochondrial protein targeting; neurodegeneration; organelle crosstalk
    DOI:  https://doi.org/10.1002/pro.70506
  7. Biomolecules. 2026 Feb 10. pii: 280. [Epub ahead of print]16(2):
    Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.
    Lara Cantarero, Janet Hoenicka, Francesc Palau.
      The mitochondrial outer membrane (OMM) plays a crucial role in maintaining cellular homeostasis by regulating mitochondrial dynamics, organelle interactions, and stress responses. In peripheral neurons-cells with high metabolic demands and long axons-the OMM acts as a vital platform for coordinating bioenergetics, calcium signaling, and redox balance. Ganglioside-induced differentiation-associated protein 1 (GDAP1), an OMM-anchored protein, has emerged as a key regulator of mitochondrial fission and transport, redox homeostasis, and mitochondrial membrane contact sites (MCSs). Genetic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), emphasizing its essential role in peripheral nerve function. This review highlights the multifaceted functions of GDAP1 in neuronal physiology and as a model protein that integrates organelle communication and mitochondrial biology. We further discuss how GDAP1 dysfunction leads to structural and functional impairments in peripheral neurons, proposing the OMM and its microenvironment as critical targets for therapeutic intervention in inherited neuropathies.
    Keywords:  Charcot-Marie-Tooth disease; GDAP1; axon; axonopathy; glial cells; lysosomes; membrane contact sites; mitochondria; neuroinflammation; neuron; neuropathies; outer mitochondrial membrane; peroxisomes
    DOI:  https://doi.org/10.3390/biom16020280
  8. Am J Med Genet A. 2026 Feb 25.
    Novel Biallelic LIG3 Mutations Causing Lethal Phenotype With Immunodeficiency.
    Gonench Kilich, Tanaya Jadhav, Kelly Maurer, Christopher Breen, Tejas Jammihal, Erica Schindewolf, Rebecca D Ganetzky, Adeline Vanderver, Cara Skraban, Ramakrishnan Rajagopalan, Kathleen E Sullivan.
      Pathogenic, biallelic variants in LIG3 are known to cause Mitochondrial DNA Depletion syndrome 20 with variable expression and severity. We describe a child with progressive encephalopathy, cataracts, movement disorder, endocrine dysfunction, and immunodeficiency who remained undiagnosed despite multiple negative clinical genomic diagnostic studies. Research reanalysis of PacBio long-read genome sequencing data identified compound heterozygous LIG3 variants, including a splice variant and a novel 98 bp insertion. Western blot confirmed loss of LIG3 protein expression and RNA-seq demonstrated aberrant transcripts. Muscle biopsy revealed mitochondrial dysfunction, with COX-deficient fibers and complex IV deficiency. Notably, this is the first reported association of LIG3 deficiency with immunologic and endocrine abnormalities, emphasizing the importance of a broad approach to phenotype-genotype.
    Keywords:  LIG3 gene; genome reanalysis; immunodeficiency; mitochondrial disease
    DOI:  https://doi.org/10.1002/ajmg.a.70104
  9. Ageing Res Rev. 2026 Feb 21. pii: S1568-1637(26)00054-1. [Epub ahead of print]117 103062
    Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
    Zongwei Fang, Catarina Barbosa, Daniela Marinho, Rita Peixoto, Ildete Luísa Ferreira, João Laranjinha, A Cristina Rego.
      Mitochondrial DNA (mtDNA) has been recognized as a key link between mitochondrial dysfunction and neuroinflammation in neurodegenerative diseases. Beyond being a vulnerable target of oxidative damage, mtDNA can act as a damage-associated molecular pattern when released from mitochondria, triggering innate immune signaling pathways in the nervous system. This review synthesizes current evidence on the mechanisms regulating mtDNA escape from mitochondria into the cytosol and its subsequent intracellular and extracellular effects, reframing mtDNA as an active driver of inflammatory processes rather than a passive by-product of mitochondrial injury. We discuss how defects in mitochondrial quality control, particularly impaired mitophagy and macroautophagy, promote the accumulation of damaged mtDNA, including its release via mitochondria-derived vesicles, exosomes or as cell-free mtDNA. By integrating mitochondrial dysfunction, immune activation, and clearance pathways, this review highlights the mitochondria-immune axis as a central contributor to neurodegeneration and cognitive decline, identifying upstream molecular targets with potential for therapeutic intervention.
    Keywords:  Damage-associated molecular patterns (DAMPs); Inflammation; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Neurodegenerative diseases; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.arr.2026.103062
  10. Biology (Basel). 2026 Feb 14. pii: 334. [Epub ahead of print]15(4):
    Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.
    Lishuang Shen.
      Leigh Syndrome Spectrum (LSS) is a rare and heterogeneous disease continuum with most published cohorts in small sizes that limit the statistical power. Large-scale meta-analyses with published case-level clinical data extracted from the literature are essential for robust population analysis but are hindered by the burden of manually standardizing the unstructured, heterogeneous, and sparse case-level data from the literature. We developed a novel workflow which is among the first to combine Generative AI (GenAI) with human-in-the-loop curation to overcome this barrier. This pipeline utilized Google's Gemini-2.5-pro and rapidly processed over 2300 cases from published case data tables in two weeks and achieved >90% accuracy in mapping raw clinical data to Human Phenotype Ontology (HPO) terms. This process rapidly yielded a harmonized LSS virtual cohort of 1679 data-rich cases, which is the largest LSS virtual cohort reported so far, and thus enables characterization of LSS phenotypic and genetic architectures, revealing that autosomal recessive (932 cases) and mitochondrial (752 cases) inheritance are the most common. The most frequently mutated genes were SURF1 (240 cases), MT-ATP6 (199), and MT-ND3 (183). HPO term consolidation identified common hallmark phenotypes, including lactic acidosis, hypotonia, bilateral basal ganglia lesions, and mitochondrial respiratory chain deficiency. The cohort's scale enabled large-scale survival analysis, revealing that defects in mitochondrial translation are associated with the poorest prognosis (84% mortality in this group) and early onset (0.23 years). Among the deceased group, patients with Complex V mutations were linked to a significantly shorter mean survival time (1.77 years) than those with Complex I (3.70 years) or IV (3.57 years) mutations. This GenAI-driven methodology establishes a scalable framework for rapidly creating analysis-ready virtual cohorts from heterogeneous literature and accelerating population-level study for rare diseases including Leigh Syndrome and other mitochondrial diseases.
    Keywords:  Leigh Syndrome Spectrum (LSS); Leigh disease; generative AI (GenAI); human phenotype ontology (HPO); large language model; rare disease
    DOI:  https://doi.org/10.3390/biology15040334
  11. Eur J Hum Genet. 2026 Feb 26.
    Mainstreaming genomic testing for mitochondrial disease in Australia.
    Megan Ball, Naomi Baker, Sze Chern Lim, Sarah Casauria, Sebastian Lunke, Alison G Compton, David R Thorburn, John Christodoulou, Zornitza Stark.
      Genomic sequencing has transformed the diagnostic approach for mitochondrial disease, yet integration into standard clinical practice is limited by access and funding. We conducted a post-implementation evaluation of genome sequencing (GS) for mitochondrial disease in Australia, which became publicly funded through the Medicare Benefits Scheme (MBS) in November 2023, to allow for broader access to testing. Test request data, including demographics, phenotypic information, and the diagnostic outcomes, were collected from November 2023 to May 2025 from the Victorian Clinical Genetics Services, the current laboratory provider of the MBS-funded service. Test uptake was 26% of predicted, with lower test rates in regional and remote areas. Over the first 19 months, 300 individuals suspected of mitochondrial disease underwent GS with a median turnaround time of 84 days (8 days-218 days). The diagnostic yield was 20%, with 56% of diagnoses in known mitochondrial disease genes. Of these, 70% (24 of 34) were in mitochondrial DNA. Seventeen diagnoses were in individuals who had prior non-diagnostic testing (exome sequencing or gene panel). We demonstrate that publicly-funded GS can deliver meaningful diagnostic outcomes for mitochondrial disease on a national scale. To maximise its impact, attention must now shift towards ensuring equitable access, particularly for regional and remote areas, and embedding sustainable mainstreaming models that support both genetic and non-genetic clinicians.
    DOI:  https://doi.org/10.1038/s41431-026-02053-6
  12. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2535298123
    Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
    William C Valinsky, Robert P Ray, Kathy S Schaefer, Jonathan B Grimm, Carla Nicolini, Luke D Lavis, David E Clapham.
      The mitochondrial permeability transition (mPT) is an evolutionarily conserved destructive process that permeabilizes the inner mitochondrial membrane in response to calcium overload. The molecular mechanism underlying the mPT is not established. To unambiguously identify essential proteins, we designed two phenotypic assays for mitochondrial calcium overload and applied them to FACS-based CRISPR screening in human cells, ultimately evaluating 19,113 genes. The first screen studied mitochondrial membrane potential (MMP) collapse in response to calcium overload. Top-ranked genes were the essential proteins of the mitochondrial calcium uniporter complex, MCU and EMRE, reflecting that the calcium-induced MMP collapse results from mitochondrial calcium entry and not the mPT. The second screen measured the permeability of the inner mitochondrial membrane. Here, the fluorescent interaction of a membrane impermeant ~600 Da dye and a mitochondrial-targeted HaloTag protein was studied under mPT activating conditions; calcium overload and the thiol-reactive molecule phenylarsine oxide. With secondary validation, we identified four protein-encoding genes that delayed or prevented the mPT under knockout: NF2, REST, BPTF, and NRLX1. Knockout of the nonmitochondrial proteins BPTF, NF2, or REST increased mitochondrial calcium retention capacity (CRC). However, calcium release or sensitivity to cyclosporin A (CsA) persisted, indicative of mPT sensitizers. Only knockout of the mitochondrial matrix protein, NLRX1, increased CRC, abolished calcium release, and was CsA-insensitive. This top-ranked hit of the mitochondrial permeability screen meets the definition of an essential mPT activator. Integral membrane proteins, including all previously proposed mPT candidates, were not essential activators.
    Keywords:  MCU; NLRX1; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1073/pnas.2535298123
  13. Nat Commun. 2026 Feb 23.
    PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
    Sangheeta Bhattacharjee, Sayan Das, Banhi Chowdhury, Benu Brata Das.
      Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5-/-) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5-/- cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.
    DOI:  https://doi.org/10.1038/s41467-026-69676-7
  14. Exp Cell Res. 2026 Feb 25. pii: S0014-4827(26)00068-6. [Epub ahead of print] 114951
    Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.
    Jiaqi Xie, Phyo W Win, Charles Newcomb, Shaopeng Zeng, Christina A Castellani, Dan E Arking.
      Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathways affected by mtDNA-CN variation, we perturbed HEK 293T cells with ethidium bromide to deplete mtDNA. Using RNASeq and methylation microarrays, we evaluated transcriptomic and methylomic changes in treated cell lines. We observed an 8-fold decrease in mtDNA-CN and compensatory shifts in mitochondrial transcription to support mtDNA replication. Nuclear transcriptomic and methylomic analysis highlighted changes in metabolic pathways, including oxidative phosphorylation and canonical glycolysis. Longitudinal analyses revealed that the identified genes and pathways have different response timing, with nuclear response lagging behind mitochondrial response. These findings further elucidate the mechanisms behind mtDNA maintenance and responses to cellular energetics as well as mitochondrial-nuclear crosstalk dynamics.
    Keywords:  Transcriptome; glycolysis; methylome; mito-nuclear crosstalk; mtDNA replication; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114951
  15. Curr Biol. 2026 Feb 24. pii: S0960-9822(26)00134-X. [Epub ahead of print]
    Regulation of mitophagy by Fis1 and Fascin1-organized actin.
    Shintaro Nakajima, Ting-Yu Wang, Tsui-Fen Chou, Yogaditya Chakrabarty, David C Chan.
      Mitophagy, the autophagic degradation of mitochondria, plays a central role in controlling the quality and quantity of mitochondria, thereby ensuring cellular health. The mitochondrial outer membrane protein Fis1 is important for several types of mitophagy, but its mechanism of action remains unclear. F-actin is recruited to autophagic cargo and is important for autophagic progression, but the mechanism for its recruitment is poorly understood. To address the molecular function of Fis1, we performed affinity purification of Fis1 and mass spectrometry and identified the actin-bundling protein Fascin1 as a physical interactor. We demonstrate that Fis1 is required for recruitment of Fascin1 as well as F-actin to mitochondria under stress conditions, including mitochondrial depolarization and iron chelation. Iron chelation also triggers mitophagy that is independent of the Parkinson's associated gene Parkin, and we show that Fis1 enables recruitment of Fascin1-organized F-actin to facilitate proper morphogenesis of autophagosomes and the ensuing mitochondrial degradation. In contrast, although Parkin-mediated mitophagy also relies on Fis1, it is unaffected by loss of Fascin1 or F-actin recruitment. These findings indicate that Fis1 has distinct modes of action in mitophagy, depending on the triggering cellular stress. They establish Fis1 as a key driver of Fascin1 and F-actin recruitment to mitochondria, events that are critical for autophagosome morphogenesis during iron-chelation-induced mitophagy.
    Keywords:  Fascin1; Fis1; actin; autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.cub.2026.01.062
  16. Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]
    The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
    Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.
      Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.
    Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
  17. bioRxiv. 2026 Feb 18. pii: 2026.02.12.705660. [Epub ahead of print]
    Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.
    Teng Gao, Chen Weng, Isaac Johnson, Michael Poeschla, Jonas Gudera, Emily King, Christopher Rouya, Adriana Donovan, Lauren Bourke, Ying Shao, Eladio Marquez, Rahul Tyagi, Leonard I Zon, Jonathan S Weissman, Vijay G Sankaran.
      Somatic mutations in mitochondrial DNA (mtDNA) provide natural barcodes that enable engineering-free lineage tracing in human tissues, but the complex dynamics of mtDNA inheritance across cell divisions and incomplete sampling of mtDNA introduce uncertainty in reconstructed lineages. Here, we present MitoDrift, a probabilistic framework that integrates Wright-Fisher drift dynamics with sparse single-cell measurements to produce confidence-refined lineage trees enriched for accurate clonal relationships. Validation with gold-standard lentiviral barcoding and whole-genome sequencing demonstrates that MitoDrift outperforms existing tree reconstruction methods in precision while maintaining high clonal recovery, enabling robust analyses linking lineage to cell state. Applying MitoDrift to human hematopoiesis reveals an age-associated decline in clonal diversity with differential impact across cell types and identifies heritable regulatory programs in hematopoietic stem cells in vivo, linking AP-1/stress-associated programs to clonal expansions. In multiple myeloma, MitoDrift captures therapy-associated clonal remodeling undetectable by copy number analysis, revealing phenotypic transitions and linking gene regulatory programs to differential drug sensitivity. Collectively, MitoDrift enables high-precision lineage tracing at scale and establishes quantitative lineage-state analysis in primary human tissues, linking clonal history to transcriptional and epigenetic programs in tissue homeostasis, aging, and disease.
    DOI:  https://doi.org/10.64898/2026.02.12.705660
  18. Res Sq. 2026 Feb 19. pii: rs.3.rs-8380062. [Epub ahead of print]
    Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.
    Bledi Petriti, Shobana Subramanian, Pete Williams, Kai-Yin Chau, Pawel Licznerski, Gerassimos Lascaratos, Soledad Aguilar-Munoa, Deborah Kamal, Haesoo Bae, Kambiz Alavian, David Garway-Heath, Elizabeth Jonas.
      Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.
    DOI:  https://doi.org/10.21203/rs.3.rs-8380062/v1
  19. Neuromuscul Disord. 2026 Feb 06. pii: S0960-8966(26)00038-6. [Epub ahead of print]61 106370
    Muscle biopsy and mitochondrial disease criteria as diagnostic tools for paediatric patients presenting with neuromuscular phenotypes: highlighting the role of secondary mitochondrial dysfunction.
    Milla-Riikka Hautakangas, Tommi Niskanen, Päivi Vieira, Heli Helander, Anne M Portaankorva, Heikki Rantala, Reetta Hinttala, Johanna Uusimaa.
      This study evaluated the diagnostic utility of muscle biopsy and the performance of the Nijmegen and modified Walker criteria in a real-life paediatric cohort with neuromuscular symptoms. A retrospective review at Oulu University Hospital included 220 paediatric patients with unexplained neuromuscular symptoms who underwent muscle biopsy between 1990 and 2024. Clinical data were collected, and patients were classified using both criteria. A genetic diagnosis was confirmed in 58 patients (26 %): 12 with primary mitochondrial diseases (21 %), 17 with secondary mitochondrial dysfunction (29 %), and 29 with other neuromuscular disorders (50 %). OXPHOS activities were measured in 189 patients (86 %); 49 (26 %) showed decreased activity, including 13 with genetic confirmation. Electron microscopy (n=175) showed mitochondrial abnormalities in 49 patients (28 %); 75 % of these had mitochondrial disease. The modified Walker criteria outperformed the Nijmegen (sensitivity 75 % vs 50 %; specificity 100 % vs 98 %). Mean Nijmegen scores were significantly higher in primary mitochondrial disease (p<0.05), also compared with patients with secondary dysfunction. In conclusion, muscle biopsy and mitochondrial disease criteria remain valuable tools distinguishing primary mitochondrial diseases. This study highlights the role of secondary mitochondrial dysfunction in non-mitochondrial genetic conditions and metabolic diseases with undefined genetic aetiologies waiting to be identified in the future.
    Keywords:  Encephalomyopathy; Mitochondrial disease criteria; Muscle biopsy; Neuromuscular symptoms; Secondary mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.nmd.2026.106370
  20. JACC Asia. 2025 Dec 03. pii: S2772-3747(25)00656-8. [Epub ahead of print]
    Energizing the Injured Heart With Allogenic Mitochondrial Organelle Complex.
    Chrishan J Ramachandra.
      
    Keywords:  animal model; anti-apoptosis; cardioprotection; ischemic reperfusion injury; mitochondria
    DOI:  https://doi.org/10.1016/j.jacasi.2025.11.004
  21. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706884. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Minghua Fan, Yingzhi Ye, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2 , a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-β burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.
    DOI:  https://doi.org/10.64898/2026.02.19.706884
  22. Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]
    Aspartate availability drives differential engagement of the malate-aspartate shuttle.
    Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.
      The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.
    Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
  23. Res Sq. 2026 Feb 16. pii: rs.3.rs-8615050. [Epub ahead of print]
    Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease.
    Daniele Mattei, Erica Brophy, Mikaela Rosen, Oriol Narcis Majos, Aloysius Domingo, Elena Meijia, Claudia De Sanctis, Beomjin Jang, Tarek Khashan, Mengxi Yang, Deborah Raymond, Casey Young, Jack Humphrey, Elisa Navarro, Amanda Allan, Katherine Leaver, Viktoriya Katsnelson, Alexander Chung, Benjamin Muller, Matthew Swan, Vicki L Shanker, Mariel Pullman, Adina Wise Adina Wise, Roberto Ortega, Kelly Astudillo, Steven Frucht, Susan Bressman, Giulietta Riboldi, Laurie J Ozelius, Rachel Saunders-Pullman, Towfique Raj.
      Monocytes are increasingly implicated in Parkinson's disease (PD) pathogenesis, with idiopathic cases showing mitochondrial and lysosomal dysfunction. However, the impact of PD-associated mutations on monocytes remains unclear. To address this, we investigated transcriptomic and functional disturbances in peripheral monocytes from patients with GBA1 - and LRRK2 -associated PD and idiopathic PD. Transcriptomic data revealed shared and mutation-specific signatures, including those related to immune dysregulation, and consistent defects in lysosomal, proteasomal and mitochondrial pathways. Network and pathway analyses further uncovered downregulation in protein translation and enrichment of integrated stress response (ISR) signatures, alongside aberrant expression of genes linked to ER stress, mitophagy and type-I interferon signaling. Protein levels of heat-shock proteins and ISR effectors were elevated at baseline and following α-synuclein exposure, consistent with impaired proteostasis. Live-cell assays demonstrated defects in lysosomal function, mitochondrial dynamics, and phagocytosis, most pronounced in GBA1 - and LRRK2 -associated PD but evident across all PD groups. Together, these findings define a PD-associated myeloid state of immunodegeneration , marked by impaired clearance, proteostasis failure, and mitochondrial dysfunction across genetic and idiopathic PD.
    DOI:  https://doi.org/10.21203/rs.3.rs-8615050/v1
  24. bioRxiv. 2026 Feb 11. pii: 2026.02.10.704675. [Epub ahead of print]
    Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.
    Maria Clara Zanellati, Zachary Coman, Disha Bhowmik, Chih-Hsuan Hsu, Richa Basundra, Shannon N Rhoads, Ngudiankama R Mfulama, Brandie M Ehrmann, Mohanish Deshmukh, Sarah Cohen.
      Cell fate transitions require coordinated remodeling of intracellular organelles, but how the organelle interactome rewires during neurogenesis remains unclear. Here we combine multispectral imaging with quantitative organelle signature analysis to simultaneously map eight organelles at single-cell resolution as human induced pluripotent stem cells (iPSCs) differentiate into forebrain-like neurons. We find compartment and time-specific rescaling of organelles and a progressive increase in higher-order membrane contacts, with mitochondria emerging as an early interaction hub. Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting plasmalogen biosynthesis, membrane homeostasis and synapse formation. Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity, identifying the ER-peroxisome axis as a key regulator of neuronal maturation.
    DOI:  https://doi.org/10.64898/2026.02.10.704675
  25. Genes (Basel). 2026 Feb 04. pii: 192. [Epub ahead of print]17(2):
    The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.
    Keri J Fogle, Sarah K Lindley, Sidney L Satterfield, Beakal A Amsalu, Joseph R Figura, Samantha L Eicher, Luke A Scherz, Michael J Palladino.
      Background/Objectives: Primary metabolic diseases including mitochondrial encephalomyopathies (ME), glycolytic enzymopathies, and disorders of lipid and amino acid metabolism can manifest with severe neurological and neuromuscular symptoms. Conversely, it is increasingly appreciated that primary neurodegenerative diseases can have metabolic etiology and pathophysiology. Pharmacological treatments have limited benefit for these classes of diseases, but dietary therapy is increasingly recognized as a tool for bolstering metabolic processes that can ameliorate neurological symptoms. The ketogenic diet is the best-established example, having long been used as a therapy for epilepsy. Replenishing metabolic intermediates (anaplerosis) especially substrates of the citric acid cycle (CAC) is currently being explored, with ongoing clinical trials of simple metabolic intermediates such as oxaloacetate or NAD+ to treat neurodegenerative diseases. We have shown ketogenic and anaplerotic therapies to be effective in a Drosophila model of ME; however, the full therapeutic potential and role of the CAC in neuronal health is still not well understood. Methods: Here, we have used genetic, behavioral, and dietary approaches to elucidate critical links between the CAC and neurological function. Results: We have found that stimulating the CAC can improve and sustain neurological health in the face of severe metabolic disease, and that its functions include a previously unrecognized role in maintaining normal circadian rhythms, whose disruption is often an early indicator or complicating factor in neurological and neurodegenerative disease. We investigated the hypothesis that the production of GTP by the CAC may be an important mechanistic contributor to the role of the CAC in neurological health and disease, and may underlie its therapeutic potential. Conclusions: Overall, our findings expand our understanding of the role of the CAC in neurological health and disease, support its development as a therapeutic target, and provide a foundation for further studies investigating the intersection between neurological disease and metabolic function.
    Keywords:  Leigh Syndrome; anaplerosis; circadian rhythms; citric acid cycle; genetics; ketogenic diet; mitochondrial encephalomyopathy; nucleoside diphosphate kinase
    DOI:  https://doi.org/10.3390/genes17020192
  26. J Pediatr Endocrinol Metab. 2026 Feb 24.
    Hypertrophic cardiomyopathy as a novel phenotypic feature of NSUN3-related mitochondrial disease: a case report with review of the literature.
    Ayşe Şenol Ersak, Tuğçe Çağıran, Ayşen Koçyiğit, Kısmet Çıkı, Yılmaz Yıldız, Ebru Aypar, Serap Ketenci İşlek, Pelin Özlem Şimşek Kiper, Göknur Haliloğlu, Ali Dursun.
       OBJECTIVES: NSUN3 encodes a mitochondrial RNA methyltransferase responsible for cytosine methylation at the tRNA wobble base, which plays a role in the regulation of mitochondrial translation. Variants in NSUN3 lead to impaired oxidative phosphorylation resulting in multisystem involvement. Reported cases to date have described developmental delay, hypotonia, optic atrophy and neurological involvement. Cardiac manifestations, however, have not yet been clearly associated with NSUN3 deficiency. Here, we report hypertrophic cardiomyopathy (HCM) as a new clinical feature and the long-term follow-up of our case, further expanding the phenotype of NSUN3-related disease.
    CASE PRESENTATION: An 18-year-old girl was referred for visual loss, progressive fatigue, muscle weakness and HCM. Initial symptoms started as hypotonia in infancy and proceeded with developmental delay, reduced visual acuity and chest pain. At the age 15 years, she was diagnosed with HCM. Cardiac magnetic resonance imaging showed concentric left ventricular (LV) hypertrophy with septal thickness measuring up to 20 mm, LV ejection fraction was preserved (70 %). Whole exome sequencing identified a homozygous likely pathogenic variant in the NSUN3 gene: NM_022072.5: c.465dup (p.Gly156ArgfsTer6), for which both parents were found to be heterozygous carriers.
    CONCLUSIONS: To our knowledge, this is the first reported case of NSUN3-related mitochondrial disease with HCM. An increasing number of reported cases will likely contribute to a more comprehensive understanding of the clinical phenotype and genotype-phenotype correlations.
    Keywords:   NSUN3 ; cardiomyopathy; hypertrophic cardiomyopathy; mitochondrial disease
    DOI:  https://doi.org/10.1515/jpem-2025-0578
  27. Endocrinol Diabetes Metab Case Rep. 2026 Jan 01. pii: EDM250140. [Epub ahead of print]2026(1):
    Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.
    Hideaki Yagasaki, Hiromune Narusawa, Daisuke Watanabe, Fumikazu Sano, Kaoru Fujioka, Sonoko Mizorogi, Yoshimi Kaga, Takeshi Inukai.
       Summary: Mitochondrial diseases cause systemic failure of energy production and can manifest as various disorders of hormone production and secretion from endocrine organs. These effects can prevent normal growth in children, resulting in adults of short stature. We therefore explored the nutritional and endocrinological status of pediatric mitochondrial disease patients with impaired growth. Four Japanese patients with genetically diagnosed mitochondrial disease were studied (one male and three females, aged 4-22 years). The age of onset ranged from 0 months to 7 years, and the causal genes identified were mtDNA, PDHA1, and NARS2 (in two sibling patients). Two patients were diagnosed with small for gestational age at birth, and their current height standard deviation scores ranged from -1.9 SD to -6.4 SD. Mitochondrial diseases can present as impaired growth with dysfunction of various organs, depending on the causal gene and the degree of heteroplasmy. Our patients had demonstrated low T3 syndrome and reduced IGF1 levels, which appeared to be influenced by impaired nutritional status. These findings emphasize the need for careful monitoring of growth trajectories alongside nutritional and endocrine evaluations to improve clinical management.
    Learning points: Mitochondrial diseases can disrupt endocrine function involving the GH-IGF1 axis and the thyroid and gonadal systems, leading to impaired growth during childhood. Patients with early-onset mitochondrial disease tend to experience severe symptoms and pronounced growth impairment. Children with mitochondrial diseases often show low IGF1 levels, low T3 syndrome, and delayed bone age, reflecting endocrine dysfunction commonly observed in chronic systemic diseases and the further influence of suboptimal nutritional status.
    Keywords:  diabetes; impaired growth; insulin-like growth factor 1; mitochondria
    DOI:  https://doi.org/10.1530/EDM-25-0140
  28. Medicine (Baltimore). 2026 Feb 27. 105(9): e47885
    A case report of combined oxidative phosphorylation deficiency 35 (COXPD35) in Palestine caused by novel compound heterozygous TRIT1 variants.
    Ali A A Doudin, Weam N I Omran, Saja M Alkomi, Ahmad Rjoub, Hamza Shoubaki, Shurooq Tayseer Abu Mufreh.
       RATIONALE: Combined oxidative phosphorylation deficiency 35 (COXPD35) is an extremely rare mitochondrial disorder inherited in an autosomal recessive pattern. It results from pathogenic variants in the TRIT1 gene, leading to hypomodified cytosolic and mitochondrial tRNAs. We report the first identified case of COXPD35 in Palestine, resulting from 2 novel variants of the TRIT1 gene.
    PATIENT CONCERNS: A 2-year-and-6-month-old female patient with seizures, neurodevelopmental delay, microcephaly, dysmorphic facial features, abnormal electroencephalogram (EEG), and thinning of the corpus callosum on Brain magnetic resonance imaging, presenting to the Emergency Department with status epilepticus, and right lower lobe pneumonia.
    DIAGNOSES: Combined oxidative phosphorylation deficiency 35 (COXPD35) caused by 2 novel TRIT1 variants that have never been previously reported in the literature, diagnosed clinically, and were identified by Whole-exome sequencing (WES) and confirmed by Sanger sequencing.
    INTERVENTIONS: The patient received 1 shot of IV diazepam 0.3 mg/kg after IV cannulation, followed by IV ceftriaxone 500 mg twice daily, IV hydrocortisone 20 mg every 4 hours, and albuterol, ipratropium bromide, and hypertonic saline nebulizers regularly. Additionally, she was given intravenous fluids at a rate of 60 mL/h of 5% dextrose saline. She was given a 200 mg dose of phenytoin IV for seizure control. Upon clinical suspicion of a mitochondrial disease, WES was performed, followed by Sanger sequencing for confirmation of the findings.
    OUTCOMES: The patient clinically improved, with cessation of seizures, recovery from pneumonia, and confirmed diagnosis of COXPD35.
    LESSONS: The identification of new TRIT1 variants and the expanding phenotypic spectrum of COXPD35 provides insights into its clinical and genotypic characteristics. WES and Sanger Sequencing confirm the diagnosis of COXPD35; however, it can be challenging in resource-limited settings.
    Keywords:  ; case report; combined oxidative phosphorylation deficiency 35 (COXPD35); mitochondrial disorder; whole-exome sequencing (WES)
    DOI:  https://doi.org/10.1097/MD.0000000000047885
  29. Sci Rep. 2026 Feb 22.
    Decoding the dark genome reveals its organisation into modular disease networks.
    Doris Kafita, Kevin Dzobo, Panji Nkhoma, Musalula Sinkala.
      The biological functions and disease relevance of the 'dark genome'-over one-third of all protein-coding genes-remain largely unknown. Here, we use integrative network and functional analyses to construct a systems-level map of dark gene contributions to human genetic diseases. We identify 16 hub dark genes, including R3HDM2 and RPUSD4, that are central to disease networks and are overwhelmingly enriched for roles in mitochondrial protein synthesis. These hubs form modular networks connecting major inflammatory conditions like psoriasis and tuberculosis, driven by specific transcription factors. Furthermore, we demonstrate that the expression of these hubs is controlled in a tissue-specific manner by thousands of genetic variants (eQTLs), providing direct mechanistic links to phenotypes such as myocardial infarction and diabetes. Our results provide a functional landscape for the dark genome, revealing its critical role in mitochondrial pathways and presenting a rich resource of novel therapeutic targets.
    Keywords:  Human Diseasome; Mitochondrial Function; Network Analysis; The Dark Genome; eQTLs
    DOI:  https://doi.org/10.1038/s41598-026-40553-z
  30. Aging (Albany NY). 2026 Feb 10. 18(1): 30-44
    Aging-associated mitochondrial circular RNAs.
    Hyejin Mun, Do-Won Ham, Nam Chul Kim, Bo-In Kwon, Young-Kook Kim, Je-Hyun Yoon.
      During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to mitochondrial chromosome, chrM, in young and old cohorts. The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblast. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction. Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle.
    Keywords:  GRSF1; MT-RNR2; TCA cycle; aging; circular RNA
    DOI:  https://doi.org/10.18632/aging.206354
  31. JACC Basic Transl Sci. 2026 Feb;pii: S2452-302X(25)00413-9. [Epub ahead of print]11(2): 101460
    OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.
    Marco Ronfini, Valentina Prando, Vittoria Di Mauro, Lolita Dokshokova, Erika Lazzeri, Irene Costantini, Lukas Alàn, Erwan Andre Riviere, Alex Incensi, Camilla Olianti, Chiara La Morgia, Rocco Liguori, Leonardo Sacconi, Vincenzo Donadio, Luca Scorrano, Valerio Carelli, Marco Mongillo, Tania Zaglia.
      Peripheral sympathetic neurodegeneration drives cardiac dysfunction in dominant optic atrophy, revealing a critical neuro-cardiac link. Optic atrophy factor-1 haploinsufficiency disrupts mitochondrial dynamics and neurotrophic signaling, causing targeted sympathetic denervation and arrhythmias. Restoring nerve growth factor transport and mitochondrial health in sympathetic neurons represents a promising therapeutic avenue for cardiac autonomic disorders. Future research must unravel mechanisms of neurocardiac crosstalk to develop precise interventions against neurogenic cardiac disease progression.
    Keywords:  dominant optic atrophy; mitochondria; nerve growth factor; optic atrophy factor-1; sympathetic neurons
    DOI:  https://doi.org/10.1016/j.jacbts.2025.101460
  32. Antioxidants (Basel). 2026 Feb 19. pii: 261. [Epub ahead of print]15(2):
    Receptor-Mitochondria Crosstalk in the Kynurenine Metabolic Pathway: Integrating Metabolomics and Clinical Mass Spectrometry.
    László Juhász, Zsolt Galla, Masaru Tanaka, László Vécsei.
      Mitochondria govern energy transfer, redox balance, and cell fate. Tryptophan catabolism generates kynurenines (KYNs) that can tune mitochondrial function, with growing evidence that G protein-coupled receptor 35 (GPR35), aryl hydrocarbon receptor (AhR), and N-methyl-D-aspartate receptors (NMDA receptors) link extracellular cues to adenosine 5 prime triphosphate (ATP) maintenance, calcium (Ca2+) handling, mitophagy, and inflammasome control. In parallel, quinolinic acid (QA)-driven de novo nicotinamide adenine dinucleotide (NAD+) synthesis connects KYN flux to tricarboxylic acid (TCA) cycle activity and sirtuin programs across tissues. Key gaps remain: receptor pharmacology is rarely integrated with NAD+ economics and respiration, and clinical workflows still lack single-run assays that quantify both kynurenine and TCA nodes. We therefore integrate receptor proximal signaling, QA-driven NAD+ supply, and unified liquid chromatography-mass spectrometry (LC-MS) measurement into one translational framework spanning kynurenic acid (KYNA), KYN, 3-hydroxykynurenine (3-HK), and QA, using mitochondrial endpoints as the common readout. We synthesize evidence for mitochondrial GPR35 signaling that preserves ATP, AhR programs that tune oxidative defenses and mitophagy, and NMDA receptor antagonism that limits excitotoxic stress. These mechanisms are linked to QA-dependent NAD+ biogenesis and alpha ketoglutarate control points, then aligned with chromatography and ionization choices suited to routine LC-MS workflows. This receptor to organelle framework couples KYN flux to respiratory control and provides a practical roadmap for standardized single-run LC-MS panels. It can strengthen target validation in ischemia, neurodegeneration, psychiatry, and oncology while improving biomarker qualification through harmonized analytics and decision-grade readouts.
    Keywords:  G protein-coupled receptors; N-methyl-D-aspartate (NMDA); aryl hydrocarbon receptor (AhR); kynurenic acid (KYNA); liquid chromatography–mass spectrometry (LC-MS); metabolomics; mitochondria; mitophagy; nicotinamide adenine dinucleotide (NAD+); receptors; tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.3390/antiox15020261
  33. Elife. 2026 Feb 23. pii: RP102104. [Epub ahead of print]13
    Protein-induced membrane strain drives supercomplex formation.
    Maximilian C Pöverlein, Alexander Jussupow, Hyunho Kim, Ville R I Kaila.
      Mitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. By combining large-scale atomistic and coarse-grained molecular simulations with analysis of cryo-electron microscopic data and statistical as well as kinetic models, we show here that the formation of the mammalian I/III2 supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We find that the SC assembly also affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and strain effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions.
    Keywords:  bioenergetics; molecular biophysics; molecular dynamics; protein–membrane interactions; respiratory complexes; structural biology; supercomplexes
    DOI:  https://doi.org/10.7554/eLife.102104
  34. bioRxiv. 2026 Feb 10. pii: 2026.02.09.704880. [Epub ahead of print]
    Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
    Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew Goldstein, Jimmy K Hu, Neil Y C Lin.
      Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multi-omics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Functional inhibition of mitochondrial pyruvate import is sufficient to sustain collective cell motility, impeding jamming transition in crowded cells. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as a key regulator that links metabolic remodeling to the endocytic control of epithelial fluidity.
    DOI:  https://doi.org/10.64898/2026.02.09.704880
  35. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2522313123
    mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
    Jie Jiang, Meiling Zuo, Kehan Zhao, Zhihao Ling, Zhida Wu, Dongfang Xue, Shouyong Mo, Yuanhui Liu, Yongjun Chen, Jie Wang, Bin Lu, Chuanzhou Li, Yaqi Duan, He He, Zhiyin Song.
      Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion-immunity-metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mitochondrial DNA (mtDNA)-ZBP1-RIPK3-mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (cGAS)-STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor coagonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS-STING activation and D-serine act as important drivers of epilepsy initiation, offering mechanistic insights into neuron-microglia-astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.
    Keywords:  cGAS–STING; epilepsy; mitochondrial DNA; neuroinflammation; serine
    DOI:  https://doi.org/10.1073/pnas.2522313123
  36. Biomolecules. 2026 Feb 09. pii: 276. [Epub ahead of print]16(2):
    Phosphatidylserine Decarboxylase Regulates Retinal Ganglion Cell Neurite Outgrowth with Altered Somal Membrane Fluidics and Mitochondrial Morphology.
    Sean D Meehan, Sofia Yarosh, Victoria Pereira, Isabella Moceri, Sanjoy K Bhattacharya.
      Mitochondrial lipid metabolism is an emerging regulator of neuronal regeneration, yet its role remains poorly defined. We investigated the function of phosphatidylserine decarboxylase (PSD), a mitochondrial enzyme that converts phosphatidylserine to phosphatidylethanolamine (PE), in retinal ganglion cell (RGC) regeneration. Using human glaucomatous degenerating optic nerves, we found PE was aberrantly accumulated with an elevated PSD expression and activity. In contrast, transcriptomes of regenerating RGCs present downregulated PSD, implicating PSD as a potential negative regulator of axonal growth. Using AAV2-mediated gene modulation, we evaluated how PSD knockdown (PSDKD) and PSD overexpression (PSDOE) alter RGC neurite outgrowth in vitro while evaluating effects on mitochondrial morphology, membrane fluidity by C-Laurdan staining, and lipidomes by LC-MS analysis. PSDOE did not support RGC neurite outgrowth, fragmented mitochondria, and increased polyunsaturated triacylglycerols. PSDKD significantly enhanced RGC neurite outgrowth and increased somal membrane fluidity accompanied by decreased cholesterol and saturated triacylglycerols. Notably, Doxorubicin, which attenuates PSD activity, increased neurite growth in PSDOE RGCs, supporting PSD's activity as a negative role for growth. Using the optic nerve crush degenerative model in C57BL/6 mice, we confirm PSDKD RGCs have higher growth competency in vivo. These findings indicate PSDKD positions RGCs in a more growth-permissive state.
    Keywords:  lipid metabolism; mitochondria; neurite outgrowth; phosphatidylethanolamine; regeneration; retinal ganglion cell
    DOI:  https://doi.org/10.3390/biom16020276
  37. Curr Issues Mol Biol. 2026 Feb 16. pii: 217. [Epub ahead of print]48(2):
    Comparative Analysis of Methodological Aspects of the Study of Extracellular Vesicles and Extracellular Mitochondria: From Isolation to Internalization.
    Natalia Yunusova, Dmitry Svarovsky, Evgenya Kaigorodova, Alexey Dobrodeev, Virab Sisakian, Svetlana Tamkovich.
      Mitochondrial transfer in mammals has been proven to occur both under physiological conditions and during pathological conditions. It has been shown that neighboring cells can exchange mitochondria via nanotunnel tubes. However, there is evidence that free mitochondria, as well as whole mitochondria and individual mitochondrial fragments, can be transported between cells within extracellular vesicles (EVs). This review discusses the methodological aspects of isolation and a minimal set of methods for characterizing mitochondria-rich EVs (mitoEVs), as well as methodological approaches for studying the nucleic acid, protein, and lipid composition. It has been shown that mitoEVs, as well as extracellular mitochondria, contain a characteristic set of nucleic acids of mitochondrial origin. First and foremost, the dominant fraction of mitochondrial nucleic acids is mitochondrial DNA (mtDNA), a circular double-stranded molecule approximately 16.6 thousand base pairs in length. The mechanisms involved in EV internalization include clathrin-dependent endocytosis, caveolin-dependent endocytosis, raft-mediated endocytosis, and macropinocytosis. Mitochondrial-enriched autologous and xenogeneic EVs are thought to be internalized by similar mechanisms. The review also presents the main sources (stem cells, platelet concentrate, peripheral blood mononuclear cells) for obtaining mitochondria-rich EVs for therapeutic purposes.
    Keywords:  exosomes; extracellular mitochondria; internalization; mitochondria-rich extracellular vesicles; mitochondrial DNAs and RNAs; mitochondrial proteins; mitochondrial transfer; platelet concentrate; stem cells
    DOI:  https://doi.org/10.3390/cimb48020217
  38. Cells. 2026 Feb 20. pii: 372. [Epub ahead of print]15(4):
    Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
    Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton, Michela Casella.
      Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control-encompassing fusion-fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis-compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS-STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.
    Keywords:  cardiovascular disease; inflammation; mitochondrial dysfunction; mitochondrial quality control; mitochondrial signaling; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/cells15040372
  39. Sci Adv. 2026 Feb 27. 12(9): eaeb0049
    Specific SLC25 carriers regulate mitochondrial protein synthesis.
    Danielle L Rudler, Laetitia A Hughes, Martin S King, Jessica Baker, Richard G Lee, Andrianto P Gandadireja, Anisha Sunil, Samuel V Fagan, Blake Payne, Nicola Gray, Tim McCubbin, Edmund R S Kunji, Oliver Rackham, Aleksandra Filipovska.
      A genome-wide knockout screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange adenosine triphosphate-magnesium (ATP-Mg) and phosphate, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multiomic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilized by choline, and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodeling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function and show that impaired transport of branched-chain amino acids, methylated basic amino acids, ATP-Mg, and choline affects mitochondrial translation.
    DOI:  https://doi.org/10.1126/sciadv.aeb0049
  40. Eur J Med Chem. 2026 Feb 20. pii: S0223-5234(26)00151-0. [Epub ahead of print]308 118706
    Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.
    Patrick A Cardwell, Alva M Casey, Suvagata Roy Chowdhury, Eloïse Marques, Chak Shun Yu, Rebecca L Taig, Stuart T Caldwell, Julien Prudent, Michael P Murphy, Richard C Hartley.
      Mitochondrial glutathione (mGSH) protects the organelle and the cell against reactive oxygen species (ROS), electrophilic metabolites and xenobiotics. Many cancers upregulate GSH to confer resistance against cell death by ferroptosis and anticancer drugs, so mGSH depletion is a potential anticancer strategy. We previously developed MitoCDNB, a mitochondria-targeted molecule that selectively depletes mGSH and disrupts mitochondrial thiol redox homeostasis. However, mGSH depletion by MitoCDNB required catalysis by glutathione-S-transferases (GSTs). Here, we develop a dual-action prodrug scaffold to deplete mGSH independently of GSTs and simultaneously release a payload to increase oxidative stress. The scaffold has four components: a triphenylphosphonium (TPP) group for targeting to the mitochondria, a GSH-reactive electrophilic dinitroaryl ring bearing a sulfonamide leaving group for depleting mGSH, an ethylenediamine-derived self-immolative linker and a phenolic payload. The rates of nucleophilic aromatic substitution (SNAr) of the sulfonamide by GSH and the cyclisation of the released linker-payload intermediate were measured and the kinetics successfully modelled as consecutive reactions. Under physiological levels of GSH (10 mM) and matrix pH (8.0), our best linker releases a 7-hydroxycoumarin reporter with a half-life of 2.5 min at 30 °C. We used the scaffold for cellular and mitochondrial uptake of a compound that depletes mGSH and releases the redox-cycling pro-oxidant, menadiol/menadione, in the mitochondrial matrix. The combination of mGSH depletion with enhanced mitochondrial ROS production showed synergistic cytotoxicity towards cancer cells, paving the way for the development of dual-action mitochondria-targeted prodrugs as potential cancer therapeutics.
    Keywords:  Cancer; Glutathione; Mitochondria; Oxidative stress; Prodrug; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118706
  41. Trends Endocrinol Metab. 2026 Feb 24. pii: S1043-2760(26)00011-1. [Epub ahead of print]
    Reversible phosphorylation influences energetic cellular metabolism by modulating mitochondrial gene expression.
    Aldara Mainé-Rodrigo, Ana Vela-Sebastián, David Pacheu-Grau.
      Mitochondria act as key metabolic regulators beyond ATP production, and the understanding of how cellular signaling modifies mitochondrial gene expression is currently being explored. Recent evidence links kinases such as mitogen-activated protein kinase-interacting kinases, hexokinase 1, and eukaryotic elongation factor 2 kinase to mitochondrial function, influencing metabolic adaptation, inflammation, and survival under nutrient stress, with implications for obesity and aging.
    Keywords:  cellular metabolism; mitochondria; mitochondrial gene expression; reversible phosphorylation
    DOI:  https://doi.org/10.1016/j.tem.2026.01.011
  42. Nat Commun. 2026 Feb 24.
    Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
    Chien Huang, Joo-Hyun Park, Ali Altıntaş, Natasa Stanic, Kristine Kyle de Leon, Signe Isacson, Panagiotis Kalogeropoulos, Hande Topel, Tobias Madsen, Sebastian Zanner, Phillip Mm Ruppert, Rocio Valdebenito, Jesper Havelund, Bjørk Ditlev Marcher Larsen, Yen-Ting Chien, Wen-Chi Huang, Yovita Permata Budi, Yi-Fan Jiang, Andréa Livia Rocha, Niedson Correia Lima-Junior, Karolina Szczepanowska, Jan-Wilm Lackmann, Aleksandra Trifunovic, Eva Kildall Hejbøl, Sönke Detlefsen, Ida Engberg Jepsen, Stefanie Hansborg Kolstrup, Ricardo Laguna-Barraza, Javier Martin-Gonzalez, Konstantin Khodosevich, Nils J Færgeman, Marcelo A Mori, Marc R Friedländer, Anita Öst, Romain Barrès, Jan-Wilhelm Kornfeld.
      Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
    DOI:  https://doi.org/10.1038/s41467-026-69686-5
  43. Autophagy Rep. 2026 ;5(1): 2629624
    Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
    Mariana Joaquim, Maike F Dohrn, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.
    Keywords:  Charcot–Marie–Tooth type 2A (CMT2A); HSPA8/HSC70; MFN2; protein import; proteasome; VCP/p97; PINK1; apoptosis; mitophagy; proteostasis
    DOI:  https://doi.org/10.1080/27694127.2026.2629624
  44. J Cardiovasc Dev Dis. 2026 Feb 03. pii: 77. [Epub ahead of print]13(2):
    Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.
    Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.
      Human iPSC-derived cardiomyocytes (iPSC-CMs) exhibit fetal-like mitochondrial networks and limited oxidative metabolism, constraining their translational utility. The key bottleneck is mitochondrial immaturity, resulting from blunted PGC-1α-NRF1/2-TFAM axis activation and insufficient nuclear-mitochondrial coordination, rather than sarcomeric or electrophysiological immaturity alone. This review synthesizes genome-guided interventions (CRISPRa and mtDNA editing) and complementary environmental strategies-including metabolic substrate switching, electromechanical stimulation, and extracellular vesicle (EV)-mediated mitochondrial transfer-to drive mitochondrial biogenesis and maturation in iPSC-CMs. We systematically reviewed studies (2005-2025) targeting (1) key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), (2) CRISPR-based transcriptional activators/repressors and mtDNA editors (DdCBE, mitoTALENs), and (3) maturation approaches such as metabolic conditioning, electromechanical stimulation, 3D tissue culture, and EV-mediated mitochondrial transfer. CRISPRa-mediated activation of PGC-1α, NRF1, and GATA4, combined with mtDNA base editors, enhances mitochondrial mass and OXPHOS function, while integration with environmental maturation strategies further promotes adult-like phenotypes. Integrative approaches that combine genome-guided interventions (CRISPRa, mtDNA editing) with environmental maturation cues yield the most adult-like iPSC-CM phenotypes reported to date. CRISPR-guided mitochondrial biogenesis thus represents a frontier for producing metabolically competent, structurally mature iPSC-CMs for disease modeling and therapy. Remaining translational challenges include efficient mitochondrial delivery, metabolic homeostasis, and multi-omics validation. We propose standardized workflows to couple nuclear and mitochondrial editing with maturation strategies.
    Keywords:  CRISPR activation (CRISPRa); PGC-1α signaling; cardiomyocyte maturation; extracellular vesicle therapy; iPSC-cardiomyocytes; metabolic conditioning in iPSC-CMs; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial genome editing; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3390/jcdd13020077
  45. iScience. 2026 Mar 20. 29(3): 114889
    Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
    Huabo Wang, Jie Lu, Colin Henchy, Steven J Mullett, Adam C Richert, Eric S Goetzman, Ahmet Toksoz, Leonardo Hale, Brandon B Wang, Nelli Mnatsakanyan, Edward V Prochownik.
      Cancer cell metabolic re-programming provides the additional energy and anabolic precursors necessary to sustain unregulated proliferation. This is partially mediated by the Warburg effect, which generates ATP while oxidizing glucose to a subset of these anabolites. Concurrently, mitochondrial mass and ATP generation via oxidative phosphorylation decline in most tumors. This raises the question of how increased glycolysis-derived anabolites can be balanced with those supplied by the TCA cycle. Using primary murine liver cancers and their derivative cell lines, we show that this can be explained by the dissociation of mitochondrial Complex V (CV or ATP synthase) into its component and functionally independent Fo and F1 domains. This occurs as a result of marked declines in MT-ATP6, a CV subunit that stabilizes Fo-F1 assembly. Serving as a proton pore, free Fo maintains a normal mitochondrial membrane potential without generating ATP, thus allowing the TCA cycle, electron transport chain, and anaplerotic reactions to function at high levels. Concurrently, free F1 functions in reverse as an ATPase to limit excess ATP accumulation. The uncoupling of TCA-cycle-derived anabolic substrate production from membrane hyperpolarization and ATP overproduction by a smaller population of highly efficient mitochondria allows TCA-cycle-generated anabolic precursors to match those generated via glycolysis.
    Keywords:  Biochemistry; Cancer; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114889
  46. Biochim Biophys Acta Bioenerg. 2026 Feb 25. pii: S0005-2728(26)00006-X. [Epub ahead of print] 149586
    Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.
    Victor V Lemeshko.
      Glycerophosphate shuttle, an important crossroad between oxidative phosphorylation system, glycolysis and lipid metabolism, consists of the rate-limiting mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) and the cytosolic dehydrogenase (GPD1). GPD2 level is relatively high in islet beta-cells, spermatozoa and neurons, required abruptly rapid periodic ATP consumption, as well as in rapidly growing normal tissues during neonatal period and many cancers. According to the computational model developed in the present work, the glycerophosphate shuttle should be significantly activated by the outer membrane potential (OMP) generated by the VDAC1,2-hexokinase complexes of mitochondrial outer membrane. This is due to the capture of cytosolic glycerol-3-phosphate2- into the mitochondrial intermembrane space by the positive OMP, thus increasing its local concentration near GPD2. The predicted acceleration is most significant at relatively high Km of GPD2 for glycerol-3-phosphate2- and strongly modulated by the VDAC's voltage-gating properties. In general, OMP generated by the VDAC1,2-hexokinase complexes might play a crucial role in the above-mentioned crossroad, converting it into the "electrical metabolic crossroad". The suggested electrical deviation of glycolysis towards the mitochondrial GPD2, as a tool for the metabolic shift to an accelerated aerobic glycolysis without an inhibition of mitochondrial respiration, highlights this metabolic switching as one of the possible options of the Warburg effect.
    Keywords:  Glycerophosphate shuttle; Glycolysis; Hexokinase; Mitochondria; Outer membrane potential; VDAC
    DOI:  https://doi.org/10.1016/j.bbabio.2026.149586
  47. bioRxiv. 2026 Feb 16. pii: 2026.02.13.705622. [Epub ahead of print]
    Excessive Ca 2+ -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury.
    David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara Price, Sandra H J Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.
      Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca 2+ -dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca 2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca 2+ -dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
    DOI:  https://doi.org/10.64898/2026.02.13.705622
  48. J Genet Genomics. 2026 Feb 25. pii: S1673-8527(26)00062-7. [Epub ahead of print]
    Mitochondrial genome editing tools: prospects in animal breeding.
    Xu Yan, Mingyue Chen, Shunkai Yang, Yuyang Guo, Yichao Dai, Yutong Chen, Haijiang Zhong, Taisen Ma, Dingrui Zha, Yutao He, Baiyu Li, Xinyu Jia, Long Guo, Jianhong Hu, Yinghui Wei, Xiaoxu Chen.
      Mitochondria are vital organelles responsible for driving cellular energy metabolism and regulating key biological processes. Their circular mitochondrial DNA (mtDNA) encodes 13 subunits of the respiratory chain proteins but is susceptible to mutations due to high levels of reactive oxygen species and limited repair mechanisms. Mutant phenotypes manifest only when heteroplasmy surpasses a critical threshold. Understanding the consequences of mtDNA mutations has long been hampered by the lack of precise editing tools. Recently, CRISPR-free, protein-only mitochondrial base editors have enabled C·G-to-T·A and A·T-to-G·C transitions. These breakthroughs facilitate the creation of relevant disease models and offer unique opportunities for animal breeding, as specific mtDNA variants are known to influence economically important traits in livestock, including production, reproduction, and stress tolerance. This review summarizes recent advances in mitochondrial genome editing technologies, including CRISPR/Cas-based systems, restriction endonucleases, double-stranded DNA deaminase toxin A (DddA)-based cytosine and adenine base editors, and DddA-free base editors, along with their delivery strategies and optimization avenues. Furthermore, we outline the associations between mtDNA polymorphisms, copy number variation, and economic traits in livestock and poultry. Finally, we discuss the potential applications of mitochondrial genome editing in animal breeding and highlight the critical safety and ethical considerations that require careful attention.
    Keywords:  Animal breeding; Economic traits; Mitochondria; Mitochondrial gene editing; mtDNA
    DOI:  https://doi.org/10.1016/j.jgg.2026.02.018
  49. Mol Ther Nucleic Acids. 2026 Mar 12. 37(1): 102860
    Rescue of mitochondrial power outages with γPNA-based miR-122 inhibitor.
    Kamalika Mukherjee, Suvendra N Bhattacharyya.
      
    DOI:  https://doi.org/10.1016/j.omtn.2026.102860
  50. Biochemistry. 2026 Feb 26.
    Characterization of Conformational Dynamics and Structural Plasticity of the Catalytic Domain of Human Mitochondrial YME1L Protease.
    Megan K Black, Angelina Kim, Ching Y Chen, Monica M Goncalves, Simrah Waseem, Siavash Vahidi, Rui Huang.
      Mitochondrial proteostasis is essential to maintain cellular function and survival. YME1L is a membrane-anchored AAA+ (ATPases Associated with diverse cellular Activities) family protease and plays a pivotal role in mitochondrial proteostasis by selectively degrading misfolded and native proteins. The precise mechanisms by which nucleotide binding and hydrolysis influence YME1L's conformational dynamics, proteolytic activity, and stability remain unclear. Here, we characterize the conformational dynamics of the YME1L catalytic domain. Using a hexameric soluble YME1L construct, we employ hydrogen/deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) spectroscopy to demonstrate that nucleotide binding reduces the backbone flexibility and modulates the side-chain dynamics of the AAA+ domain, while Zn2+ binding stabilizes the protease domain. We also reveal long-range functional crosstalk between the AAA+ and protease domains of YME1L. We use functional assays to show the importance of a salt bridge between the AAA+ and protease domains in facilitating ATP-dependent substrate degradation by YME1L. Additionally, we show that ATP binding stabilizes the structure of the catalytic domain of YME1L and protects it from chemical- and heat-induced aggregation. These findings explain the nucleotide-driven regulation of YME1L and provide insights into our understanding of its proteolytic activity and structural stability under stress conditions.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00535
  51. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  52. NAR Mol Med. 2026 Jan;3(1): ugag013
    Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.
    Maria Mahmood, Sarah D P Wilhelm, Marisa I Mendes, Desiree E Smith, Rosan Kenana, Kyle Hoffman, Angelica A Moresco, Victoria Mok Siu, Ilka U Heinemann.
      Cytoplasmic histidyl-tRNA synthetase (HARS1) is an essential protein in translation, ligating histidine to its cognate tRNAHis. HARS1 is one of several aminoacyl-transfer RNA (tRNA) synthetases associated with Charcot-Marie-Tooth disease, an axonal peripheral neuropathy. Advances in genetic testing identify many variants of uncertain significance. We characterize a novel heterozygous allele in HARS1, c.1200G > T (p.Leu400Phe) with a familial inheritance pattern of peripheral neuropathy. Using a humanized yeast model and biochemical assays, we determined that HARS-L400F causes HARS aggregation, reduced thermal stability, and a temperature-dependent reduction of aminoacylation activity. In humanized yeast, L400F leads to a pronounced growth defect, especially at elevated temperatures. Contrary to previously described pathogenic HARS alleles, cognate amino acid or tRNA substrate supplementation does not ameliorate the growth defect. We show that, in a humanized yeast model, HARS L400F leads to the activation of the integrated stress response (ISR) and upregulated chaperone expression. The yeast growth phenotype can be rescued by inhibition of the ISR using a specific inhibitor of general control non-depressible 2 (GCN2) kinase, opening a novel therapeutic avenue for pathogenic HARS1 alleles that do not respond to substrate supplementation.
    DOI:  https://doi.org/10.1093/narmme/ugag013
  53. Nat Commun. 2026 Feb 25.
    Regional nonsense constraint offers biological and clinical insights into genetic disease.
    Alexander J M Blakes, Nicola Whiffin, Colin A Johnson, Jamie M Ellingford, Siddharth Banka.
      Reliably predicting the molecular impact of premature termination codons (PTCs) is essential for the clinical interpretation of "loss-of-function" variants in human disease. Measures of selective constraint can identify genes and genomic regions which are intolerant to deleterious genetic variation. However, existing loss-of-function constraint metrics do not comprehensively account for nonsense-mediated mRNA decay (NMD), a quality control pathway which critically regulates PTCs. Here, we use sequencing data from 730,947 individuals to develop an NMD-informed regional nonsense constraint metric. We find 2764 genes with significant regional nonsense constraint, including 641 known autosomal dominant disease genes. Using sequencing data in 32,260 trios from three rare disease cohorts, we find that de novo nonsense and frameshift variants are 9.5-fold enriched and associated with up to 5.9-fold higher odds of diagnosis in constrained regions versus unconstrained regions. We use these data to identify 22 candidate disease genes with clusters of de novo variants in constrained regions. These findings enhance clinical variant interpretation, deliver mechanistic insights in human disease, and empower the discovery of novel disease genes.
    DOI:  https://doi.org/10.1038/s41467-026-69983-z
  54. Res Sq. 2026 Feb 16. pii: rs.3.rs-8704245. [Epub ahead of print]
    Nutrient State, Aging, and Diet Modulate SAM50-Dependent Mitochondrial Remodeling and Systemic Metabolic Signatures.
    Antentor Othrell Hinton, Sepiso K Masenga, Victoria Baskerville, Mark Petrovic, Benjamin Rodriguez, David L Hubert, Tyne W Miller-Fleming, Young Do Koo, Prasanna Katti, Prasanna Venkhatesh, Annet Kirabo, Edgar Garza Lopez, Amber Crabtree, Andrea Marshall, Campbell Blake, Chandravanu Dash, Praveena Prasad, Alexandria Murphy, Jeremiah Afolabi, Mark A Phillips, Chantell Evans, Estevão Scudese, Jenny C Schafer, Julia Berry, Bret C Mobley, Dao Fu Dai, Harrison Mobley, Nathan C Winn, Mohd M Khan, Dea Pulatani, Joseph Sorrentino, Joyonna Gamble-George, Melanie McReynolds, Celestine Wanjalla.
      Although Sorting and Assembly Machinery 50 (SAM50) is known to regulate nutritional and metabolic stress related to ageing, its exact role is not well understood. This experimental study combines both human and animal models to understand the role that SAM50 plays in nutrient, age-related metabolic remodeling. We also wanted to define the clinical relevance of SAMM50 genetic variation in human disease. Our study integrated clinical and genetic data from three large and independent human biobanks to assess the clinical implications of genetic variation in SAMM50. We then conducted mechanistic studies in mice using Serial Block-Face Scanning Electron Microscopy and Transmission Electron Microscopy for three-dimension analysis of mitochondrial morphology, immunoblotting, metabolomics/lipidomics, and assessment of metabolic parameters in models of fasting, aging, and a high-fat diet (HFD). Descriptive and inferential statistics were used to describe and test associations in GraphPad prism version 10. Our study demonstrated that common genetic variation within the SAMM50 genetic locus was significantly associated with liver-related metabolic disorders. In mice, nutrient status was associated with expression levels of Sam50 and proteins involved in the respiratory complex. Aging was associated with impaired mitochondria, decreased Sam50 expression, and increased triglyceride and lipid peroxidation, with increased lipid droplet-mitochondria contacts. An HFD was associated with a reduction in Sam50 expression, disruption of mitochondrial structure, and metabolic dysfunction, effects that were only partly reversed by returning to a normal diet. Our results demonstrate that SAM50 expression is associated with nutrient state and age-related signals, thereby orchestrating mitochondrial structure to influence systemic metabolic health.
    DOI:  https://doi.org/10.21203/rs.3.rs-8704245/v1
  55. J Dent Res. 2026 Feb 24. 220345251411909
    Endoplasmic Reticulum-Mitochondria Calcium Drives Salivary Bioenergetics.
    S N Min, X D Mao, J Z Su, L L Wu, G Y Yu, X Cong.
      Saliva secretion requires continuous energy supply throughout the day. Mitochondria dynamically adapt to fluctuating energy demands, yet the mechanisms underlying the adaptions remain poorly understood. Here, we employed real-time intravital imaging and fluorescence lifetime imaging microscopy (FLIM) to monitor mitochondria functions in submandibular glands. We revealed distinct mitochondrial distribution patterns; in acinar cells, mitochondria were predominantly distributed near the cell membranes or scattered throughout the cytoplasm with extensive endoplasmic reticulum (ER)-mitochondria contact sites, whereas in ductal cells, mitochondria were densely packed within the cytoplasm. At resting states, mitochondria exhibited larger volumes, fewer numbers, and higher oxidative phosphorylation activity in acinar cells compared with those in ductal cells. Upon stimulation with pilocarpine, mitochondrial motility, NAD(P)H levels, NAD(P)H enzyme-bound fractions, and mitochondrial adenosine triphosphate (ATP) production were significantly elevated. Pilocarpine-induced secretion, mediated by both aquaporin 5 translocation and the opening of paracellular pathway, was markedly attenuated by oligomycin A, an ATP synthase inhibitor. Notably, pilocarpine increased mitochondria-ER contact sites to 1.7 times the control level (from 18% to 31%), and blocking mitochondrial calcium uptake significantly suppressed pilocarpine-induced NAD(P)H and ATP production. These findings highlight the critical role of ER-mitochondria calcium transfer in sustaining bioenergetics required for salivary secretion, providing new insights into mitochondrial functional adaptation and its physiological significance in intact secretory systems.
    Keywords:  NADH; energy metabolism; mitochondria associated membranes; muscarinic acetylcholine receptor; secretion; submandibular gland
    DOI:  https://doi.org/10.1177/00220345251411909
  56. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705530. [Epub ahead of print]
    Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Martin Picard, Abbey-Gale Mannings, Michael Cohen, Dennis Wolan, Terence E Ryan, Russell T Hepple.
       Background: Skeletal muscle in wasting conditions often exhibits a common set of phenotypes that include atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. Mitochondria are frequently implicated in driving muscle pathology in these conditions, although which aspects of mitochondrial function are most relevant is poorly understood.
    Methods: To address this gap, we focused on mitochondrial permeability transition (mPT), a well-established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle. We performed a broad assessment of the consequences of mPT in skeletal muscle, focusing on features that are common in wasting conditions. We then tested whether tumor-host factors could promote mPT and compared differentially expressed genes (DEGs) with mPT and a mouse model of pancreatic cancer cachexia.
    Results: Inducing mPT in mouse skeletal muscle bundles in a Ca 2+ retention capacity assay progressively altered mitochondrial morphology, beginning with cristae swirling and condensation, progressing to mitochondrial cristae displacement, and culminating in breach of the outer mitochondrial membrane; features that are common in wasting conditions. Inducing mPT with Bz423 in single mouse muscle fibers increased mROS and Caspase 3 (Casp3) activity and was prevented by inhibitors of mPT, mROS or Casp3. Incubating single muscle fibers with Bz423 for 24 h reduced fiber diameter by ∼20% which was prevented by inhibiting mPT, mROS, or Casp3. Inducing mPT caused a complex I-specific mitochondrial respiratory impairment and increased co-localization of lysosomes with mitochondria. Inducing mPT also fragmented the AChR cluster at the muscle endplate and was prevented by inhibiting mPT or Casp3. The Ca 2+ threshold for mPT and mitochondrial calcein colocalization were reduced by pancreatic tumor-conditioned media in skeletal muscle or C2C12 myoblasts, respectively, and these effects were counteracted by mPT inhibition or cyclophilin D knockout. Finally, there was significant overlap between the transcriptome of mPT and that seen in diaphragm muscle in a mouse model of pancreatic cancer cachexia, particularly during the muscle wasting phase.
    Conclusions: We conclude that inducing mPT in skeletal muscle recapitulates muscle phenotypes common with muscle wasting conditions like cachexia. Furthermore, mPT is engaged by tumor-host factors and had significant overlap with DEGs seen during the muscle wasting phase in a mouse model of pancreatic cancer cachexia, warranting further investigation of mPT as a therapeutic target.
    DOI:  https://doi.org/10.64898/2026.02.12.705530
  57. Res Sq. 2026 Feb 20. pii: rs.3.rs-8744427. [Epub ahead of print]
    Hot Mitochondria and the Second Law of Thermodynamics.
    Alexei Tkachenko, Belem Yoval-Sánchez, Alexander Galkin.
      Mitochondria are central hubs of cellular bioenergetics, converting chemical free energy into ATP while inevitably releasing heat during respiration. Fluorescence-based thermometry has been interpreted to show intracellular "hot spots" more than 10 °C above the bulk physiological temperature, implying that mitochondria might operate far outside conventional thermal bounds. Such claims, however, appear inconsistent with basic biophysics: the small size of mitochondria, their aqueous and highly conductive environment, and their limited power output all argue against large steady-state temperature gradients. This discrepancy has prompted renewed scrutiny of both the physical limits of intracellular heat transfer and the biological interpretation of nanoscale thermal measurements. A key open question is whether nonequilibrium biochemical processes, such as respiration-driven proton pumping, could act as nanoscale heat pumps that maintain higher local temperatures than allowed by passive diffusion alone. Here, we develop a model-independent thermodynamic analysis based solely on the Second Law of Thermodynamics to bound the maximal temperature difference that any biochemically driven mechanism can sustain across the inner mitochondrial membrane and show that even under idealized conditions the achievable temperature rise is restricted to a small fraction of a degree, effectively closing this loophole.
    DOI:  https://doi.org/10.21203/rs.3.rs-8744427/v1
  58. Parkinsonism Relat Disord. 2026 Feb 19. pii: S1353-8020(26)00079-9. [Epub ahead of print]145 108252
    Molecular analysis of mitochondrial complex I in the levodopa short duration response in Parkinson's disease.
    Ana Gabrielle Bispo, Felipe Gouvêa de Souza, Matheus Epifane-de-Assunção, Camille Sena-Dos-Santos, Gustavo Barra-Matos, Dafne Dalledone Moura, Gracivane Lopes Eufraseo, Caio Santos Silva, Gilderlanio Santana-de-Araújo, Ândrea Ribeiro-Dos-Santos, Bruno Lopes Santos-Lobato, Giovanna C Cavalcante.
       INTRODUCTION: Significant advances have been made in elucidating the pathophysiological mechanisms of Parkinson's disease (PD). Levodopa remains the main therapeutic option - although it presents heterogeneous clinical benefits among patients. Mutations related to levodopa metabolic pathways have been investigated, but not for mtDNA. Since levodopa metabolism is highly dependent on ionic gradients, endocytosis, and vesicular transport - all ATP-dependent processes - the normal function of OXPHOS is essential not only for adequate levodopa metabolism but also for its therapeutic efficacy. This study aimed to analyze levodopa short duration responsiveness profiles considering the mitochondrial genomic component in Brazilian admixed populations.
    METHODS: A total of 49 patients with PD underwent a levodopa challenge test (LCT), followed by whole mitochondrial genome sequencing, pathogenicity prediction of identified variants, and in silico structural analyses.
    RESULTS: Variants most frequently affected ND4, ND5, and ND6 subunits in both groups (responsive and non-responsive). Among them, the responsive group presented variants in MT-ND4 (m.12018C > G - T420S) and ND5 (m.13130C > A - P265H) as those with the most significant structural impact, suggesting a loss of the native conformation and alterations in protein efficiency. Additionally, five unique variants were detected only among non-responsive patients, two of which were absent from the dbSNP and ClinVar databases, which indicates the possibility that they are novel variants and potentially population-specific.
    CONCLUSION: We provide molecular evidence suggesting that variants in mitochondrial ND4, ND5, and ND6 subunits, in addition to mitochondrial ancestry, may contribute to distinct levodopa short duration response in PD patients.
    Keywords:  Mitochondria; Mitochondrial genome; Parkinson's disease; levodopa
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.108252
  59. Elife. 2026 Feb 26. pii: RP87528. [Epub ahead of print]12
    Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury.
    Preethi Somasundaram, Madeline M Farley, Melissa A Rudy, Katya Sigal, Andoni I Asencor, David G Stefanoff, Malay Shah, Puneetha Goli, Jenny Heo, Shufang Wang, Nicholas M Tran, Trent A Watkins.
      Stress signaling is important for determining the fates of neurons following axonal insults. Previously, we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here, we show that PERK acts primarily through activating transcription factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.
    Keywords:  axon regeneration; integrated stress response; mouse; neurodegeneration; neuroscience; retinal ganglion cell
    DOI:  https://doi.org/10.7554/eLife.87528
  60. Diseases. 2026 Feb 02. pii: 56. [Epub ahead of print]14(2):
    Mitochondrial Resilience in Glaucoma: Targeting NAD+ Metabolism and Oxidative Stress in Retinal Ganglion Cell Degeneration with Nicotinamide Riboside and Berberine: Preliminary Clinical Evidence.
    Federico Visalli, Francesco Cappellani, Giuseppe Gagliano, Alfonso Spinello, Alessandro Avitabile, Ludovica Cannizzaro, Matteo Capobianco, Caterina Gagliano, Marco Zeppieri.
       BACKGROUND: Glaucoma is a chronic neurodegenerative disorder characterized by the selective vulnerability of retinal ganglion cells (RGCs), in which mitochondrial dysfunction, redox imbalance, and impaired bioenergetic signaling play central pathogenetic roles. Mitochondrial homeostasis in RGCs critically depends on maintaining intracellular NAD+ pools, which support oxidative phosphorylation, sirtuin-mediated deacetylation, and antioxidant gene expression. Nicotinamide riboside (NR), a potent NAD+ precursor, and berberine (BBR), an AMPK activator derived from Berberis aristata, have recently emerged as synergistic modulators of mitochondrial metabolism and oxidative stress resistance.
    METHODS: This study retrospectively assessed clinical outcomes associated with combined nutraceutical supplementation of nicotinamide riboside (NR) and berberine (BBR) in patients with primary open-angle glaucoma undergoing stable topical hypotensive therapy. We have included a narrative review in the current literature regarding NAD+ biology, AMPK-sirtuin signaling, and oxidative stress responses in retinal ganglion cell (RGC) degeneration. Due to the absence of comparator groups receiving only NR or only berberine in this retrospective cohort, the combined supplementation has been regarded as a biologically complementary strategy, and the potential for synergistic efficacy remains a subject for further investigation.
    RESULTS: Translationally, a retrospective clinical cohort receiving combined NR and BBR supplementation showed functional stabilization of the visual field and structural preservation of the retinal nerve fiber layer over a six-month follow-up, in line with the proposed mitochondrial protective mechanisms.
    CONCLUSIONS: The clinical trends identified in this retrospective cohort have substantiated the translational significance of NR + BBR supplementation as a potential adjunctive approach in glaucoma management. NAD+ repletion and engagement of the AMPK-SIRT-NRF2 pathway may enhance mitochondrial resilience in RGCs. Collectively, these findings offer initial clinical evidence advocating for additional controlled studies on NR + berberine supplementation, while mechanistic interpretations have been derived from the existing literature and are hypothesis-generating.
    Keywords:  NAD+ metabolism; berberine; glaucoma; mitochondrial dysfunction; neuroprotection; nicotinamide; nicotinamide riboside; oxidative stress; retinal ganglion cells
    DOI:  https://doi.org/10.3390/diseases14020056
  61. Int J Mol Sci. 2026 Feb 19. pii: 1981. [Epub ahead of print]27(4):
    Mesenchymal Stromal Cells and Extracellular Vesicles: A Novel Therapeutic Paradigm for Mitochondrial Dysfunctions.
    Eman Salem Algariri, Fazlina Nordin, Min Hwei Ng, Izyan Mohd Idris, Norwahidah Abdul Karim, Gee Jun Tye, Wan Safwani Wan Kamarul Zaman.
      Mitochondrial dysfunction is a central pathological feature of a wide range of inherited and acquired disorders and is characterized by impaired oxidative phosphorylation, disrupted cellular energy metabolism, and excessive oxidative stress. Although advances in molecular diagnostics have improved disease recognition, effective disease-modifying therapies remain limited, and clinical outcomes are often suboptimal, highlighting the need for novel therapeutic strategies. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have emerged as promising candidates for targeting mitochondrial dysfunction due to their regenerative, immunomodulatory, and metabolic regulatory properties. In this review, we provide a comprehensive overview of recent in vitro and in vivo studies investigating the capacity of MSCs and MSC-EVs to restore mitochondrial function by enhancing mitochondrial respiration, improving cellular bioenergetics, and reducing oxidative stress across diverse disease models. We further discuss the underlying mechanisms involved, including mitochondrial transfer, delivery of functional mitochondrial components, and modulation of the cellular microenvironment. Finally, we highlight the key advantages, translational potential, and remaining challenges associated with MSC- and MSC-EV-based therapies for mitochondrial dysfunction.
    Keywords:  MSC-EVs; MSC-base therapy; exosomes; mitochondrial diseases; mitochondrial transfer; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms27041981
  62. Nat Cell Biol. 2026 Feb 27.
    An extracellular vesicle-mediated mitochondrial transfer network critical for testosterone synthesis.
    Kai Xia, Suyuan Zhang, Hao Peng, Hainan Chen, Cuifeng Yang, Jiajie Yu, Peng Luo, Qiying Lu, Hong Chen, Li Huang, Yifei Xiong, Lerong Zhao, Lei Jia, Lu Li, Yuan Qiu, Yan Guo, Congyuan Liu, Hang Fan, Ziran Dai, Guihua Liu, Qiong Ke, Tao Wang, Weiqiang Li, Lili Chen, Chunhua Deng, Haipeng Xiao, Andy Peng Xiang.
      Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles containing defective mitochondria, which are eliminated by CD206hi tMacs in a TREM2-dependent process. Deletion of Trem2 in tMacs disrupts this transfer, leading to impaired testosterone synthesis. Conversely, LCs acquire extracellular vesicles containing functional mitochondria from MHCIIhi tMacs through ITGβ1-VCAM1 interactions. Loss of Vcam1 in LCs hinders this mitochondrial transfer, thereby compromising testosterone production. Together, our findings reveal an unrecognized mitochondrial transfer network between LCs and tMacs that safeguards LC homeostasis and testosterone production, offering valuable insights into intercellular communication mechanisms that maintain tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41556-026-01896-x
  63. Toxins (Basel). 2026 Feb 19. pii: 103. [Epub ahead of print]18(2):
    Cell-Penetrating Botulinum Neurotoxin Type A Proteins Alleviate Skeletal Muscle Hypertrophy with Associated Alterations of Mitochondrial Homeostasis.
    Lu Li, Xuan Wei, Liling Jiang, Zhen Gao, Jia Liu.
      Skeletal muscle is the largest metabolic demanding organ in human body. Alterations of skeletal muscle in shape and size significantly affect its biological functions. Botulinum neurotoxin type A1 (BoNT/A1) has been successfully used in clinics to treat masseter, trapezius and gastrocnemius hypertrophy. Here, we used a healthy rat-based skeletal muscle hypertrophy model to evaluate the muscle-reducing activity of recombinant BoNT/A1 (rBoNT/A1) with genetically fused cell-penetrating peptides (CPPs), which was previously reported to increase the cellular uptake of BoNT/A1. Analyses of treated muscle sections using hematoxylin-eosin and immunofluorescence staining showed that both wild-type rBoNT/A1 without modification (WT-rBoNT/A1) and rBoNT/A1 with CPP fusion (CPP-rBoNT/A1) could induce myocomma atrophy and altered gastrocnemius muscle fiber proportions as a result of denervation and reinnervation. Importantly, rBoNT/A1 with the fusion of a specific CPP, zinc finger protein (ZFP), resulted in the highest degree of muscle atrophy and greatest increase in the ratio of type I muscle fibers over type II fibers. An examination of gastrocnemius muscle cells at the subcellular levels using TEM staining revealed swelled mitochondria and diminished mitochondrial crista upon rBoNT/A1 administration. Transcriptomic RNA sequencing (RNA-Seq) analysis followed by RT-qPCR validation showed that rBoNT/A1 treatment also caused changes in mitochondrial biogenesis and mitophagy. Collectively, our results demonstrated that rBoNT/A1 proteins could alleviate skeletal muscle hypertrophy, with associated alterations of mitochondrial homeostasis.
    Keywords:  botulinum neurotoxin type A; cell-penetrating peptides; hypertrophy; mitochondrial homeostasis; skeletal muscle
    DOI:  https://doi.org/10.3390/toxins18020103
  64. Res Sq. 2026 Feb 16. pii: rs.3.rs-8780765. [Epub ahead of print]
    Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
    Zoya R Bangash, Hiroyoshi Matsui, Bedri Ranxhi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou.
      Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression attenuated α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30 , Uch-L5R , RNF185 , and the mitochondrial ornithine carrier SLC25A15 . At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions and reduced mitochondrial accumulation of α-Syn. Our findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and altered mitochondrial-associated proteostasis during α-Syn expression.
    DOI:  https://doi.org/10.21203/rs.3.rs-8780765/v1
  65. J Am Soc Nephrol. 2026 Feb 24.
    Discoidin Domain Receptor 1 Translocation to the Mitochondria Promotes Oxidative Stress and Apoptosis in Acute Kidney Injury.
    Gema Bolas, Corina M Borza, Fabian Bock, Xinyu Dong, Oscar Hanson, Manuel Chiusa, Shirong Cao, Ming-Tsun Tsai, Agnes B Fogo, Ming-Zhi Zhang, Raymond C Harris, Craig R Brooks, Roy Zent, Ambra Pozzi.
       BACKGROUND: Mitochondrial damage with overproduction of mitochondrial reactive oxygen species (mtROS) and apoptosis is a hallmark of acute kidney injury (AKI). Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine kinase that contributes to AKI. Mass spectrometry analysis of DDR1 interacting proteins identified several mitochondrial proteins, suggesting that DDR1 associated with mitochondria. Thus, we analyzed whether DDR1 translocated to mitochondria and promoted mitochondrial dysfunction following AKI.
    METHODS: We analyzed DDR1 localization in kidneys of patients with AKI and mice following ischemia reperfusion-induced AKI. To determine whether mitochondrial DDR1 (mitDDR1) regulated mitochondrial functions, we generated kidney cells expressing wild-type or a kinase dead DDR1. Then, we investigated the location of wild-type or mutated DDR1 upon collagen stimulation; the steps involved in DDR1 mitochondrial translocation; and the contribution of mitDDR1 in regulating mtROS production and apoptosis.
    RESULTS: mitDDR1 was detected in injured human and mice kidneys and collagen-activated DDR1 translocated to the mitochondria where it increased mtROS production and tubule cell apoptosis. Collagen-activated DDR1 translocated to the outer membrane of mitochondria through its association with the chaperone mtHsp60 and induced oxidative stress and apoptosis by promoting tyrosine phosphorylation of p66Shc, a regulator of the cellular redox state and apoptosis. Moreover, cells expressing a kinase dead DDR1, treated with a DDR1 inhibitor, or expressing p66Shc mutated in the DDR1-targeted phosphorylation sites had reduced mtROS and apoptosis.
    CONCLUSIONS: We describe a novel non-canonical pathway whereby activated DDR1 translocates to the mitochondria to promote oxidative stress and cell apoptosis.
    DOI:  https://doi.org/10.1681/ASN.0000001045
  66. Antioxidants (Basel). 2026 Feb 18. pii: 259. [Epub ahead of print]15(2):
    Targeted Reduction of Excessive Mitochondrial Superoxide by Mitoquinone Rescues Cognitive Impairment Without Affecting Spontaneous Recurrent Seizures in a Mouse Model of Temporal Lobe Epilepsy.
    Segewkal H Heruye, Stephanie A Matthews, Shruthi H Iyer, Malavika Deodhar, Ted J Warren, Peter J West, Kristina A Simeone, Timothy A Simeone.
      Cognitive impairment is a major comorbidity in temporal lobe epilepsy (TLE), yet its underlying pathophysiology remains poorly understood and current therapies provide minimal benefit. While oxidative stress has traditionally been viewed as a precursor to cell death-mediated cognitive decline, cell death is absent in many patients and preclinical models with memory impairment. Here, we tested whether excessive mitochondrial reactive oxygen species (ROS) actively contribute to memory impairment through mechanisms distinct from cell death. Using Kv1.1 knockout (KO) mice, a TLE model with mitochondrial respiratory chain complex I (MRCI) impairment, we found elevated hippocampal mitochondrial superoxide, impaired recognition memory, deficits in synaptic plasticity, and abnormal sharp wave-ripple oscillations. Applying the MRCI inhibitor rotenone to wild-type hippocampal slices caused increased superoxide and mirrored electrophysiology deficits. Both acute and sub-chronic treatment with the mitochondria-targeted antioxidant mitoquinone (MitoQ) reduced superoxide levels, rescued synaptic plasticity, restored network activity, and normalized memory performance in KO mice-without altering seizure frequency, severity, or neuronal excitability. Our results identify mitochondrial superoxide as a reversible driver of hippocampal dysfunction in epilepsy and demonstrate that mitochondria-targeted antioxidant therapy can restore cognition despite persistent seizures. This study provides proof-of-concept for novel treatments improving cognitive comorbidities in TLE beyond seizure control.
    Keywords:  Kv.1.1; MitoQ; long-term potentiation; memory; mitochondria; seizure
    DOI:  https://doi.org/10.3390/antiox15020259
  67. Nat Metab. 2026 Feb 23.
    Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
    Maryam Ahmadian, A Melisa Aksu, Preetveer Dhillon, Zane J Zerbel, Yosip Kelemen, Oluwafemi Gbayisomore, Nicolás Gómez-Banoy, Serena J Chen, Shannon M Reilly.
      Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
    DOI:  https://doi.org/10.1038/s42255-026-01467-2
  68. Cell. 2026 Feb 25. pii: S0092-8674(26)00109-1. [Epub ahead of print]
    Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease.
    Ankur Garg, Skyler Y Blume, Helen Huynh, Alec M Barrios, Onurkan O Karabulut, Qian Zhao, Ayush D Midha, Adam W Turner, B Vittorio Resnick, Xuewen Chen, Ayushi Agrawal, JaeYeon Kim, Liuji Chen, Qitao Ran, Alison M Ryan, Reece C Larson, Mina Negahban, Sophia C K Nelson, Andrew C Yang, Michela Traglia, Reuben Thomas, Ramon Sun, Mercedes Paredes, M Ryan Corces, Hening Lin, Isha H Jain.
      Vitamins are essential metabolites that must be obtained from external sources. In modern times, they have become widely available, leading to their ad hoc consumption. We developed a nutritional genomics framework to systematically identify monogenic diseases responsive to micronutrient modulation. Genome-wide CRISPR screens under varying vitamin B2 and B3 levels revealed dozens of candidate disease genes amenable to rescue by individual vitamins. In the vitamin B3 screen, NAD(P)HX dehydratase (NAXD) was the top hit; this enzyme repairs an aberrant, hydrated form of NADH (6-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide [NADHX]), and its loss causes severe neurodevelopmental disease. In our Naxd knockout (KO) mouse, we observed NADHX accumulation, NAD+ depletion, and impaired serine biosynthesis in neonatal KO brains. Spatial metabolomics, single-nuclei RNA sequencing (snRNA-seq), and histology pinpointed cortical and brain endothelial cell vulnerability. Low-vitamin B3 diets accelerated pathology, whereas vitamin B3 supplementation extended lifespan by more than 40-fold. These findings establish a nutritional genomics framework and demonstrate the therapeutic potential of precision vitamin interventions.
    Keywords:  CRISPR screens; NAD(H); NADH(X); NAXD; genomics; inborn errors of metabolism; metabolism; niacin; vitamin B3; vitamins
    DOI:  https://doi.org/10.1016/j.cell.2026.01.022
  69. Mol Cell. 2026 Feb 25. pii: S1097-2765(26)00096-1. [Epub ahead of print]
    MEDAG functions as an A-kinase-anchoring protein in adipocytes.
    Fen Long, Adhideb Ghosh, Tianyu Xu, Lianggong Ding, Chunyan Wu, Radhika Khandelwal, Falko Noé, Wenfei Sun, Hua Dong, Tongtong Wang, Anne Hoffmann, Vincent Gardeux, Bart Deplancke, Laith Abu-Nawwas, Patrik Stefanicka, Lukas Varga, Jonatan R Ruiz, Matthias Blüher, Miroslav Balaz, Anand Kumar Sharma, Christian Wolfrum.
      Induction of catabolic adipocyte activity independent of mitochondrial uncoupling to induce energy expenditure has received increasing attention. In this study, we identified mesenteric estrogen-dependent adipogenesis gene (MEDAG), a poorly studied gene, as a promising therapeutic target for enhancing energy expenditure in adipocytes. We demonstrated that adipose MEDAG expression positively correlates with obesity and metabolic dysfunction in humans. Consistently, adipocyte-specific ablation of Medag in mice leads to increased energy expenditure, offering protection from diet-induced obesity. Mechanistically, we show that MEDAG functions as an A-kinase-anchoring protein (AKAP), which can directly regulate protein kinase A (PKA) activity through a negative feedback loop, involving direct interaction with PKA leading to MEDAG phosphorylation and consequent feedback fine-tuning of PKA activity. Specifically, the direct interaction of MEDAG with the PKA-RIIβ subunit regulates the stability of PKA-RIIβ to prevent PKA hyperactivation. These findings position MEDAG as a target for adipose energy expenditure and uncover its AKAP activity.
    Keywords:  AKAP; MEDAG; PKA; cAMP-PKA signaling; catabolic adipocytes; energy expenditure; glucose uptake and utilization; lipolysis; metabolic diseases; obesity
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.001
  70. J Neurol Sci. 2026 Feb 06. pii: S0022-510X(26)00079-1. [Epub ahead of print]483 125797
    Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.
    Jiongming Bai, Xinyuan Pang, Hongfen Wang, Ying Zhang, Yahui Zhu, Jiarui Zhao, Yifan Li, Mao Li, Xusheng Huang.
       BACKGROUND: Recent studies increasingly implicate mitochondrial DNA (mtDNA) alterations in neurodegenerative diseases, but findings across studies remain inconsistent. We aimed to characterize mtDNA indices across whole blood, plasma and CSF compartments and evaluate their clinical relevance.
    METHODS: We enrolled two study cohorts: (1) a whole blood cohort of 102 ALS patients; and (2) a plasma and cerebrospinal fluid (CSF) cohort including 132 ALS patients and 62 non-neurodegenerative controls. The D-loop and COX3 regions were selected as representative mtDNA fragments, while B2M was used as a nuclear reference. Quantification was performed using SYBR Green-based quantitative PCR.
    RESULTS: In whole blood, higher D-loop/COX3 ratios were associated with better functional status and longer survival. In the cell-free compartments, CSF ccf-mtDNA markers (D-loop and COX3) were significantly higher in ALS than in controls, whereas plasma abundance showed no significant group difference. Within ALS, higher ccf-mtDNA indices tended to correlate with greater disease severity and more rapid functional decline. In addition, higher plasma and CSF D-loop/COX3 ratios showed marginal trends toward association with faster disease progression.
    CONCLUSIONS: This study systematically characterizes mtDNA alterations in whole blood, plasma and CSF samples of ALS, offering new insights into mtDNA involvement in neurodegeneration.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Circulating cell-free mitochondrial DNA (ccf-mtDNA); Mitochondrial dysfunction; mtDNA copy number
    DOI:  https://doi.org/10.1016/j.jns.2026.125797
  71. NAR Mol Med. 2026 Jan;3(1): ugag012
    Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation.
    Rodolphe Suspène, Béibhinn O'Hora, Constance de Maere d'Aertrycke, Lydie Couturier, Théo Defresne, Pierre Khalfi, XiongXiong Li, Jean-Pierre Vartanian.
      Hypoxia is a hallmark of the tumour microenvironment, driving metabolic reprogramming, immune activation, and genome instability. Here, we showed that cobalt chloride (CoCl2), a hypoxia-mimicking agent, potently induces the expression of the DNA cytidine deaminase APOBEC3A (A3A) in THP-1, a human monocytic cell line. A3A upregulation occurred in a dose-dependent manner, independently of type I interferon signalling, and was accompanied by increased double-strand DNA breaks. Transcriptomic profiling revealed broad hypoxia-driven reprogramming, characterized by activation of the stress response and downregulation of mitochondrial signalling pathways. Mechanistically, cobalt chloride induced mitochondrial dysfunction, metabolic reprogramming, and cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA was transcribed by RNA polymerase III into immunostimulatory RNA, which activated the RIG-I/TRAF6/NF-κB signalling cascade to drive A3A expression. Inhibition or knockdown of RNA polymerase III markedly reduced both A3A levels and DNA damage, highlighting the central role of this pathway. All together, our findings reveal a novel interferon-independent signalling route through which hypoxia-induced mitochondrial stress activates A3A, directly linking metabolic dysfunction to genome instability. This mechanism involves mitochondrial perturbation as a key driver of APOBEC3-mediated mutagenesis in hypoxic tumours and other diseases associated with mitochondrial stress.
    DOI:  https://doi.org/10.1093/narmme/ugag012
  72. Ann Pediatr Cardiol. 2025 Sep-Oct;18(5):18(5): 517-520
    Risk of sudden cardiac death due to inorganic pyrophosphate A2 deficiency in a Pakistani infant: Diagnostic and management challenges in low-resource settings.
    Fiza Adnan Khan, Salman Kirmani, Muhammad Kamran Younis Memon, Saleem Akhtar.
      Inorganic pyrophosphate A2 (PPA2) deficiency is a rare autosomal recessive mitochondrial disorder associated with cardiomyopathy and sudden cardiac death (SCD). Limited cases have been reported globally, with none documented in Pakistan. This case reports the first genetically confirmed case of PPA2 deficiency in an asymptomatic, 13-month-old Pakistani male. Following the sudden death of his sibling, a cardiac and genetic evaluation was performed. Whole-exome sequencing revealed a homozygous mutation in the patient's PPA2 gene, with parents being carriers. A multidisciplinary management approach was adopted, focusing on lifestyle modification and risk mitigation. Diagnostic challenges and the importance of genetic evaluation in families with unexplained SCD, particularly in regions of high levels of consanguinity, are highlighted. Individuals with a family history of SCD should be screened for any genetic predisposition to cardiac disease. Strengthening investigative services and adopting a multidisciplinary approach is essential for early diagnosis and management.
    Keywords:  Cardiac genetics; inorganic pyrophosphate A2 deficiency; mitochondrial disease; pediatric cardiology; sudden cardiac death
    DOI:  https://doi.org/10.4103/apc.apc_152_25
  73. Cell. 2026 Feb 25. pii: S0092-8674(26)00104-2. [Epub ahead of print]
    Large-scale proteomics across neurological disorders uncovers biomarker panel and targets in multiple sclerosis.
    Jakob Maximilian Bader, Christine Makarov, Sabrina Richter, Maximilian Thomas Strauss, Friederike Held, Maria Wahle, Michael Baggio Lorenz, Lara Pöschl, Patricia Skowronek, Marvin Thielert, Achim Berthele, Wen-Feng Zeng, Constantin Ammar, Isabell Bludau, Benjamin Schubert, Fabian J Theis, Christiane Gasperi, Bernhard Hemmer, Matthias Mann.
      Cerebrospinal fluid (CSF) is central to neurological diagnostics, yet biomarkers are lacking for many clinical needs. To enable its large-scale proteomic characterization, we developed a high-throughput mass spectrometry workflow quantifying approximately 1,500 proteins per CSF sample across 5,000 individuals, covering a spectrum of neurological disorders. This revealed proteomic alterations associated with blood-CSF barrier impairment, age, and sex, enabling deconvolution of shared and disease-specific signatures. We then focused on multiple sclerosis (MS), using an improved analytical technology that quantified 2,100 proteins per sample. From these data, we derived a 22-protein panel that distinguished MS from related inflammatory diseases and outperformed established markers in challenging cases. A targeted mass spectrometry assay using isotope-labeled standards validated this panel in an independent cohort, offering a clinically compatible format. Additionally, we highlight proteins of therapeutic interest and demonstrate proteome-based staging of individuals along the relapsing-progressive MS spectrum, which correlates with clinical outcomes.
    Keywords:  biomarkers; blood CSF barrier impairment; cerebrospinal fluid; multiple sclerosis; oligoclonal bands; proteomics; targeted mass spectrometry
    DOI:  https://doi.org/10.1016/j.cell.2026.01.017
  74. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2535701123
    When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase.
    Léa Herpe, Mélanie Aminot, Nicolas Pichaud.
      Complex I is known as the primary entry point for electrons within the mitochondrial electron transport system (ETS). However, the glycerol-3-phosphate (G3P) shuttle, composed of cytosolic and mitochondrial G3P dehydrogenase (cG3PDH and mtG3PDH, respectively), transfer reducing equivalents from the cytosol to the mitochondrial matrix. The mtG3PDH feeds electrons into the ETS via FADH2 oxidation, but with theoretically lower energy conversion efficiency than complex I. It is thus believed to be an "alternative" pathway, only supporting mitochondrial respiration when complex I fails. mtG3PDH also plays an important role in reactive oxygen species (ROS) production. To investigate the role of this understudied protein in mitochondrial bioenergetics and redox homeostasis, we generated Drosophila melanogaster mutant lines for mtG3PDH (GPO1) using a CRISPR/Cas9-based approach and determined several physiological and metabolic parameters. A drastically higher mortality rate was observed among the GPO1 flies, as well as a lethargic behavior characterized by an inability to climb. These results are in accordance with an impaired mitochondrial efficiency (ATP/O) mainly due to decreased ATP production (~60% decrease) and O2 consumption (~33% decrease), rather than elevated ROS. In fact, GPO1 flies produced ~70% less ROS than controls, likely due to the reduced direct and reverse electron transfer-related ROS production from mtG3PDH. These results support an essential role of mtG3PDH in mitochondrial bioenergetic, challenging its alternative aspect, and confirming its importance in mitochondrial redox homeostasis.
    Keywords:  Drosophila; comparative physiology; glycerol-3-phosphate; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1073/pnas.2535701123
  75. Front Pediatr. 2026 ;14 1766864
    Progressive encephalopathy associated with novel compound heterozygous NAXE mutations in a Chinese patient: case report and literature review.
    Yanjie Zhu, Peifeng He, Rong Luo, Xiaolu Chen.
       Background: NAD(P)HX epimerase (NAXE) deficiency is a rare, often fatal, autosomal recessive neurometabolic disorder of early childhood, characterized by acute neurological regression triggered by febrile illness. Here, we report a case with compound heterozygous NAXE mutations (c.733A > C and c.389A > C) associated with a milder phenotype, thereby expanding the known disease spectrum.
    Case report: A previously healthy 19-month-old girl presented with acute neurological regression after a high-grade fever, losing motor skills and exhibiting lethargy. Initial investigations showed leukocytosis, elevated C-reactive protein, and MRI findings of sulcal/cisternal widening and spinal cord signal changes. Given the unexplained encephalopathy, whole-exome sequencing was performed, which identified compound heterozygous NAXE mutations, confirming the diagnosis. Management included intravenous immunoglobulin, corticosteroids, and NAD + precursors. Neurological improvement was observed during the hospital course, and near-complete motor recovery was achieved by the 11-month follow-up.
    Conclusion: This case underscores the need to consider NAXE-related encephalopathy in children with fever-induced acute neurological decline. The discovery of a novel compound heterozygous variant combination [c.389A > C [p.His130Pro] and c.733A > C [p.Lys245Gln]] defines a milder phenotypic spectrum and mandates early genetic testing for timely diagnosis and prognostic insight. Importantly, given the single-case nature of this observation, conclusion regarding treatment efficacy remains hypothesis-generating and require validation in additional cases.
    Keywords:  NAD(P)HX epimerase gene; NAXE gene; case report; neurometabolic disorder; progressive encephalopathy
    DOI:  https://doi.org/10.3389/fped.2026.1766864
  76. Expert Rev Cardiovasc Ther. 2026 Feb 24.
    Strategic targeting of mitochondria in ischemic heart disease: mechanisms and emerging therapies.
    Gino A Kurian, Eren Rose Gino.
       INTRODUCTION: Ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Mitochondrial dysfunction is central to ischemia - reperfusion injury, contributing to bioenergetic failure, oxidative stress, calcium overload, and impaired adaptive responses, making mitochondria an important therapeutic target.
    AREAS COVERED: This review integrates mechanistic and translational evidence linking mitochondrial dysfunction, structural injury, and adaptive-response failure in IHD. Key pathways discussed include reverse electron transport - driven reactive oxygen species generation, mitochondrial permeability transition pore activation, disrupted fusion - fission dynamics, mitophagy imbalance, and proteostasis collapse. Emerging therapeutic strategies such as mitochondria-targeted antioxidants, cardiolipin-stabilizing peptides, metabolic modulators, mitochondrial transplantation, and genome-directed approaches are evaluated alongside diagnostic innovations including circulating mitochondrial DNA, mitomiRs, and molecular imaging. A structured literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published between January 2000 and March 2025.
    EXPERT OPINION: Precision targeting of mitochondrial injury and adaptive failure offers stage-specific therapeutic opportunities in IHD; however, successful translation requires biomarker-guided stratification, optimized delivery systems, and temporally aligned clinical trial design.
    Keywords:  Ischemic heart disease; cardiolipin; ischemia–reperfusion injury; mitochondrial biomarkers; mitochondrial dysfunction; mitochondrial permeability transition pore; mitochondrial quality control; precision cardiology
    DOI:  https://doi.org/10.1080/14779072.2026.2637751
  77. Nature. 2026 Feb 23.
    First-of-a-kind stem-cell therapies set for approval in Japan.
    Asher Mullard.
      
    Keywords:  Cell biology; Diseases; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-00585-x
  78. Parkinsonism Relat Disord. 2026 Feb 20. pii: S1353-8020(26)00076-3. [Epub ahead of print]145 108250
    Mitochondrial insertions/deletions (INDELs) burden in Parkinson's disease: an analysis from a Brazilian cohort.
    Gustavo Barra-Matos, Felipe Gouvea de Souza, Caio Santos Silva, Matheus Epifane-de-Assunção, Marcella Vitória Belém Souza, Letícia Cota Cavaleiro de Macêdo, Tatiane Piedade de Souza, Dafne Dalledone Moura, Giovanna C Cavalcante, Ândrea Ribeiro-Dos-Santos, Bruno Lopes Santos-Lobato, Gilderlanio Santana de Araújo.
       INTRODUCTION: Mitochondrial DNA (mtDNA) alterations are increasingly associated with Parkinson's disease (PD), particularly due to their role in oxidative stress. However, the contribution of mtDNA insertions and deletions (INDELs) to PD remains poorly understood, particularly in genetically admixed populations such as Brazilians.
    METHODS: To explore this, we sequenced the complete mtDNA from blood samples of 179 admixed individuals from the Brazilian Amazon (104 people with PD and 75 controls). Data processing included FastQC, MultiQC, FastP, BWA, and mtDNA-Server 2.
    RESULTS: We identified a significantly higher burden of mtDNA INDELs in PD compared with controls in Complex I genes (OR = 9.23; 95% CI: 2.22-63.55; FDR = 0.044). Differences in heteroplasmy levels were also observed in the ATP6, ND4, and ND5 genes. Importantly, we discovered seven new PD-associated INDELs (m.13763_13763delinsCCA, m.13885_13885delinsCTG, m.13888_13890delinsT, m.13767_13769delinsC, m.13810_13812delinsG, m.13813_13813delinsGCA, and m.13764_13764delinsCAT) that are particularly more frequent among individuals harboring uniparental lineages of Native American origin.
    CONCLUSION: Our findings report novel mtDNA INDELs, particularly in Complex I, which may contribute to PD susceptibility and highlight the importance of investigating mitochondrial genomic variation in underrepresented populations. These associations should be interpreted as preliminary, and further longitudinal studies with independent cohorts are required to confirm these observations.
    Keywords:  Admixed populations; INDELs; Mitogenome; Parkinson's disease; Underrepresented populations
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.108250
  79. Int J Mol Sci. 2026 Feb 17. pii: 1908. [Epub ahead of print]27(4):
    Epigenetic Clocks, Resilience, and Multi-Omics Ageing: A Review and the EpiAge-R Conceptual Framework.
    Hidekazu Yamada.
      Epigenetic clocks have successfully estimated biological age by identifying CpG sites whose DNA methylation levels correlate with chronological age. However, these statistical models provide limited mechanistic insight into the biological underpinnings of ageing. While they capture the "pace" of ageing, they fail to quantify the "resilience" of biological systems-the capacity to recover, reorganize, and maintain homeostasis under stress. To overcome this limitation, we introduce EpiAge-R (Epigenetic Age with Resilience), a mechanistic framework that shifts the focus from passive correlation to active recovery potential. The EpiAge-R framework integrates multilayered biological information-including long-read methylation sequencing, chromatin context, histone modification balance, 3D genome topology, and mitochondrial dynamics-into a unified Resilience Index. By distinguishing between degenerative methylation drift (damage) and adaptive repair processes (resilience), EpiAge-R aligns with nonlinear multi-omics ageing trajectories. This framework provides a quantitative foundation for next-generation biomarkers and precision longevity interventions, aiming to define optimal health rather than statistical normality.
    Keywords:  ageing biomarkers; aging clocks; biological resilience; epigenetic clocks; flourishing; health capital; multi-omics integration; nanopore sequencing
    DOI:  https://doi.org/10.3390/ijms27041908
  80. Lancet Neurol. 2026 Mar;pii: S1474-4422(26)00038-4. [Epub ahead of print]25(3): 215-217
    Broad lessons from negative trials in rare diseases.
    Laurent Servais, Maryam Oskoui.
      
    DOI:  https://doi.org/10.1016/S1474-4422(26)00038-4
  81. Free Radic Biol Med. 2026 Feb 19. pii: S0891-5849(26)00147-4. [Epub ahead of print]248 210-221
    Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.
    Ryan J Mailloux.
      Alpha-ketoglutarate dehydrogenase (KGDH; EC 1.2.4.2) catalyzes the fourth step of the tricarboxylic acid (TCA) cycle and links carbohydrate, fatty acid and amino acid metabolism to the aerobic production of ATP. KGDH is classically viewed as indispensable to energy metabolism and strictly located to mitochondria. Therefore, it is generally thought that the loss of its activity has catastrophic consequences for mammalian cells. However, recent advances in molecular biology and redox biology tools coupled with the implementation of new genetically modified mouse lines and cultured cells knocked down for components of KGDH have revealed it is a multifunctional cellular enzyme that localizes to the mitochondria and nucleus where it uses superoxide (O2•-)/hydrogen peroxide (H2O2) and metabolites related to its catalysis (e.g., alpha-ketoglutarate (KG), succinyl-CoA, succinate) to control cell fate decisions. In addition, it has been revealed that over-stimulation of KGDH causes severe oxidative stress through the hyper-production of O2•-/H2O2 and disturbs cell signals and epigenome regulation, which has been linked to cancer cell transformation, metabolic diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), and inflammation. Furthermore, inhibition of KGDH with competitive inhibitors, redox modifications, or shRNAs has shown that the targeted disruption of the enzyme can alleviate these diseases. The aim of this review is to update the literature on KGDH. It is not just a TCA cycle enzyme anymore.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.050
  82. JCI Insight. 2026 Feb 26. pii: e200105. [Epub ahead of print]
    TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.
    Yan Tang, Stanislovas S Jankauskas, Li Liu, Xujun Wang, Alus M Xiaoli, Fajun Yang, Gaetano Santulli, Daorong Feng, Jeffrey E Pessin.
      Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using whole-body and cardiomyocyte-specific TIGAR knockout mice, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin-dependent, as double knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increased Parkin expression in multiple cell lines. Our findings reveiled how early cardiac metabolism programmed lifelong cardiac function through epigenetic mechanisms, and identifyied developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.
    Keywords:  Cardiology; Cell biology; Diabetes; Heart failure; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.200105
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