bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–03–08
sixty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
  2. Functions of J-domain proteins in mitochondrial protein biogenesis.
  3. A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.
  4. Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
  5. Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
  6. Mitochondrial complex assembly in epilepsy of primary mitochondrial disease origin.
  7. Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
  8. Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
  9. Identification of the Subcompartment-Specific Mitochondrial Proteome by APEX2 Proximity Labeling in Saccharomyces cerevisiae.
  10. Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
  11. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  12. Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
  13. Lipid droplets meet mitochondria at the MIM protein insertase.
  14. Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
  15. STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
  16. Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
  17. Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
  18. Expanding the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
  19. Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
  20. Function and regulation of the mitochondrial stress response.
  21. Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
  22. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  23. MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
  24. Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
  25. Case Report: Pediatric nephrology-expanding the genotypic spectrum of COQ2-related nephropathy with a novel splice site variant in CoQ10-responsive SRNS.
  26. β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.
  27. Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.
  28. Optimized Mechanical Isolation of Mitochondria From Saccharomyces cerevisiae Preserving Atg32 for Quantitative Analysis.
  29. Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
  30. Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.
  31. Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
  32. Abnormal Newborn Screening Resembling Carnitine Palmitoyltransferase 1a Deficiency in Three Patients With COASY Protein Associated Neurodegeneration.
  33. Unconventional model organisms bend our view on mitochondrial cristae.
  34. Cardiac mitochondrial adaptations supporting high-altitude tolerance in deer mice.
  35. WASHC3 knockout disrupts mitochondrial protein homeostasis and energy metabolism in cardiomyocytes.
  36. Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
  37. CHCHD2 links mitochondrial dysfunction and α-synuclein misfolding in Parkinson's disease.
  38. Integrative multi-omics and machine learning identify mitochondrial biomarkers for pathogen-specific sepsis stratification and translational prioritization.
  39. Photoreceptor deletion of pyruvate dehydrogenase E1 subunit α1 induces retinal degeneration and reprograms retinal metabolism.
  40. Imaging and quantifying organelle contact sites using a reversible splitFAST complementation system.
  41. In vitro and in vivo rescue of dopaminergic neurons in Parkinson's disease models after Parkin gene therapy.
  42. LYPLAL1 Rare Loss-of-Function Variants in Humans and Deletion in Human Hepatoma Cells Protect Against MASLD.
  43. 3-Methyl Glutaconic Aciduria and Elevated Plasma Growth Differentiation Factor 15 Level in an Adult with Monoallelic SPG7 Pathogenic Variant.
  44. Mitochondrial transfer and transplantation in the immune cells: Mechanistic foundations, medical applications, and future prospects.
  45. Immune regulators PALS-25 and PALS-22 localize to mitochondria and regulate mitochondrial fragmentation in C. elegans.
  46. Defects in auxiliary fuel oxidation and mitochondrial pyruvate transport mark transition to overt heart failure in Tgαq*44 mice.
  47. Coenzyme Q10 Supplementation in a Child with Biallelic COQ8A Variants: A Case Report.
  48. Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.
  49. Deciphering the role of mitochondrial cytochrome C oxidase subunit 4 in cardiac health and disease.
  50. Inside Mexico's stem-cell industry.
  51. High-frequency biparental inheritance of plant mitochondria upon chilling stress and loss of a genome-degrading nuclease.
  52. A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.
  53. How to discover novel genes that cause Parkinson's disease.
  54. PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
  55. Congenital skeletal muscle myopathy due to the recently described digenic inheritance of TTN and SRPK3 genetic variants: a case study.
  56. Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.
  57. From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases.
  58. Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
  59. Role of LRRK2 in physiological activities, diseases, and therapy.
  60. ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
  61. AI can write genomes - how long until it creates synthetic life?
  62. Mitochondrial Pyruvate Metabolism Controls Alveolar Stem Cell Fate and Inflammatory Balance.
  1. Autophagy Rep. 2026 ;5(1): 2635914
    Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.
      Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.
    Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2635914
  2. Protein Sci. 2026 Apr;35(4): e70516
    Functions of J-domain proteins in mitochondrial protein biogenesis.
    Vitasta Tiku, Georg Bossenz, Janine Kirstein, Thomas Becker.
      Mitochondrial biogenesis and functions depend on the import and assembly of more than 1000 proteins that are made as precursors on cytosolic ribosomes. The majority of these precursor proteins are transported from the ribosome to the translocase of the outer membrane (TOM complex), which constitutes the main entry site for mitochondrial precursors. The transient localization of mitochondrial precursor proteins in the cytosol represents a major burden for cellular proteostasis since these proteins can aggregate and accumulate in different cellular compartments, causing proteotoxic stress. Inside mitochondria, protein translocases sort the precursor proteins into the mitochondrial subcompartments-outer and inner membrane, the intermembrane space and matrix. The imported proteins have to be folded and efficiently assembled into functional protein complexes. Molecular chaperones such as Hsp70 monitor these processes to minimize proteotoxic stress. J-domain proteins stimulate the ATPase activity of Hsp70 and recruit the chaperones to their clients in the biogenesis of mitochondrial proteins. They ensure protein targeting to mitochondria, drive protein import into mitochondria, as well as folding and assembly of mitochondrial proteins. Here, we summarize the emerging view of how J-domain proteins guide mitochondrial precursor proteins from their synthesis in the cytosol until their folding into a mature protein and assembly into protein complexes in mitochondria.
    Keywords:  ER‐SURF; Hsp70; J‐domain protein; TOM complex; mitochondria; protein targeting
    DOI:  https://doi.org/10.1002/pro.70516
  3. Mol Neurobiol. 2026 Mar 04. pii: 485. [Epub ahead of print]63(1):
    A Heteroplasmic MT-CO2 m.8024G > A Variant Is Associated with Mitochondrial Bioenergetic Deficiency and Optic Atrophy.
    Jing Wu, Cunhui Pan, Ruowei Zhu, Xi Huang, Xiaoting Lou, Li Yang.
      Leber's hereditary optic neuropathy (LHON) is a hereditary neurodegenerative disorder caused by pathogenic mitochondrial DNA (mtDNA) variants. While MT-CO2 defects are implicated in neurodegeneration, their direct association with optic atrophy has not been reported. We identify a heteroplasmic MT-CO2 variant, m.8024G > A (p.Glu147Lys), in a patient with progressive optic atrophy and explore its potential association with mitochondrial dysfunction. A 13-year-old male with progressive unilateral-then-bilateral vision loss underwent comprehensive ophthalmic/neurological evaluation, trio whole-exome sequencing, and mtDNA sequencing. The pathogenicity of the identified variant was assessed in patient-derived fibroblasts using mitochondrial stress tests, ATP/ROS assays, enzymatic profiling, BN-PAGE, mitochondrial membrane potential, mtDNA copy number, ultrastructural microscopy, and immunoblotting. Functional analyses revealed that this variant, which reduces the expression of mtDNA-encoded electron transport chain (ETC) subunits and induces severe Complex IV deficiency, reduced cellular oxygen consumption rate (OCR), impaired ATP synthesis, decreased mtDNA copy number, and elevated reactive oxygen species (ROS) production. Concurrently, mutant cells exhibited enhanced mitophagy with preserved flux, a compensatory response to persistent mitochondrial damage. Unlike canonical optic neuropathy associated with homoplasmic mtDNA mutations, this heteroplasmic variant is linked to mitochondrial dysfunction potentially related to tissue-specific heteroplasmy and altered mitophagic responses. We report a heteroplasmic m.8024G > A mutation in MT-CO2 associated with childhood-onset isolated optic atrophy. Functional analyses in patient fibroblasts show that this variant is associated with MT-CO2 structural perturbation, Complex IV dysfunction, altered mitophagy, and mitochondrial energy failure-supporting its potential pathogenic relevance. This study expands the genotypic and phenotypic spectrum of mitochondrial optic neuropathies and provides mechanistic insights into the pathogenesis of heteroplasmic mtDNA variant-related disease.
    Keywords:  MT-CO2; Mitochondrial complex IV; Optic atrophy; Optic neuropathy
    DOI:  https://doi.org/10.1007/s12035-026-05774-3
  4. Genet Med. 2026 Jan;pii: S1098-3600(25)00267-9. [Epub ahead of print]28(1): 101620
    Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
    Thiloka Ratnaike, Siddharth Ramanan, Nour Elkhateeb, Ramya Narayanan, Jenny Yang, Eszter Sara Arany, Manya Mirchandani, Rachael Piper, Katherine Schon, M Eren Kule, Christopher Gilmartin, Angela Lochmüller, Emogene Shaw, Rita Horváth, Patrick F Chinnery.
       PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
    METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
    RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
    CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.
    Keywords:  HPO; Mitochondrial disease; Phenotype similarity; Rare disease; UMAP
    DOI:  https://doi.org/10.1016/j.gim.2025.101620
  5. Sci Adv. 2026 Mar 06. 12(10): eaed3579
    Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
    Kenneth Ehses, Jorge P López-Alonso, Odetta Antico, Yannik Lang, Till Rudack, Abdussalam Azem, Miratul M K Muqit, Iban Ubarretxena-Belandia, Rubén Fernández-Busnadiego.
      Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo-electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo-electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.
    DOI:  https://doi.org/10.1126/sciadv.aed3579
  6. Seizure. 2026 Feb 18. pii: S1059-1311(26)00050-6. [Epub ahead of print]
    Mitochondrial complex assembly in epilepsy of primary mitochondrial disease origin.
    Gavin P McStay.
      Primary mitochondrial diseases are caused by mutations in genes required for expression, function or assembly of the mitochondrial oxidative phosphorylation system. The pathology of primary mitochondrial diseases is varied and a subset of these are associated with epilepsy and seizures. Mutations are found in each of the 5 complexes of the oxidative phosphorylation system in both structural subunits and assembly factors along with mitochondrially encoded components of the protein synthesis machinery. This review will highlight the mutations identified in clinical case studies that are associated with epilepsy and seizures and include the studies using cell systems and other model organisms where molecular characterisation of oxidative phosphorylation is more extensive. The molecular causes of epilepsy have not been well characterised in the relevant cells. This review identifies gaps in knowledge and suggestions for future studies to advance the understanding of the molecular pathogenesis of epilepsy that is associated with primary mitochondrial disease.
    Keywords:  Biogenesis; Electron transport chain; Epilepsy; Mitochondria; Oxidative phosphorylation; Seizures
    DOI:  https://doi.org/10.1016/j.seizure.2026.02.016
  7. Life Sci Alliance. 2026 May;pii: e202503602. [Epub ahead of print]9(5):
    Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
    Ekaterina O Zorikova, Sabita Chourasia, Irit Rosenhek-Goldian, Sidney R Cohen, Semen V Nesterov, Atan Gross.
      Mitochondria orchestrate energy conversion and cell fate, yet label-free approaches that report both functional and physical states at the single-organelle level are nonexistent. Here, we combine atomic force microscopy (AFM) imaging with single-mitochondrion phenotyping by quantifying stiffness, height, and spontaneous low-frequency height fluctuations at the nanoscale. Across respiratory activators, inhibitors, and uncouplers, the integrated 0- to 20-Hz fluctuation power correlates with mitochondrial membrane potential (ΔΨm) and does not covary with changes in mitochondrial height (a proxy for swelling). In liver mitochondria lacking mitochondrial carrier homolog 2 (MTCH2), a regulator of mitochondrial metabolism, dynamics, and apoptosis, AFM reveals a compact, mechanically stiff, high-fluctuation state consistent with hyperpolarization and distinct from inhibited/uncoupled signatures. Extending the assay to mitochondria isolated from mouse embryonic fibroblasts, AFM data can distinguish between genotypes: loss of the mitochondrial pro-fusion proteins mitofusin 1 or 2 (MFN1 or MFN2) yields stiff, low-fluctuation mitochondria with reduced ΔΨm, whereas MTCH2 loss produces stiff, high-fluctuation, high-ΔΨm mitochondria. These three label-free features provide reproducible single-organelle "fingerprints" that resolve bioenergetic states and molecular defects and complement fluorescence and respirometry.
    DOI:  https://doi.org/10.26508/lsa.202503602
  8. Acta Histochem. 2026 Feb 28. pii: S0065-1281(26)00016-4. [Epub ahead of print]128(2): 152331
    Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
    Aswathy P Nair, Aishwarya Janaki P, Janani Gopalarethinam, Abishek Kumar B, Balachandar Vellingiri, Mohana Devi Subramaniam.
      Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.
    Keywords:  Leber’s Hereditary Optic Neuropathy; Mitochondria transfer; Mitochondrial disease; Stem cells; Tunneling Nanotubes
    DOI:  https://doi.org/10.1016/j.acthis.2026.152331
  9. Bio Protoc. 2026 Feb 20. 16(4): e5605
    Identification of the Subcompartment-Specific Mitochondrial Proteome by APEX2 Proximity Labeling in Saccharomyces cerevisiae.
    Lorenz Spänle, Johannes M Herrmann.
      The cellular compartments of eukaryotic cells are defined by their specific protein compositions. Different strategies are used for the identification of the subcellular proteomes, such as fractionation by differential centrifugation of cellular extracts. The localization of mitochondrial proteins is particularly challenging, as mitochondria consist of two membranes of different protein composition and two aqueous subcompartments, the intermembrane space (IMS) and the matrix. Previous studies identified subcompartment-specific proteomes by using combinations of hypotonic swelling and protease digestion followed by mass spectrometry. Here, we present an alternative, more unbiased method to identify the proteomes of mitochondrial subcompartments by use of an improved ascorbate peroxidase (APEX2) that is targeted to the IMS and the matrix. This method allows the subcompartment-specific labeling of proteins in mitochondria isolated from cells of the baker's yeast Saccharomyces cerevisiae, followed by their purification on streptavidin beads. With this method, the proteins located in the different mitochondrial subcompartments of yeast cells can be efficiently and comprehensively identified. Key features • Coverage of ~75% of previous combined annotated mitochondrial proteome studies with high confidence in sub-localization probabilities. • Provides detailed steps from starting culture to MS sample preparation, including the isolation of mitochondria. • Allows for easy adaptations to compare different conditions and treatments. • The whole experiment requires at least five days to complete.
    Keywords:  APEX2; Mitochondria isolation; Mitochondrial proteome; Proximity labeling; S. cerevisiae; Sub-localization
    DOI:  https://doi.org/10.21769/BioProtoc.5605
  10. Nat Commun. 2026 Mar 05.
    Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
    Injae Chung, Caroline S Pereira, John J Wright, Guilherme M Arantes, Judy Hirst.
      Respiratory complex I is a multi-subunit energy-transducing membrane enzyme essential for mitochondrial and cellular energy metabolism. It couples NADH oxidation and ubiquinone-10 (Q10) reduction to the concomitant pumping of four protons to generate the proton-motive force that powers oxidative phosphorylation. Despite recent advances in structural knowledge of complex I, many mechanistic aspects including the reactive binding poses of Q10, how Q10 reduction initiates the proton transfer cascade, and how protons move through the membrane domain, remain unclear. Here, we use electron cryomicroscopy to determine structures of mammalian complex I, reconstituted into phospholipid nanodiscs containing exogenous Q10 and reduced by NADH, to global resolutions of 2.0 to 2.6 Å. Two conformations of a reduced Q10H2 molecule are observed, fully inserted into the Q-binding channel in the turnover-relevant closed state. By comparing the quinone species bound in oxidised and reduced complex I structures, paired with molecular dynamics simulations to investigate the charge states of key surrounding residues, we propose a series of substrate binding poses that Q10 transits through for reduction. Our highly hydrated structures exhibit near-continuous proton-transfer connections along the length of the membrane domain, enabling comparisons between them to assist in identifying the proton-transfer control points that are essential to catalysis.
    DOI:  https://doi.org/10.1038/s41467-026-70030-0
  11. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  12. Mol Genet Metab Rep. 2026 Mar;46 101302
    Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
    Gerardo G Piroli, Rebecca Myers, Lynda Holloway, Andrew Hayek, Ellen Linebaugh, Julie R Jones, Cindy Skinner, Steven A Skinner, Norma Frizzell, Richard Steet.
      Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.
    Keywords:  Complex III; Mitochondria; Mitochondrial transplantation; Respiration; UQCRC1; UQCRC2
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101302
  13. Nat Cell Biol. 2026 Mar 05.
    Lipid droplets meet mitochondria at the MIM protein insertase.
      
    DOI:  https://doi.org/10.1038/s41556-026-01901-3
  14. Biomed Pharmacother. 2026 Mar 02. pii: S0753-3322(26)00159-9. [Epub ahead of print]197 119127
    Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
    Yanxing Hu, Huyan Chen, Chenyun Ding, Shengbo Zhang, Qing Chen, Hongying Sun, Qiaozhen Yang.
      Mitochondrial metabolism and innate immune signaling are increasingly recognized as intersecting pathways in chronic inflammatory disease. Here, we identify a metabolically driven mechanism linking the TCA cycle imbalance to mucosal inflammation in oral lichen planus (OLP). Multi-omics analysis revealed that fumarate hydratase (FH) is upregulated in OLP tissues and cells, leading to significant fumarate depletion. This metabolic shift induces mitochondrial dysfunction, characterized by enhanced oxidative phosphorylation, proton leak, and TFAM downregulation. These changes destabilize the mitochondrial genome, promote mtDNA leakage into the cytosol, and activate the cGAS-STING pathway, resulting in TBK1-IRF3- NF-κB -driven inflammatory responses. Genetic knockdown of FH or pharmacological supplementation with monomethyl fumarate (MMF) restored mitochondrial homeostasis, prevented mtDNA release, and attenuated immune activation. Furthermore, depletion of mtDNA using 2',3'-dideoxycytidine (ddC) validated the essential role of mtDNA in sustaining cGAS-STING dependent inflammation. Co-treatment with fumarate further suppressed cytosolic mtDNA and enhanced repression of innate signaling. These findings uncover a functional FH-fumarate-mtDNA-cGAS-STING axis in OLP and reveal fumarate as a key metabolic modulator of mitochondrial immune surveillance. Our work provides conceptual and therapeutic insight into the role of mitochondrial metabolism in non-infectious mucosal inflammation.
    Keywords:  Citric acid cycle; DNA; Fumarate hydratase; Inflammation; Lichen planus; Mitochondrial; Mitochondrial diseases; Oral
    DOI:  https://doi.org/10.1016/j.biopha.2026.119127
  15. Nat Commun. 2026 Mar 06.
    STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
    Isshin Shiiba, Yuto Ishikawa, Hijiri Oshio, Naoki Ito, Fuya Yamaguchi, Shun Nagashima, Hideya Ando, Keitaro Umezawa, Yuri Miura, Yuhei Araiso, Koki Nakamura, Yusuke Hirabayashi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondria form contact sites with multiple organelles to coordinate diverse cellular processes. Melanosomes, lysosome-related organelles, undergo stepwise maturation to synthesize and store melanin, but how they interact with mitochondria remains unclear. Here we show that mitochondria-melanosome contacts dynamically increase during melanosome maturation and are mediated by STIM1-MFN2 interactions. Using a NanoBiT-based reporter system, MiMSBiT (Mitochondria-Melanosome contact reporter applying NanoBiT), to monitor reversible mitochondria-melanosome contacts in living cells, we demonstrate that STIM1 localizes to melanosomes and promotes their contact with mitochondrial MFN2. A transient decrease in melanosomal lumen calcium induces STIM1 clustering and enhances its association with MFN2. These contacts locally increase mitochondrial ATP availability, leading to melanosome lumen acidification via proton channel activation. This acidification facilitates PMEL fibrillation, a key step in melanosome maturation. Together, our findings reveal a mechanism by which mitochondria-melanosome contacts regulate melanosome maturation.
    DOI:  https://doi.org/10.1038/s41467-026-70282-w
  16. Front Cell Dev Biol. 2026 ;14 1745201
    Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
    Yishuo Ji, Ying Wang, Xiaowei Yu, Yi Jin, Kai Zhao, Yue Hu, Zhenglin He.
      Aging and aging-related diseases are increasingly viewed as systemic disorders arising from disrupted inter-organ communication, yet the mechanisms linking local metabolic stress to organism-wide dysfunction remain unclear. The liver occupies a central position in this network, but how hepatic mitochondrial stress is translated into circulating signals that remodel distant tissues is incompletely understood. Here, we synthesize evidence identifying hepatic mitochondria as a systemic signaling hub that integrates metabolic and inflammatory stress and disseminates blood-borne cues during aging. We focus on three major classes of mitochondrial outputs: UPRmt-driven mitokines, including fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15); metabolites generated through mitochondrial metabolic reprogramming; and mitochondrial danger signals such as mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (mtDNA). These signals act through endocrine, metabolic, and immune pathways to reshape mitochondrial function, inflammation, and energy homeostasis across multiple organs. We further discuss how aging shifts hepatic mitochondrial signaling from adaptive to maladaptive states and emphasize that liver-centered regulation operates within bidirectional networks involving the gut, skeletal muscle, and immune system. Finally, we outline translational challenges and potential strategies for modulating hepatic mitochondrial outputs to restore systemic homeostasis in aging and aging-related diseases.
    Keywords:  UPRmt; aging; diseases; hepatic mitochondria; inter-organ communication; mitokines; mtDNA; mtROS
    DOI:  https://doi.org/10.3389/fcell.2026.1745201
  17. Eur J Neurosci. 2026 Mar;63(5): e70449
    Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
    Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.
      Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.
    Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles
    DOI:  https://doi.org/10.1111/ejn.70449
  18. Neurogenetics. 2026 Mar 03. pii: 20. [Epub ahead of print]27(1):
    Expanding the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
    King Lam Lai, Thomas B Smith, Reza Maroofian, Maha S Zaki, Swetha Ramadesikan, Tamara Reynolds, Daniel C Koboldt, Jesse M Hunter, Jorge Vidaurre, Mihaela Atanasova, Brian D Marsden, Wyatt W Yue, Henry Houlden, Robert W Taylor, William G Newman, Raymond T O'Keefe.
      
    Keywords:  COXPD54; Mitochondria; PRORP; Perrault syndrome; RNase P complex; Rare disease
    DOI:  https://doi.org/10.1007/s10048-026-00892-5
  19. Mol Biol Cell. 2026 Mar 04. mbcE25110560
    Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
    Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.
      Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.
    DOI:  https://doi.org/10.1091/mbc.E25-11-0560
  20. Nat Struct Mol Biol. 2026 Mar 05.
    Function and regulation of the mitochondrial stress response.
    Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.
      As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
    DOI:  https://doi.org/10.1038/s41594-026-01769-9
  21. Mitochondrion. 2026 Feb 28. pii: S1567-7249(26)00027-9. [Epub ahead of print]88 102137
    Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
    Wei Wang, Xiang Dong, Chun-Yu Cao, Hong-Bo Li, Ya-Feng Lv.
      Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encoding the mitochondrial helicase Twinkle, disrupt mtDNA maintenance and underlie a subset of PS cases. Here, we generated the first mouse models carrying patient-specific TWNK missense mutations c.814G > A (p.Ala272Thr) and c.1166C > T (p.Ala389Val), both in homozygosity and compound heterozygosity, using CRISPR/Cas9 editing. Mutant mice exhibit profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy, while overall growth remains normal. Molecular assays reveal a significant reduction in mtDNA copy number and ATP content in muscle and brain, accompanied by impaired respiratory-chain function. These phenotypes faithfully recapitulate core features of human PS, establishing a genetically precise in vivo platform to dissect disease mechanisms and to evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.
    Keywords:  Mitochondrial dysfunction; Mouse model; Perrault syndrome; Sensorineural hearing loss; TWNK; mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2026.102137
  22. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  23. Am J Physiol Cell Physiol. 2026 Mar 04.
    MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
    Mireille Khacho, Yan Burelle.
      Muscle stem cells (MuSCs) are essential for muscle regeneration, but their function declines with aging 1-4, neuromuscular disorders5-8 , and non-genetic muscle-wasting conditions9 . Their regenerative capacity is also influenced by environmental factors, including dietary changes such as high-fat diets and diabetes 10-12, impacting their ability to restore muscle integrity. Understanding the mechanisms that regulate MuSC function is thus crucial for developing strategies to preserve muscle health and improve regenerative potential in both physiological and pathological contexts. Recent advances have unveiled a crucial role for mitochondria in controlling MuSC quiescence, fate decisions, and differentiation into myofibers. Several studies have now shown that disruption of mitochondrial function, through genetic or pharmacological means, leads to dysregulation of MuSC functions and impaired myogenic lineage progression. Mitochondrial abnormalities in MuSCs have also been shown to contribute to the loss of regenerative capacity observed in conditions such as aging, sepsis, in myopathies. Together, this evidence and others have sparked great interest for understanding how these organelles regulate MuSC behavior and exploring the therapeutic potential of mitochondria targeted therapies to improve or maintain muscle regeneration. This review aims to provide a comprehensive overview of the role of mitochondria in regulating MuSC quiescence, fate decisions and myogenesis under both normal and diseased conditions. It summarizes current knowledge, highlights existing gaps, and explores emerging areas related to bioenergetic properties and metabolic signaling, mitochondrial network dynamics, quality control, and inter-organelle cross-talk across different MuSC states. It also discusses potential therapeutic strategies targeting mitochondrial function to enhance MuSC regenerative capacity and counteract muscle degeneration.
    Keywords:  Muscle stem cells; metabolism; mitochondrial dynamics; mitophagy; stem cell fate
    DOI:  https://doi.org/10.1152/ajpcell.00027.2026
  24. Neuromolecular Med. 2026 Mar 07. pii: 15. [Epub ahead of print]28(1):
    Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
    Gaurav Singh, Simranpreet Kaur, Khadga Raj Aran.
      Parkinson's disease (PD), is slowly advancing disease condition of the nervous system, which leads to interruption of normal motor function, resulting in symptoms such as tremor, muscle rigidity, bradykinesia, and postural instability. PD is commonly also accompanied by motor impairment, associated with broad non-motor symptoms, of which sensory prob 21qwlems are including behavioural and sleeping disorders and autonomic dysfunctions. The disease is characterised by slow degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc), and pathological misfolded α-synuclein (α-syn) deposition protein. Mitochondrial Rho GTPase (Miro1) is one of the major regulators of neuronal energy transport, mitochondrial motility, and communication in the central nervous system (CNS). It also regulates the quality of mitochondria in their interaction with regulatory proteins, PTEN-induced kinase 1 (PINK1), Parkin, and Leucine-rich repeat kinase2 (LRRK2). Studies stated that there are a few PD-related genes that are correlated with Miro1, which influences its activity. The dysregulation or genetic mutations of Miro1 disrupt the mitochondrial activities, including the transport, mitophagy, and calcium (Ca2+) homeostasis, particularly among dopaminergic neurons. These imbalances augment oxidative stress, mitochondrial dysfunction, and α-syn aggregation, which eventually regulate neuron exposure and are a risk factor in the development of PD. This review highlights the role of Miro1 in the development and pathophysiology of PD, with particular emphasis on recent experimental and clinical findings. It also focuses on the therapeutic prospect of Miro1-targeted approaches as new emerging interventions to reduce the development of the disease.
    Keywords:  Calcium homeostasis; Miro1; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12017-026-08917-w
  25. Front Med (Lausanne). 2026 ;13 1682564
    Case Report: Pediatric nephrology-expanding the genotypic spectrum of COQ2-related nephropathy with a novel splice site variant in CoQ10-responsive SRNS.
    Yu-Ren Huang, Abhijeet Pal, Anne Chun-Hui Tsai.
      Coenzyme Q10, also known as CoQ10, CoQ, and ubiquinone is an essential component of the mitochondrial electron-transport chain and functions as an energy transfer molecule as well as a redox carrier and is a lipid-soluble antioxidant. Biallelic pathogenic variants in one of the 10 genes encoding proteins involved in its synthesis, establishes the diagnosis of primary CoQ10 deficiency. COQ2, or parahydroxybenzoate-polyprenyltransferase (EC 2.5.1.39), catalyzes one of the final reactions in the biosynthesis of CoQ, the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. COQ2 related CoQ10 deficiency can present with multiple system atrophy, cardiomyopathy and steroid resistant nephrotic syndrome (SRNS). Multiple papers have suggested CoQ supplement can treat SRNS. We report a 9-year-old girl presenting with steroid-resistant nephrotic syndrome, whose renal biopsy revealed focal segmental glomerulosclerosis. She showed only a partial response to combined therapy with tacrolimus, lisinopril, and losartan. Whole exome sequencing identified two compound heterozygous variants in the COQ2 gene (NM_015697.7): a known pathogenic variant, c.683A>G, inherited from her father, and a novel splice-site variant, c.692+3A>G, inherited from her mother and currently classified as a variant of uncertain significance (VUS). Notably, previously reported patients carrying the c.683A>G variant typically present with early-onset, severe disease. In contrast, our patient's relatively late onset and isolated nephropathy suggests that the novel variant may be pathogenic but associated with a milder phenotype. Prompt genetic diagnosis enabled early initiation of high-dose CoQ10 supplementation (ubiquinone, 30 mg/kg/day), which led to marked clinical improvement and may have prevented further renal function deterioration or the development of other systemic manifestations.
    Keywords:  COQ2; case report; genetics; nephrotic syndrome; ubiquinone
    DOI:  https://doi.org/10.3389/fmed.2026.1682564
  26. Sci Rep. 2026 Mar 17.
    β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.
    Mari Saida, Noritaka Saeki, Hiroshi Sakai, Jun Iwanami, Atsushi Yokoyama, Shun Sawatsubashi, Motoi Kanagawa, Norio Sato, Yuuki Imai.
      Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit-acquired weakness (ICU-AW) as part of post-intensive care syndrome. To identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed the 'sirtuin signaling pathway' and 'mitochondrial dysfunction' significantly enriched and Sirt3, a major mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, was downregulated. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among these proteins, mass spectrometry detected several proteins in the acetylated band, including multiple complex I subunits. Whether these are direct SIRT3 targets remains to be determined. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with β-nicotinamide mononucleotide (β-NMN) partially rescued energy production. In vivo, acute-phase administration of β-NMN preserved mitochondrial morphology and skeletal muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness associated with Sirt3 downregulation, and highlights β-NMN supplementation as a promising NAD⁺-targeted therapeutic strategy for mitigating ICU-AW.
    Keywords:   β-NMN; Mitochondrial respiration; Sepsis; Sirt3; Skeletal muscle weakness
    DOI:  https://doi.org/10.1038/s41598-026-43172-w
  27. Acta Neuropathol. 2026 Mar 04. pii: 23. [Epub ahead of print]151(1):
    Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.
    Ngan Le Kim Tran, Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Molly M Watkins, Hanna J Sledge, J Raphael Gibbs, Bryan J Traynor, Clifton L Dalgard, Sonja W Scholz, Dennis W Dickson, Wolfdieter Springer, Owen A Ross.
      Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration.
    Keywords:  Lewy body disease; Mitochondrial haplogroup; Neuropathology; mtDNA
    DOI:  https://doi.org/10.1007/s00401-026-02993-9
  28. Bio Protoc. 2026 Feb 20. 16(4): e5610
    Optimized Mechanical Isolation of Mitochondria From Saccharomyces cerevisiae Preserving Atg32 for Quantitative Analysis.
    Ariann E Mendoza-Martínez, J Ernesto Bravo-Arévalo, Ulrik Pedroza-Dávila, Soledad Funes.
      Mitophagy is a highly conserved process among eukaryotic cells, playing a primordial role in mitochondrial quality control and overall cellular homeostasis. In Saccharomyces cerevisiae, Atg32 is the only identified mitophagy receptor localized to the mitochondrial outer membrane, making this yeast a particularly powerful model for molecular studies of mitophagy that require the isolation of intact mitochondria. However, traditional methods for isolating mitochondria from yeast often rely on enzymatic cell wall digestion and homogenization, which can compromise the stability of mitochondrial surface proteins such as Atg32. In this protocol, we describe an optimized mechanical approach for yeast cell disruption using glass beads in a cold, protease-inhibited buffer to preserve mitochondrial integrity and facilitate the detection of Atg32. Subsequent differential centrifugation and washing steps yield mitochondrial fractions suitable for downstream biochemical analyses. This workflow eliminates enzymatic digestion steps, reduces sample variability, and allows parallel processing of multiple strains or experimental conditions. Overall, this method offers a rapid, low-cost, and reproducible alternative for crude mitochondrial isolation, ensuring excellent preservation of Atg32 and broad compatibility with quantitative and comparative studies. Key features • Mechanical cell disruption using glass beads preserves mitochondrial integrity and enables reliable immunodetection of Atg32 without requiring enzymatic spheroplasting. • Rapid, low-cost, and highly reproducible workflow suitable for processing multiple yeast strains or experimental conditions in parallel. • Optimized cold, protease-inhibited lysis conditions minimize Atg32 degradation and improve detection sensitivity in mitochondrial fractions.
    Keywords:  Atg32; Immunodetection; Mitochondria fraction; Mitophagy; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.21769/BioProtoc.5610
  29. J Neurochem. 2026 Mar;170(3): e70395
    Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
    Yesim Kaya, Kevser Kübra Kırboğa.
      Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.
    Keywords:  3D disease modeling; brain organoids; induced pluripotent stem cells; neurodegenerative diseases
    DOI:  https://doi.org/10.1111/jnc.70395
  30. J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 89-95
    Progressive Myopathy and Respiratory Failure in a 7-Year-Old Boy With m.3251A>G MT-TL1 Mutation.
    Daria Hoang, Alan Pestronk, Jafar Kafaie.
       ABSTRACT: We report a pediatric case of severe isolated mitochondrial myopathy because of the rare m.3251A>G variant of the MT-TL1 gene. A 7-year-old boy presented to the hospital with acute-on-chronic weakness and respiratory insufficiency. Initial laboratory tests were notable for elevated lactate, aldolase, and lactate dehydrogenase. Despite a negative autoimmune panel, he was presumed to have myositis and treated with steroids and intravenous immunoglobulin. He continued to deteriorate, eventually requiring intubation and ventilation. Muscle biopsy revealed numerous ragged red fibers, abnormal intracellular lipid droplets with no lymphocytic inflammation, and increased succinate dehydrogenase reactivity, reflecting mitochondrial proliferation in many fibers. Steroids were discontinued, and he was started on a mitochondrial cocktail of cofactors with clinical improvement. Genetic testing identified the m.3251A>G variant, confirming primary mitochondrial disorder. This case expands the known phenotype of the m.3251A>G mutation. We also discuss clinical and histopathological differences between mitochondrial and inflammatory myopathies.
    Keywords:  MELAS; histopathology; immune myopathy; mitochondrial myopathy; muscle biopsy
    DOI:  https://doi.org/10.1097/CND.0000000000000547
  31. Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627
    Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
    Akriti Prashar, Rosa Puertollano.
      Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102627
  32. JIMD Rep. 2026 Mar;67(2): e70066
    Abnormal Newborn Screening Resembling Carnitine Palmitoyltransferase 1a Deficiency in Three Patients With COASY Protein Associated Neurodegeneration.
    Matthew Lynch, Sophie Manoy, Claire Murray, Geoff Wallace, Nolette Pereira, Ricky Price, Anita Inwood, Jim McGill, David Coman.
      COASY protein associated neurodegeneration is a rare, progressive autosomal recessive neuroferritinopathy due to pathogenic mutations in the COASY gene, coding for the mitochondrial located coenzyme A synthase. Clinical manifestations include seizures, progressive spasticity, dystonia, neuropathy, cognitive decline and neuropsychiatric abnormalities. Both foetal and childhood onset phenotypes are described. We report three patients with COASY protein associated neurodegeneration who were identified on newborn screening with a dried bloodspot acylcarnitine pattern consistent with carnitine palmitoyltransferase 1a deficiency, that is, an elevated ratio of free carnitine (C0) to the sum of palmitoylcarnitine (C16) and octanoylcarnitine (C18):[C0/(C16+C18)]. Two siblings, who died in infancy, displayed neurological features from birth, with magnetic resonance imaging of the brain displaying immature cortical sulcation, parenchymal atrophy and pontocerebellar hypoplasia. The third patient presented with global developmental delay, pyramidal signs and seizures with brain magnetic resonance imaging at age 15 months demonstrating a thin corpus callosum, symmetric diffusion restriction throughout the basal ganglia and evidence of deposition in the globus pallidus. This report demonstrates that phenotypes of COASY protein associated neurodegeneration should be included in the differential diagnosis of dried blood spot acylcarnitine pattern suggestive of carnitine palmitoyltransferase 1a deficiency and may represent new potential for early diagnosis.
    Keywords:  COASY protein associated neurodegeneration; carnitine palmitoyltransferase 1a deficiency; inborn error of metabolism; newborn bloodspot screening
    DOI:  https://doi.org/10.1002/jmd2.70066
  33. J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):
    Unconventional model organisms bend our view on mitochondrial cristae.
    Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.
      Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.
    Keywords:   Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae
    DOI:  https://doi.org/10.1242/jcs.264310
  34. J Physiol. 2026 Mar 04.
    Cardiac mitochondrial adaptations supporting high-altitude tolerance in deer mice.
    Megan Margiotta, Isabella Antonacci.
      
    Keywords:  cardiac mitochondria; high altitude; hypoxia; lactate dehydrogenase; mitochondrial respiration; reactive oxygen species
    DOI:  https://doi.org/10.1113/JP290836
  35. Front Cardiovasc Med. 2026 ;13 1682381
    WASHC3 knockout disrupts mitochondrial protein homeostasis and energy metabolism in cardiomyocytes.
    Sujin Kim, Deung-Dae Park, Amelia Glazier, Wolfgang Rottbauer, Steffen Just.
       Introduction: The WASH complex regulates endosomal actin dynamics and vesicular trafficking and is essential for neuronal integrity and motor function. Although variants in WASHC4, WASHC5, and WASHC3 are linked to neurodevelopmental abnormalities, the role of WASHC3 beyond the nervous system, particularly in cardiac mitochondrial regulation, remains unclear.
    Methods: We modeled WASHC3 loss of function in zebrafish and human cardiomyocytes. Washc3 was suppressed in zebrafish embryos by antisense oligonucleotide-mediated knockdown, and a stable Washc3 knockout line was generated using CRISPR/Cas9. Washc3-deficient zebrafish hearts were analyzed by quantitative LC-MS/MS proteomics with GO/KEGG enrichment and transcript-level assays. Mitochondrial bioenergetics was assessed by Seahorse XF assays in primary zebrafish cardiomyocytes and in human AC16 cardiomyocytes following AAV-shRNA-mediated WASHC3 knockdown.
    Results: Washc3 knockdown embryos exhibited neuromuscular degeneration, impaired locomotion, and early cardiac dysfunction. In contrast, Washc3 knockout zebrafish showed normal early development but developed progressive pericardial degeneration and epicardial remodeling in aged animals. Cardiac proteomics revealed downregulation of mitochondrial proteins, particularly oxidative phosphorylation components, supported by pathway enrichment and concordant transcript-level findings. Mitochondrial respiration was significantly impaired in both Washc3-deficient zebrafish cardiomyocytes and WASHC3-depleted human AC16 cardiomyocytes.
    Discussion: These findings identify a previously unrecognized role for WASHC3 in maintaining cardiac mitochondrial protein homeostasis and bioenergetic function and provide a framework linking neuromuscular and cardiac phenotypes to impaired mitochondrial bioenergetics in energy-demanding tissues.
    Keywords:  WASH complex; WASHC3; mitochondrial function; proteomics; zebrafish
    DOI:  https://doi.org/10.3389/fcvm.2026.1682381
  36. Nat Rev Neurosci. 2026 Mar 04.
    Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
    Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.
      Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.
    DOI:  https://doi.org/10.1038/s41583-026-01031-7
  37. Trends Neurosci. 2026 Feb 27. pii: S0166-2236(26)00026-3. [Epub ahead of print]
    CHCHD2 links mitochondrial dysfunction and α-synuclein misfolding in Parkinson's disease.
    Derek Narendra, Brent J Ryan.
      Parkinson's disease comprises multiple biological subtypes and a heterogeneous clinical course. A recent study by Liao et al. identifies CHCHD2 mutations as a mitochondrial entry point that links metabolic dysfunction to α-synuclein pathology. These findings highlight how rare sporadiclike monogenic forms of Parkinson's disease may inform mechanistic and therapeutic stratification.
    Keywords:  disease stratification; dopaminergic neurons; mitochondrial metabolism; neurodegeneration; oxidative stress; protein aggregation
    DOI:  https://doi.org/10.1016/j.tins.2026.02.002
  38. Eur J Med Res. 2026 Mar 06.
    Integrative multi-omics and machine learning identify mitochondrial biomarkers for pathogen-specific sepsis stratification and translational prioritization.
    Chaoyuan Jin, Ruijinlin Hao, Bate Gonggaoang, Qingxia Dai, Xingxing Ren, Jie Shen.
       BACKGROUND: Sepsis is a leading cause of critical illness and mortality, yet substantial heterogeneity limits risk stratification and biomarker translation. Mitochondrial dysfunction is widely implicated in sepsis, but genetically supported, multi-layer regulatory features and their clinical relevance remain incompletely characterized.
    METHODS: We integrated publicly available sepsis GWAS summary statistics (general sepsis: 1634 cases/454,714 controls; gram-positive sepsis: 168/456,180; gram-negative sepsis: 383/455,965) with blood-based molecular QTL resources (including GTEx v8 whole blood, n = 670) to prioritize mitochondrial genes and infer regulatory cascades. Independent whole-blood transcriptomic cohorts (the GAinS cohort, GSE65682, n = 802; GSE54514, n = 163) were used for clinical and pathogen-specific expression characterization. We developed machine learning models using mitochondrial gene features and evaluated performance by internal tenfold cross-validation.
    RESULTS: We identified mitochondrial genes with convergent genetic, epigenetic, and transcriptional regulatory evidence, showing stronger effects in inner membrane and matrix compartments. Transcriptomic analyses supported clinically relevant dysregulation and pathogen-associated patterns. In predictive modeling, aggregating mitochondrial gene features improved discrimination, with the best-performing random forest model achieving an AUC of 0.91 under internal cross-validation. These results require validation in independent external cohorts.
    CONCLUSIONS: This study provides a genetically supported, multi-omics framework linking compartment-specific mitochondrial dysregulation to sepsis heterogeneity and nominates candidate biomarkers for prioritization. The reported model performance reflects internal resampling and requires validation in independent clinical cohorts and future multi-omics profiling (including metabolomics) before translational implementation.
    Keywords:  Epigenetics; Mendelian randomization; Mitochondrial dysfunction; Multi-omics; Sepsis
    DOI:  https://doi.org/10.1186/s40001-026-04065-w
  39. Mol Metab. 2026 Mar 02. pii: S2212-8778(26)00027-X. [Epub ahead of print] 102343
    Photoreceptor deletion of pyruvate dehydrogenase E1 subunit α1 induces retinal degeneration and reprograms retinal metabolism.
    Hongwei Ma, Lilliana R York, Shujuan Li, Grayson Gagnon, Junhuang Zou, Haoran Yu, Jun Yang, Yun Le, Mark Eminhizer, Isabella Mascari, Jianhai Du, Xi-Qin Ding.
      Rod and cone photoreceptors are among the most energy-demanding cells in the body, exhibiting a high rate of ATP consumption. Their primary energy source is glucose, which is metabolized through both glycolysis and mitochondrial pyruvate oxidative phosphorylation. The pyruvate dehydrogenase E1 subunit α1 is a critical component of the pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl-CoA, thereby regulating mitochondrial pyruvate metabolism. To determine the significance of mitochondrial pyruvate metabolism in these cells, we investigated the impact of photoreceptor-specific Pdha1 deletion in the mouse retina. Rod- or cone-specific Pdha1 knockout mice at 2-4 months were used. These mice were evaluated across multiple modalities, including retinal structure and integrity (morphometry), retinal function (electroretinogram), photoreceptor ultrastructure (transmission electron microscopy), retinal metabolic profiles (mass spectrometry), gene expression (RT-PCR), and retinal stress response (glial activation analysis). Mice with rod- or cone-specific Pdha1 deletion exhibited retinal degeneration phenotype, manifested by impaired retinal morphology and light responses and significant retinal glial activation. Mechanistically, these retinas displayed profound metabolism reprogramming, evidenced by changes in key glycolysis and decreased tricarboxylic acid (TCA) cycle intermediates, carbohydrates, amino acids, nucleotides and their derivatives. This metabolic remodeling was further supported by enhanced glycolysis and decreased TCA cycle gene expression and was accompanied by impaired mitochondrial morphology. Our findings demonstrate that PDHA1 is essential for photoreceptor energy metabolism and for maintaining both their structural and functional integrity, thus highlighting the critical importance of proper mitochondrial glucose metabolism for photoreceptor health.
    Keywords:  Glucose metabolism; Mitochondrial metabolism; PDHA1; Photoreceptor; Photoreceptor metabolism; Pyruvate dehydrogenase; Pyruvate metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2026.102343
  40. Methods Enzymol. 2026 ;pii: S0076-6879(25)00527-0. [Epub ahead of print]727 75-91
    Imaging and quantifying organelle contact sites using a reversible splitFAST complementation system.
    Jason A Weesner, Chi-Lun Chang.
      Organelle contact sites are crucial hubs for inter-organelle logistics; yet, visualizing these dynamic foci of sub-micro scale in living cells is challenging. In this chapter, we describe how to use the FABCON (Fluorogen-Activated Bimolecular complementation at CONtact sites) toolkit to detect and quantify contact sites. FABCON labels contact sites via a reversible, fluorogen-dependent complementation of the splitFAST system. This protocol first describes the engineering principle of FABCON, allowing customization to model systems of interest. Next, we provide detailed instructions for using FABCON to monitor mitochondria-lipid droplet interactions in mammalian cells and how to quantify levels of contact sites via intensity-based measurement and line scanning. FABCON can be broadly applied to visualize and quantify other contact sites. With proper validation and optimization, FABCON provides a robust platform to study the dynamic regulation of organelle contact sites.
    Keywords:  Bimolecular fluorescence complementation; Lipid droplets; Mitochondria; Organelle contact sites; SplitFAST
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.023
  41. Gene Ther. 2026 Mar 05.
    In vitro and in vivo rescue of dopaminergic neurons in Parkinson's disease models after Parkin gene therapy.
    Takeshi Hioki, Masaaki Nishimura, Xiuxia Sun, Sarah Melissa Jacobo, Miyu Nakayama, Mitsuhiro Nishihara, Kimio Tohyama, Po-Ting Liu, Takuro Okai, Maiko Tanaka, Gabriele Proetzel.
      Young-onset Parkinson's disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9 vectors with different promoters were engineered to deliver PRKN cDNA with efficient human Parkin (hParkin) expression in dopaminergic (DA) neurons as shown in PRKN-null human induced pluripotent stem cell (iPSC) derived DA neurons. Further, we show that AAV9-PRKN treatment can protect nigral DA neurons in two mouse PD models, the 6-hydroxydopamine (6-OHDA)-lesion and the α-synuclein (α-Syn) pre-formed fibrils (PFFs)-lesion model. In summary, AAV9-PRKN gene therapy demonstrates neuroprotective properties and may represent a promising approach for PRKN-PD, with potential broader applications in idiopathic PD and other neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41434-026-00599-0
  42. J Lipid Res. 2026 Mar 03. pii: S0022-2275(26)00039-8. [Epub ahead of print] 101013
    LYPLAL1 Rare Loss-of-Function Variants in Humans and Deletion in Human Hepatoma Cells Protect Against MASLD.
    Rawdat Hussain, Chinmay Raut, Ponnandy Prabhu, Akram Irshaid, Yash Hegde, Yue Chen, Asmita Pant, Antonino Oliveri, Xiaochao Wei, Lishi Yin, Tiffany L Russell, Brian Halligan, Clay F Semenkovich, Elizabeth K Speliotes.
      Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells.
    Keywords:  LYPLAL1; MASLD; UK BioBank; liver; steatosis; β-oxidation
    DOI:  https://doi.org/10.1016/j.jlr.2026.101013
  43. Acta Myol. 2025 Dec;44(4): 138-142
    3-Methyl Glutaconic Aciduria and Elevated Plasma Growth Differentiation Factor 15 Level in an Adult with Monoallelic SPG7 Pathogenic Variant.
    Bukola A Olarewaju, Ehab Y Harahsheh, Khaled I Dweik, Judy B Tejon, Shaymaa Shurrab, Stephen A Johnson, Dimitar K Gavrilov, Mayowa A Osundiji.
      Pathogenic variants in SPG7 cause autosomal dominant progressive muscular atrophy. SPG7 encodes an inner mitochondrial membrane protein, paraplegin. Burgeoning lines of evidence have continued to suggest important roles for paraplegin in mitochondria function. Here we report elevated levels of biochemical markers of mitochondria dysfunction [3-methylglutaconic acid and 3-methylglutaric acid (in urine and blood) as well as plasma Growth Differentiation Factor 15 (GDF 15)] in a 65-year-old woman with a heterozygous pathogenic SPG7 variant [c.1529C > T (p.Ala510Val)], and evidence of muscle disease as well as chronic cerebral vasculopathy.
    Keywords:  aciduria; atrophy; methyl-glutaconic; mitochondria; muscle; paraplegin
    DOI:  https://doi.org/10.36185/2532-1900-1593
  44. Autoimmun Rev. 2026 Feb 28. pii: S1568-9972(26)00025-X. [Epub ahead of print]25(3): 104011
    Mitochondrial transfer and transplantation in the immune cells: Mechanistic foundations, medical applications, and future prospects.
    Xiaofeng Liu, Xinyu Feng, Deping Zhan, Heng Yin.
      Mitochondria exhibit tissue-specific physiological functions and are central to the maintenance of cellular homeostasis. Emerging evidence indicates that intercellular mitochondrial transfer is regulated by multiple determinants and exerts a profound influence on the function of both innate and adaptive immune cells. The underlying mechanisms are highly heterogeneous, involving distinct cellular contexts, microenvironmental cues, and modes of intercellular communication. This review summarizes the major triggers and mechanistic pathways governing mitochondrial transfer in immune cells and immune-related diseases, and discusses the therapeutic potential of this process while highlighting key challenges that currently limit its clinical translation. By integrating recent mechanistic insights and translational perspectives, this review aims to provide a conceptual framework for the development of mitochondrial transfer-based strategies in the treatment of immune-mediated disorders.
    Keywords:  Immune cells; Mitochondrial transfer; Neutrophils; T cells
    DOI:  https://doi.org/10.1016/j.autrev.2026.104011
  45. iScience. 2026 Mar 20. 29(3): 114814
    Immune regulators PALS-25 and PALS-22 localize to mitochondria and regulate mitochondrial fragmentation in C. elegans.
    Spencer S Gang, Max W Strul, Desmond Richmond-Buccola, Emily R Troemel.
      The nematode C. elegans controls immunity against intracellular pathogens such as microsporidia, using the pals gene family, which has expanded in C. elegans compared to mammals. pals-22 is a negative regulator that restrains pals-25, which serves as a positive regulator of immunity. pals-22 and pals-25 encode proteins that bind each other and can act in the intestine and epidermis, but their subcellular localization and mechanism of action have not been described. Here, we show that PALS-22 and PALS-25 proteins localize to mitochondria, with PALS-25 being required for PALS-22 localization to mitochondria. The C-terminus of PALS-25 directs mitochondrial localization, and the N-terminus is required for signaling. The loss of PALS-22 causes mitochondrial fragmentation, which occurs after activating the intracellular pathogen response (IPR), a transcriptional program induced by intracellular infection. Mitochondrial fragmentation induced by knockdown of fission/fusion factors increases resistance against microsporidia infection. Thus, the PALS-22/25-mediated fragmentation of mitochondria enhances resistance against intracellular infection.
    Keywords:  Cell biology; Cellular physiology; Immunity
    DOI:  https://doi.org/10.1016/j.isci.2026.114814
  46. J Transl Med. 2026 Mar 03.
    Defects in auxiliary fuel oxidation and mitochondrial pyruvate transport mark transition to overt heart failure in Tgαq*44 mice.
    Mariola Olkowicz, Agata Jedrzejewska, Urszula Tyrankiewicz, Filip Aleksander Fedak, Piotr Berkowicz, Grzegorz Kwiatkowski, Hernando Rosales-Solano, Kanchan Sinha Roy, Agnieszka Karas, Oliwia Krol, Marta Tomczyk, Ryszard T Smolenski, Janusz Pawliszyn, Stefan Chlopicki.
      
    Keywords:  Branched-chain amino acid accumulation; Energy metabolism; Heart failure; Ketone oxidation; Mitochondrial pyruvate uptake; Non-targeted proteomics
    DOI:  https://doi.org/10.1186/s12967-026-07883-y
  47. Case Rep Neurol. 2026 Jan-Dec;18(1):18(1): 121-127
    Coenzyme Q10 Supplementation in a Child with Biallelic COQ8A Variants: A Case Report.
    Hirotaka Motoi, Risa Watanabe, Ayano Shirai, Yusuke Sakata, Yukiko Kuroda, Yoshihiro Watanabe, Shuichi Ito.
       Introduction: Pathogenic variants in COQ8A cause a rare form of primary coenzyme Q10 (CoQ10) deficiency that can lead to childhood-onset cerebellar ataxia and developmental delay. However, reports of pediatric cases remain limited, and evidence regarding therapeutic response to CoQ10 supplementation in children is still scarce.
    Case Presentation: We report a 7-year-old boy with compound heterozygous COQ8A variants who presented with progressive cerebellar ataxia and intellectual disability. Oral CoQ10 supplementation was initiated at a dose of 10 mg/kg/day after institutional ethics approval. During 1 year of treatment, the Scale for the Assessment and Rating of Ataxia (SARA) score improved from 17 to 9, and serum CoQ10 concentration increased from 622 to 9.100 ng/mL. Mild cognitive improvement was also observed, with the intelligence quotient increasing from 53 to 64. Brain MRI demonstrated radiological stabilization of cerebellar atrophy. No adverse effects related to CoQ10 supplementation were observed throughout the treatment period.
    Conclusion: This case demonstrates the clinical benefit and safety of CoQ10 supplementation in pediatric-onset COQ8A-related ataxia. Early genetic diagnosis and timely initiation of CoQ10 therapy may lead to meaningful neurological improvement and stabilization of disease progression in affected children.
    Keywords:  COQ8A; Cerebellar ataxia; Coenzyme Q10 deficiency; Mitochondrial disorder
    DOI:  https://doi.org/10.1159/000550495
  48. Cell Biochem Funct. 2026 Mar;44(3): e70190
    Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.
    Bhanu Priya Awasthi, Bhanupriya Tanwar, Akshi Shree, Sumedha Saluja, Jayanth Kumar Palanichamy, Sameer Bakhshi, Archna Singh.
      The interaction of cellular organelles is crucial for maintaining intracellular homeostasis, particularly highlighting the impact of the cytoskeleton on mitochondrial dynamics. The aim of our study is to find direct molecular connections between cytoskeletal disturbance and mitochondrial failure which are inadequately characterized particularly in B-ALL. We investigated the effects of cytoskeleton inhibition on mitochondria in B-ALL using Pironetin (an alpha-tubulin inhibitor) and Latrunculin B (an actin inhibitor). Our findings indicate that these inhibitors caused mitochondrial fragmentation, characterized by smaller, rounder mitochondria with disordered cristae, increased Drp1 expression (fission protein), and decreased Mfn 1/2 and OPA 1 (fusion proteins) together with significantly modified the expression of essential mitochondrial transporters, such as VDAC and ANT2. These alterations were linked to increased mitochondrial membrane depolarization & mitochondrial reactive oxygen species and gradual mtDNA depletion, indicative of impaired oxidative phosphorylation (increased non-mitochondrial oxygen consumption, decreased mitochondrial reserve capacity) and diminished mitochondrial functionality. These mitochondrial alterations indicate that communication between the cytoskeleton and mitochondria is essential for preserving mitochondrial homeostasis. This study potentially enhances our understanding of how cancer cells modulate mitochondrial function during progression or therapeutic interventions.
    Keywords:  cytoskeleton; latrunculin B; leukemia; mitochondria; pironetin
    DOI:  https://doi.org/10.1002/cbf.70190
  49. Life Sci. 2026 Feb 26. pii: S0024-3205(26)00104-9. [Epub ahead of print] 124295
    Deciphering the role of mitochondrial cytochrome C oxidase subunit 4 in cardiac health and disease.
    Pranjali Anil Indian, Mansi Vinodkumar Trivedi, Anil Bhanudas Gaikwad.
      Cardiovascular diseases (CVDs) are the primary cause of mortality across the globe, making maintaining cardiac health and homeostasis imperative. The cardiac muscle cells have a 30% stake of the area occupied by mitochondria. The efficient generation of ATP, despite metabolic and other cellular shifts, is crucial for maintaining sufficient blood flow throughout the system. Therefore, maintaining mitochondrial health by balancing the levels of intracellular reactive oxygen species (ROS) and quality control systems is vital for cardiac cell survival. This review highlights the role of cytochrome c oxidase subunit 4 (COX4), which is primarily located in the mitochondrial electron transport chain, in the context of the heart. There are two isoforms, i.e., COX4-1 and COX4-2. The intricate balance between the two isoforms combats cellular stress while maintaining efficient ATP generation through oxidative phosphorylation. However, persistent stress impairs the ability of COX4 to dynamically shift between isoforms, resulting in massive ROS production and less efficient mitochondrial respiration, which ultimately hampers cardiac function. The subsequent review highlights the role of COX4, its dynamic isoform shifts, and the contribution of COX-4 to cardiac physiology, as well as its contribution to date in aggravating CVDs. Additionally, compounds capable of modulating COX4 in cardiac disease conditions both preclinically as well as clinically are being explored.
    Keywords:  Cardiovascular diseases; Cytochrome C oxidase subunit 4; Heart failure; Mitochondrial dysfunction; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.lfs.2026.124295
  50. Nature. 2026 Mar 05.
    Inside Mexico's stem-cell industry.
    Gemma Conroy.
      
    Keywords:  Business; Gene therapy; Law; Stem cells; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-026-00533-9
  51. Nat Plants. 2026 Mar 03.
    High-frequency biparental inheritance of plant mitochondria upon chilling stress and loss of a genome-degrading nuclease.
    Enrique Gonzalez-Duran, Zizhen Liang, Joachim Forner, Dennis Kleinschmidt, Weiqi Wang, Liwen Jiang, Kin Pan Chung, Ralph Bock.
      Mitochondria are inherited maternally in the vast majority of eukaryotes. Occasional transmission of paternal mitochondria (paternal leakage) can lead to heterochondriomy and recombination between maternal and paternal mitochondrial genomes. Despite its potential physiological and evolutionary consequences, the extent of paternal leakage and the cellular processes governing mitochondrial inheritance remain largely unknown. Here we have established a robust genetic screen to detect paternal mitochondrial inheritance in tobacco (Nicotiana tabacum). Our data reveal an unexpectedly high paternal transmission frequency of 0.18%, which increased markedly to 7.34% when the organellar exonuclease DPD1 was disrupted and pollen development occurred at low temperature. Notably, paternally transmitted mitochondria restored growth, development and male fertility in progeny that inherited dysfunctional mitochondria from the maternal parent. Together, our findings uncover molecular mechanisms underlying maternal mitochondrial inheritance, and highlight the potential of biparental transmission to rescue mitochondrial function and generate novel mitochondrial genotypes through recombination.
    DOI:  https://doi.org/10.1038/s41477-026-02242-7
  52. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261427020
    A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.
    Anastasia Ambrose, Morganne McCabe, Shalini Bahl, David Sinasac, Thomas Snyder, Saadet Mercimek-Andrews.
       Background: Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome.
    Objective: To treat this patient with triheptanoin to improve neurodevelopmental outcome.
    Design: Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy.
    Methods: A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry.
    Results: Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well.
    Conclusion: Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.
    Keywords:  6-oxo-pipecolate; ALDH7A1; developmental delay; neurodevelopmental outcome; pyridoxine-dependent epilepsy; triheptanoin
    DOI:  https://doi.org/10.1177/26330040261427020
  53. Curr Opin Neurobiol. 2026 Mar 05. pii: S0959-4388(26)00015-2. [Epub ahead of print]98 103179
    How to discover novel genes that cause Parkinson's disease.
    Matthew J Farrer.
      Parkinson's disease (PD) is an age-associated movement disorder with many variable symptoms, albeit with no treatments to slow or halt clinical progression. Its etiology is multifactorial with a genetic heritability of ∼27%, and even monogenic disease in families manifests with incomplete/reduced penetrance and variable expressivity. Over the past 28 years, genetic linkage studies have identified causal mutations to inform clinical diagnosis, modeling, and therapeutic development. Indeed, clinical trials to lower alpha-synuclein (SNCA) expression or inhibit leucine-rich repeat kinase 2 (LRRK2) activity are far advanced. Evolutionarily, the population frequencies of several Mendelian discoveries have been driven by positive selection as they provide an advantage in immune defense. Their precise molecular deficits converge about synaptic, mitophagy/autophagic, and immune processes, while physiologic modeling highlights peripheral inflammation as a driver of dopaminergic neuronal loss leading to motor dysfunction. In addition, genome-wide association studies have identified a large number of loci and genetic variants. Nevertheless, these require much larger sample sizes to see ever diminutive effects, as predicted by Fisher's infinitesimal model. Most of the heritability of PD is not explained by single-nucleotide polymorphisms, and few of these associated variants are biologically informative as their effect sizes are too small and pleiotropic. Despite technologic advances to enable global genome sequencing and rare-variant discovery, association is not causation. Rather the discovery of new genes and pathogenic variants that cause PD requires a family-based approach. This is best accomplished with 1) singleton patients with young-onset PD and their asymptomatic first-degree relatives and 2) comparative analysis of the genomes of affected individuals in multi-incident pedigrees. Complimentary investments in longitudinal family-based studies that extend beyond movement disorders are needed to inform disease prognosis, enable biomarker discovery and validation, and enable clinical trials.
    DOI:  https://doi.org/10.1016/j.conb.2026.103179
  54. Int J Stem Cells. 2026 Mar 06.
    PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
    Ji-Hee Kim, Su-Jung Park, Jeong-A Lee, Chong Kun Cheon.
      Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.
    Keywords:  Arts syndrome; Induced pluripotent stem cells; Neural stem cells; Nicotinamide mononucleotide; PRPS1 protein; Senescence
    DOI:  https://doi.org/10.15283/ijsc25127
  55. Neuromuscul Disord. 2026 Mar 02. pii: S0960-8966(26)00058-1. [Epub ahead of print] 106390
    Congenital skeletal muscle myopathy due to the recently described digenic inheritance of TTN and SRPK3 genetic variants: a case study.
    Dominic Spicer, Lucas Dejong, Abhi Kulkarni, Karin S Kassahn, Roula Ghaoui.
      The recently described skeletal myopathy from dual inheritance of TTN and SRPK3 genetic variants has demonstrated digenic inheritance constitutes an under-recognised burden amongst inherited neuromuscular disorders. Neuromuscular specialist input is essential to guide appropriate genetic testing for these elusive diagnoses. Here we present the first case since the initial discovery of this condition, of an adult age diagnosis of TTN/SRPK3 congenital myopathy. Our proband achieved an adult age diagnosis but had congenital symptoms previously diagnosed 'minimal change myopathy' from a childhood muscle biopsy. Their presentation was phenotypically consistent with the initial cohort. He exhibited congenital limb-girdle weakness/wasting, delayed motor developmental milestones, restrictive ventilatory deficit, Achilles tendon contractures and hyperCKaemia but no evidence of cardiomyopathy. Genetic diagnosis was achieved through research-based whole-genome sequencing and targeted SRPK3 gene review, after finding a TTN variant. Knowledge of these specific variants and inheritance pattern enabled diagnosis, where standard panel testing had missed it.
    Keywords:  Digenic inheritance; Myopathy; Neuromuscular; Pathogenic gene; SRPK3; TTN; Whole genome sequencing
    DOI:  https://doi.org/10.1016/j.nmd.2026.106390
  56. Front Neurosci. 2026 ;20 1764964
    Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.
    Yanxu Zheng, Wenke Zhou, Haozhe Chang, Kuihong Zheng.
      Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have become major global causes of disability and mortality. Their complex pathogenic mechanisms remain incompletely understood, and effective disease-modifying therapies are still lacking. Traditional animal models and two-dimensional (2D) cell culture systems exhibit notable limitations in structural complexity, human relevance, and translational validity, making it difficult to faithfully recapitulate human-specific neuropathology. In recent years, brain organoid technology derived from induced pluripotent stem cells (iPSCs) has advanced rapidly, enabling the self-organization of diverse neuronal and glial cell types within a three-dimensional (3D) architecture that partially mimics human brain development and disease-related pathological events. When integrated with CRISPR-Cas9-based genome editing and multi-omics profiling, organoids support causal mechanism studies, target validation, and individualized drug-response prediction, highlighting their growing value in early-stage drug discovery. Despite current challenges-including insufficient maturation, lack of vascularization and immune components, and batch variability-the continuous progress in bioengineering, microfluidic systems, and artificial intelligence (AI)-driven multimodal data analysis is steadily expanding the translational potential of organoids as human-relevant preclinical models. Overall, brain organoids provide an essential foundation for constructing physiologically relevant and predictive research platforms for neurodegenerative diseases, offering new opportunities for therapeutic development and precision medicine.
    Keywords:  CRISPR-Cas9 genome editing; brain organoids; drug discovery; induced pluripotent stem cells (iPSCs); neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1764964
  57. Cell Commun Signal. 2026 Mar 04.
    From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases.
    Weilong Hong, Shiyun Long, Milad Ashrafizadeh, Gautam Sethi, Chenyang Duan.
      
    Keywords:  Damage-associated molecular patterns (DAMPs); Endosymbiosis; Immunometabolism; Inflammation; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1186/s12964-026-02736-z
  58. Front Pharmacol. 2026 ;17 1748360
    Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
    Marcos Roberto de Oliveira.
      Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich's ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type-specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.
    Keywords:  dimethyl fumarate; mitochondria; mitochondrial biogenesis; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1748360
  59. Chin Med J (Engl). 2026 Mar 05. 139(5): 653-671
    Role of LRRK2 in physiological activities, diseases, and therapy.
    Zhuoran Wang, Qingfang Li, Lingxi Yan, Mingyu Du, Xiawei Wei.
       ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is a critical target for the treatment of Parkinson's disease (PD) and potentially other diseases. LRRK2 is involved in intracellular signaling, immune response, and inflammation, with key roles in both the central nervous system and peripheral tissues. LRRK2 mutations are linked to cellular dysfunction including mitochondrial and neuronal damage and can disrupt signaling pathway balance, thereby contributing to PD and other disorders. Inhibiting LRRK2 kinase activity shows potential for treating PD by correcting cellular imbalances and reducing neuronal damage. However, risks associated with regulating a multifunctional protein must be addressed. Further research on the molecular partners and tissue-specific functions of LRRK2 is essential for developing targeted therapies and improving treatment options for related diseases. This review offers a comprehensive analysis of LRRK2, with a focus on its physiological functions, disease involvement, and emerging therapeutic strategies.
    Keywords:  Immune response; Inflammation; Clinical trial; Inhibitors; Intracellular signaling; LRRK2; Novel targets; Parkinson’s disease; Targeted therapy
    DOI:  https://doi.org/10.1097/CM9.0000000000003989
  60. Redox Biol. 2026 Mar 03. pii: S2213-2317(26)00107-2. [Epub ahead of print]92 104109
    ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
    Yosuke Nagai, Keiichiro Matoba, Rimei Nishimura.
      Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) serve as central molecular switches that couple cytoskeletal dynamics with redox regulation and mitochondrial quality control. Dysregulated ROCK signaling promotes mitochondrial fragmentation, oxidative stress, and metabolic inflexibility, thereby linking nutrient overload to multi-organ dysfunction in diabetes, obesity, and cardiometabolic disease. Recent advances have identified ROCK1 as a key regulator of mitochondrial dynamics and bioenergetics: ROCK1 directly phosphorylates the fission protein Drp1 and suppresses the AMPK-PGC-1α pathway, resulting in impaired fatty acid oxidation, decreased mitochondrial biogenesis, and enhanced oxidative injury. Pharmacological or genetic inhibition of ROCK restores mitochondrial structure, energy metabolism, and redox balance across the heart, kidney, and liver, underscoring its therapeutic relevance. In contrast, ROCK2 plays more complementary roles in immune regulation and fibrotic remodeling, as evidenced by the clinical success of selective ROCK2 inhibition. In addition, metabolic drugs such as statins and GLP-1 receptor agonists can indirectly attenuate ROCK activity, suggesting feasible translational strategies for cardiometabolic disease. Despite these advances, isoform-specific mechanisms remain incompletely defined, and selective ROCK1 inhibitors have not yet been developed. Future studies should focus on clarifying ROCK1-specific signaling in mitochondrial homeostasis, developing tissue-targeted inhibitors, and combining ROCK modulation with metabolic or antioxidant therapies. A further understanding of the ROCK-mitochondria axis will enable the design of precise interventions to restore redox equilibrium and prevent progression of metabolic and cardiovascular disorders.
    Keywords:  Cardiometabolic diseases; Metabolic remodeling; Mitochondrial dynamics; ROCK1; Redox signaling
    DOI:  https://doi.org/10.1016/j.redox.2026.104109
  61. Nature. 2026 Mar 04.
    AI can write genomes - how long until it creates synthetic life?
    Ewen Callaway.
      
    Keywords:  Genomics; Machine learning; Synthesis
    DOI:  https://doi.org/10.1038/d41586-026-00681-y
  62. Inflammation. 2026 Mar 03.
    Mitochondrial Pyruvate Metabolism Controls Alveolar Stem Cell Fate and Inflammatory Balance.
    Zuokuan He, Xue Li, Xuan Miao, Guiying Xu, Sisi Wang, Li Li, Qi Wu, Huaiyong Chen.
      
    Keywords:  Alveolar type 2 cells; Epithelial repair; Lung injury; Mitochondrial pyruvate carrier 2
    DOI:  https://doi.org/10.1007/s10753-026-02470-1
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