bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–04–12
sixty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
  2. Ophthalmic manifestations of mitochondrial disorders.
  3. A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
  4. Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
  5. Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
  6. mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
  7. Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
  8. MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
  9. Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
  10. Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
  11. Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
  12. Mitochondria transfer in tissue homeostasis and diseases.
  13. Mechanisms of human mitochondrial leaderless mRNA translation initiation.
  14. Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
  15. Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function.
  16. Human pluripotent stem cell engineering with CRISPR-Cas9 for Parkinson's disease.
  17. STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
  18. Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.
  19. Silver nanoparticles induce binding of mitochondrial DNA polymerase gamma subunit Polg2 and mitochondrial dysfunction in HeLa cells.
  20. Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
  21. PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
  22. Fluorescence-Based Quantification of Mitochondrial Damage in Human Airway Smooth Muscle Cells.
  23. Diffusive spreading across dynamic mitochondrial network architectures.
  24. Molecular pathogenesis and gene therapy-based intervention of GTPBP3-related mitochondrial disease.
  25. Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.
  26. Mitochondrial Transfer: From Bench to Bedside.
  27. Exercise induces sex-specific assembly of mitochondrial supercomplexes.
  28. Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.
  29. Novel NDUFV1 variant in progressive cavitating leukodystrophy with microcephaly: a case report.
  30. Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
  31. Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
  32. A unified ACSF3-mtFAS model linking mitochondrial energy metabolism to human anthropometric evolution.
  33. Recalibrating cell fate: targeting the mitochondrial signaling hub with natural active compounds to inhibit regulated cell death in diabetic kidney disease.
  34. Mitochondrial transplantation for osteoarthritis: from molecular mechanisms to clinical translation.
  35. Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
  36. Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders.
  37. Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
  38. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  39. DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
  40. Decoding the Heterodimer Stability of Pro-Apoptotic Effectors via Multiscale Simulations: Mutational Insights Into Mitochondrial Signaling.
  41. Leber Hereditary Optic Neuropathy in the Elderly: A Case Report.
  42. Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.
  43. TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.
  44. Single-Cell and Spatial Omics: Methods and Applications.
  45. Identifying targeting signals and distinct localization-based roles of yeast aldehyde dehydrogenase Hfd1.
  46. Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
  47. In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
  48. Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
  49. Correction of a recurrent pathogenic variant in methylmalonic acidemia using adenine base editing.
  50. Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
  51. Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice.
  52. IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.
  53. RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response.
  54. Novel heterozygous UCHL1 variant causing severe optic atrophy and vision loss.
  55. Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.
  56. ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
  57. Clinical and Genetic Spectrum of ACO2-Linked Dominant Optic Atrophy.
  58. Rethinking Mitochondria: The Extracellular Dimension.
  59. Public support for mitochondrial donation: an Australian knowledge and attitudes study.
  60. Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
  61. Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.
  62. Mapping the mammalian dark metabolome by in vivo isotope tracing.
  63. Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
  64. Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.
  65. Glycosylation-driven necroptosis in retinal degeneration: dual rescue by AAV8 gene therapy and RIPK1 inhibition.
  1. Nat Commun. 2026 Apr 09.
    The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-71630-6
  2. Prog Retin Eye Res. 2026 Apr 03. pii: S1350-9462(26)00032-7. [Epub ahead of print] 101466
    Ophthalmic manifestations of mitochondrial disorders.
    Megan F Baxter, Grace A Borchert, Emma L Blakely, Claire W Ruan, Robert E MacLaren, Robert McFarland, Robert W Taylor.
      Mitochondrial diseases are the most common group of inherited neurometabolic disorders and frequently involve multiple organ systems with high energy demands. Ophthalmic manifestations are a common occurrence in affected individuals and may be the earliest or predominant clinical feature. However, the marked clinical heterogeneity of mitochondrial eye disease often delays recognition and therefore diagnosis. Mitochondria play a central role in cellular metabolism through the process of oxidative phosphorylation. Genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can impair this key metabolic process leading to clinical disease. Diagnosing such mitochondrial diseases is however often complicated - the same genetic change can result in different symptoms (variable expressivity); different genes can cause similar conditions (allelic and locus heterogeneity); a single genetic change may affect multiple body systems (pleiotropy); and the proportion of affected mitochondrial DNA molecules can vary between tissues (mtDNA heteroplasmy). While the diagnostic process will certainly be influenced by the initial clinical presentation, perhaps more important is clinician awareness and early consideration of an underlying mitochondrial disorder. Early and accurate molecular genetic diagnosis is both available and essential, not only for prognostication and management, but also for reproductive counselling, access to appropriate clinical trials, cascade testing of relevant family members and consideration of emerging mitochondrial therapeutics(1,2). In this review, we summarise the biochemical and genetic foundations of mitochondrial eye disease, describe the spectrum of clinical phenotypes, outline diagnostic approaches and considerations, and highlight the importance of precise early diagnosis in guiding management and reproductive decision-making.
    Keywords:  mitochondria; mitochondrial counselling; ophthalmology
    DOI:  https://doi.org/10.1016/j.preteyeres.2026.101466
  3. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123
    A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
    Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.
    Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis
    DOI:  https://doi.org/10.1073/pnas.2535453123
  4. bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]
    Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
    Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.
      Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.
    DOI:  https://doi.org/10.64898/2026.03.29.715103
  5. Front Bioeng Biotechnol. 2026 ;14 1765995
    Optimized ND4 allotopic expression for gene therapy of Leber's hereditary optic neuropathy.
    Evgeniy V Lapshin, Alexander D Egorov, Alexander S Malogolovkin, Nizami B Gasanov, Svetlana A Smirnikhina, Vyacheslav Yu Tabakov, Alexander V Karabelsky.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by central vision loss, primarily resulting from mutations disrupting the electron transport chain. The most prevalent LHON-causing mutation is mt.11778G>A in the mitochondrial MT-ND4 gene, which encodes a critical subunit of complex I. Allotopic expression, a promising gene therapy strategy, aims to deliver a functional nuclear version of ND4 into the cell nucleus and target the resulting protein to the mitochondria. The efficiency of this approach critically depends on the mitochondrial targeting signal used. In this study, we screened five different MTS sequences to optimize the allotopic expression of ND4 in a HEK-293 cellular model of LHON harboring the mt.11778G>A mutation. We identified MTS-cox8k as the most effective signal for restoring mitochondrial function. Treatment with this construct significantly mitigated key pathological hallmarks: reactive oxygen species decreased by 72%, mitochondrial calcium levels dropped by 47%, and mitochondrial membrane potential (ΔΨm) increased by 38%. These results underscore the therapeutic potential of allotopic ND4 expression and highlight the critical importance of MTS optimization for developing effective treatments for mitochondrial diseases like LHON.
    Keywords:  Leber’s neuropathy; gene therapy; mitochondrial function test; mitochondrial localization; mitochondrial transport
    DOI:  https://doi.org/10.3389/fbioe.2026.1765995
  6. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2526136123
    mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
    Rupa Banerjee, Vanessa Trauschke, Nils Bertram, Ina Aretz, Christof Osman, Don C Lamb, Dejana Mokranjac.
      Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a variety of cellular processes. The conformational cycles of several Hsp70 chaperones, driven by ATP binding and hydrolysis, and regulated by cochaperones and substrate proteins, were analyzed in vitro in great detail. In contrast, little is known about the conformation Hsp70s adopt in their natural environments. In mitochondria, mtHsp70 is distributed between the TIM23 complex at the inner membrane, where it is involved in import of proteins from the cytosol, and a matrix-pool that is primarily involved in folding of proteins and prevention of their aggregation. Here, we used fluorescence microscopy to analyze the conformation of mtHsp70 at the single molecule level within physiologically active mitochondria. Our results revealed that the majority of mtHsp70 molecules are present in a substrate-bound state, suggesting that the mtHsp70 network functions at the limits of its capacity. To understand the biological significance of this finding, we modulated the levels of unfolded proteins in the matrix. Unfolded proteins reduced the association of mtHsp70 with the TIM23 complex and specifically impaired mtHsp70-dependent import of proteins. Our data show that unfolded proteins lead to a redistribution of mtHsp70 within mitochondria revealing how mitochondrial proteostasis stress is signaled to the cell-unfolded proteins remove mtHsp70 from the import sites, reducing the efficiency of protein import and initiating cellular programs to rescue or remove dysfunctional mitochondria. Thus, mtHsp70 acts as a mitochondrial quality control sensor that converts proteostasis stress into impaired protein import.
    Keywords:  Hsp70 chaperones; mitochondria; protein homeostasis; protein import; single molecule FRET
    DOI:  https://doi.org/10.1073/pnas.2526136123
  7. Free Radic Biol Med. 2026 Apr 06. pii: S0891-5849(26)00266-2. [Epub ahead of print]
    Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
    Ajay Ashok, Kin-Sang Cho, Wai Lydia Tai, Lu Huang, Hio Tong Kam, Suman Chaudhary, Karen Chang, Sarita Pooranawattanakul, Julie Chen, Anton Lennikov, Dong Feng Chen.
      Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.
    Keywords:  Mitochondrial transplantation; PC12 cells; SH-SY5Y cells; nerve regeneration; neuroprotection; optic nerve crush; retinal ganglion cells
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.069
  8. Comput Struct Biotechnol J. 2025 ;27 1673-1676
    MitoEdit: A pipeline for optimizing mtDNA base editing and predicting bystander effects.
    Devansh Shah, Kelly McCastlain, Ti-Cheng Chang, Xun Zhu, Gang Wu, Mondira Kundu.
      Human mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Recent advances in mtDNA base editing technologies offer exciting opportunities to model and study these mutations. However, current approaches are hindered by the challenge of unintended bystander edits, which are often identified only through labor-intensive empirical testing, leading to inefficiencies in construct development. To address this limitation, we developed MitoEdit, an innovative computational tool designed to optimize mtDNA base editing by leveraging empirical base editor patterns. MitoEdit enables users to input DNA sequences in a simple text-based format, specify the target base position and define the desired modification. The tool outputs a list of candidate target windows, predicts the number and functional impact of bystander edits and provides flanking nucleotide sequences tailored for TALE (transcription activator-like effectors) array protein binding. In silico evaluations demonstrate that MitoEdit accurately predicts the majority of bystander edits, reducing the number of constructs that need to be tested empirically. By streamlining the design process, MitoEdit accelerates the development of mitochondrial base editing constructs, thereby facilitating functional studies and enabling faster discovery. Ultimately, MitoEdit has the potential to advance disease modeling and support the development of therapeutic strategies for mitochondrial-related disorders.
    Keywords:  Base editing; Genome engineering; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.csbj.2025.04.027
  9. J Neurol. 2026 Apr 10. pii: 263. [Epub ahead of print]273(5):
    Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
    Ignazio Giuseppe Arena, Shamini Saravanabavan, Rita Horvath, Jelle van den Ameele.
      Primary mitochondrial diseases (PMDs) represent a clinically and genetically heterogeneous group of disorders characterized by impaired oxidative phosphorylation and multisystem involvement, commonly affecting the nervous system. As therapeutic development accelerates, there is a growing need for robust biomarkers capable of supporting diagnosis, stratifying patient subgroups, monitoring disease progression, and providing sensitive pharmacodynamic readouts for clinical trials. This review summarizes recent advances in three major non-invasive biomarker domains relevant to PMDs: circulating serum and molecular biomarkers, functional and digital endpoints, and neuroimaging modalities. Circulating markers, such as FGF21, GDF15, NfL, and NAD⁺-related signatures, have each been proposed for diagnosis and to follow disease progression, while multi-omics approaches are paving the way toward integrated molecular phenotyping. Digital health technologies, including accelerometry and gait analytics, enable objective quantification of real-world functional impairment, although disease-specific validation remains an unmet need. Neuroimaging offers mechanistic insights through metabolic (MRS, CEST), perfusion (ASL), and molecular modalities (mitochondrial PET tracers). Cutting-edge tools, such as Multi-Spectral Optoacoustic Tomography (MSOT), Raman spectroscopy, and Near-Infrared Spectroscopy (NIRS), promise real-time or spatially resolved assessment of mitochondrial function. Together, these developments outline multidimensional biomarker approaches for PMDs, with the potential to directly measure target engagement and clinically meaningful phenotypes in future therapeutic trials. Future progress will depend on longitudinal validation, harmonized acquisition protocols, and the integration of multimodal platforms to support upcoming therapeutic trials and precision medicine strategies.
    Keywords:  Biomarkers; Clinical trials; Digital health technologies; Functional endpoints; Magnetic resonance imaging; Mitochondrial disease; Neuroimaging; Phenotyping; Positron emission tomography; Precision medicine; Wearable devices
    DOI:  https://doi.org/10.1007/s00415-026-13794-1
  10. Nat Metab. 2026 Apr 10.
    Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
    Tomas Paulenda, Maxim N Artyomov.
      
    DOI:  https://doi.org/10.1038/s42255-026-01493-0
  11. Circ Res. 2026 Apr 10. 138(8): e326982
    Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.
    Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
  12. Int J Biol Sci. 2026 ;22(6): 3144-3173
    Mitochondria transfer in tissue homeostasis and diseases.
    Lei Qin, Donghao Gan, Zecai Chen, Zhen Xu, Mingyue Wu, Bimin Gao, Yufeng Long, Xihong Mou, Wenqing Li, Weihong Yi, Guozhi Xiao.
      Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria are segregated and transported from parent to daughter cells during division or differentiation, a process known as vertical mitochondria transfer (VMT). A growing body of literature indicates that various cell types can export mitochondria for delivery to developmentally unrelated cell types without division, a process termed horizontal mitochondria transfer (HMT). In this review, we summarize current understanding of the modes of mitochondria transfer and illustrate the phenomenon of HMT across different tissue backgrounds, including the immune, cardiovascular, respiratory, hepatic, renal, musculoskeletal, adipose, and reproductive systems. Moreover, updated applications and functions of mitochondria transfer are discussed. Additionally, we also highlight the therapeutic potential of mitochondria transfer in current preclinical and clinical trials for inherited mitochondrial diseases, cancer, wound healing, and injuries of the respiratory and central nervous systems.
    Keywords:  extracellular vesicles (EVs); gap junctions (GJs); horizontal mitochondria transfer; intercellular mitochondria transfer; tunneling nanotubes (TNT); vertical mitochondria transfer
    DOI:  https://doi.org/10.7150/ijbs.129709
  13. Nat Commun. 2026 Apr 04.
    Mechanisms of human mitochondrial leaderless mRNA translation initiation.
    Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.
      Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNAMet before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNAMet and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.
    DOI:  https://doi.org/10.1038/s41467-026-71535-4
  14. Cell Commun Signal. 2026 Apr 06.
    Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
    Eve Harding, Veronica Bazzani, Carlo Vascotto.
      
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling
    DOI:  https://doi.org/10.1186/s12964-026-02858-4
  15. bioRxiv. 2026 Mar 11. pii: 2026.03.06.710200. [Epub ahead of print]
    Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function.
    Chiemela Ohanele, Nahum F Arefeayne, Nasab Ghazal, Ethan H Liu, Nina C Turcanu, Matthew J Horchar, Biplab Dasgupta, Adriana Harbuzariu, Chunhui Xu, Victor Faundez, Jennifer Q Kwong.
      Cardiac morphogenesis is an intricate process that requires a precise coordination between metabolic and structural maturation, but how these processes are linked remain unclear. In previous work, we identified one candidate underlying this connection: the mitochondrial citrate carrier (SLC25A1), a critical regulator of embryonic heart development. Here, using systemic and cardiomyocyte-specific Slc25a1 deletion in mice together with SLC25A1 knockout (KO) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we demonstrate that SLC25A1 functions cell-autonomously within cardiomyocytes to regulate differentiation, mitochondrial maturation, and ventricular morphogenesis. Transcriptomic analysis of SLC25A1-deficient hearts revealed dysregulation of gene programs regulating cardiomyocyte differentiation and mitochondrial function. Consistent with these changes, loss of SLC25A1 in developing cardiomyocytes impaired mitochondrial function and resulted in defective ventricular wall compaction in vivo. Likewise, SLC25A1 KO hiPSC-CMs exhibited defective cardiomyocyte differentiation, disorganized myofibrils, and immature mitochondrial organization and function in vitro. Together, our findings position SLC25A1 as a cardiomyocyte-intrinsic, cell-autonomous regulator that links mitochondrial citrate export to developmental gene programs, revealing a mitochondrial regulatory axis for cardiomyocyte maturation and cardiac morphogenesis that contributes to congenital heart disease.
    DOI:  https://doi.org/10.64898/2026.03.06.710200
  16. Exp Mol Med. 2026 Apr 10.
    Human pluripotent stem cell engineering with CRISPR-Cas9 for Parkinson's disease.
    Seung Bin Park, Ji-Soo Kim, Yuri Ha, Min Seong Kim, Tae Wan Kim.
      Parkinson's disease (PD) entails loss of substantia nigra dopamine (DA) neurons and α-synuclein pathology. Currently, no effective disease-modifying therapies have been developed. Human pluripotent stem cells (hPS cells) can generate DA neurons on scale, enabling human genetic PD modeling of mitochondrial, lysosomal and synaptic connection failure that leads to DA neuron degeneration. Clustered regularly interspaced short palindromic repeats (CRISPR) extends this human model by providing causal, isogenic interrogation and transcriptional regulation of PD genes and reporter knock-ins that support purification and high-content screening. hPS cell-based DA cell grafts can restore motor function yet face >90% acute cell death and product heterogeneity in vivo post implantation. CRISPR enabled not only an in vivo cell survival screen to identify the cell death regulators but also a reporter-guided enrichment of DA neurons and chemogenetic control of grafted DA cell function in vivo. Here we summarize this progress and outline a practical road map to accelerate the development of precise human models and advanced hPS cell-based cell therapies for PD.
    DOI:  https://doi.org/10.1038/s12276-026-01679-2
  17. Autophagy. 2026 Apr 11.
    STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
    Jin-Yi Lin, Ze-Bo Huang, Evandro F Fang, Guang Lu.
      PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
    Keywords:  Alzheimer disease; PINK1; PRKN; STUB1; VCP/p97; memory; mitochondrial homeostasis; mitophagy; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2026.2658848
  18. Nat Genet. 2026 Apr 08.
    Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.
    Rocio Rius, Alexander J M Blakes, Yuyang Chen, Joachim De Jonghe, François Lecoquierre, Ruebena Dawes, Benjamin Cogne, Hyung Chul Kim, Javeria R Alvi, Florence Amblard, Morad Ansari, Annabelle Arlt, Christina Austin-Tse, Sarah Baer, Meena Balasubramanian, Elsa V Balton, Giulia Barcia, Ana Beleza-Meireles, Jonathan A Bernstein, Jasmin Beygo, Pierre Blanc, Nuria C Bramswig, Frederik Braun, Daniel Buchzik, Daniel G Calame, Jamie Campbell, Charles Coutton, Chloe A Cunningham, Nitsuh Dargie, Christel Depienne, Katrina M Dipple, Anne Dieux, Abhijit Dixit, Lauren Dreyer, Haowei Du, Salima El Chehadeh, Michael Field, Lisa J Ewans, Vanessa Geiger, Richard A Gibbs, Ian Glass, Olivier Grunewald, Paul Gueguen, Tobias B Haack, Hamza Hadj Abdallah, Radu Harbuz, Ingo Helbig, Judit Horvath, Alexander Hustinx, Bertrand Isidor, Marie-Line Jacquemont, Fraser Jamie, Médéric Jeanne, Riley Kessler, Hannah Klinkhammer, G Christoph Korenke, Urania Kotzaeridou, Peter Krawitz, Steven Laurie, Richard J Leventer, Rebecca J Levy, James R Lupski, Pierre Marijon, Kaitlin E McGinnis, Rodrigo Mendez, Olfa Messaoud, Caroline Nava, Mevyn Nizard, Anne O'Donnell-Luria, Melanie C O'Leary, Simone Olivieri, Amitav Parida, Davut Pehlivan, Anna Jenne Prentice, Jennifer E Posey, Chloe M Reuter, Véronique Satre, Caroline Schluth-Bolard, Thomas Smol, Tipu Sultan, John Taylor, Christel Thauvin-Robinetvin, Julien Thevenon, Eloise Uebergang, Sandra Ueberberg, Catherine Vincent-Delorme, Evangeline Wassmer, Emma Westwood, Matthew T Wheeler, Elif Yilmaz Gulec, Adeline Vanderver, Arastoo Vossough, Stephan J Sanders, Siddharth Banka, Gregory M Findlay, Daniel G MacArthur, Cas Simons, Nicola Whiffin.
      Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.
    DOI:  https://doi.org/10.1038/s41588-026-02554-6
  19. Ecotoxicology. 2026 Apr 07. pii: 95. [Epub ahead of print]35(5):
    Silver nanoparticles induce binding of mitochondrial DNA polymerase gamma subunit Polg2 and mitochondrial dysfunction in HeLa cells.
    Xueling Peng, Qingdai Liu.
      
    Keywords:  AgNPs; Manomaterials; Mitochondria; Polg2
    DOI:  https://doi.org/10.1007/s10646-026-03081-0
  20. Orphanet J Rare Dis. 2026 Apr 09. pii: 143. [Epub ahead of print]21(1):
    Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
    Annamaria Sapuppo, Grete Francesca Privitera, Vincenzo Sortino, Piero Pavone, Agata Polizzi, Martino Ruggieri, Raffaele Falsaperla.
      
    Keywords:  Blueprint genetics; Buccal swab; Clinical phenotype; Diagnostic sensitivity; Early onset; Mitochondrial diseases; Next-generation sequencing; Pediatric neurology
    DOI:  https://doi.org/10.1186/s13023-026-04213-9
  21. J Cell Biol. 2026 Jun 01. pii: e202508040. [Epub ahead of print]225(6):
    PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
    Shan Zhao, Jie Zhang, Tengfei Ma, Jinglin Li, Mei Duan, Xin Wang, Meijiao Li, Chonglin Yang.
      Mitochondria form highly complex and dynamic networks to maintain their homeostasis. However, the underlying mechanisms remain elusive. Here we report a PI(3)P-dependent mechanism that regulates the mitochondrial dynamics required for formation of mitochondrial networks. Using genetic screening, we reveal that mutations of Caenorhabditis elegans EXC-5/FGD lead to formation of spherical and unconnected mitochondria. EXC-5 binds to endosomal PI(3)P generated by the PI 3-kinase VPS-34 and is recruited to endosome-mitochondrion contacts, where it acts as the guanine nucleotide exchange factor to activate the CDC-42 GTPase. Loss of exc-5 or vps-34 similarly disrupts mitochondrial and actin networks as well as mitochondrial recruitment of DRP-1, leading to failure of mitochondrial fission, branching, and elongation. In contrast, expression of constitutively activated CDC-42 ameliorates the defective mitochondrial networks in an actin-dependent manner. Together, these findings suggest a PI(3)P-EXC-5-CDC-42 axis that acts at endosome-mitochondrion contacts to regulate actin organization for maintenance of mitochondrial dynamics and networks.
    DOI:  https://doi.org/10.1083/jcb.202508040
  22. Am J Physiol Cell Physiol. 2026 Apr 09.
    Fluorescence-Based Quantification of Mitochondrial Damage in Human Airway Smooth Muscle Cells.
    Sanjana Mahadev Bhat, Gary C Sieck.
      Mitochondrial quality control is essential for maintaining cellular homeostasis by balancing the removal of damaged mitochondria (mitophagy) with the generation of new mitochondria (mitochondrial biogenesis). A key feature of mitochondrial damage is loss of mitochondrial membrane potential (ΔΨm), which initiates mitophagy, enabling effective mitochondrial clearance. Although an array of tools exists to assess mitochondrial damage (depolarization), many rely on acute, non-physiological depolarization or provide semiquantitative measures of mitochondrial damage, limiting their ability to resolve intact versus damaged mitochondria within heterogeneous mitochondrial networks. Therefore, in the present study we developed and validated an imaging-based assay to quantify intact mitochondria in human airway smooth muscle (hASM) cells using dual-fluorescence labeling. This approach combines a ΔΨm-dependent (MitoTracker Red FM) dye with a ΔΨm-independent label (CellLight Mitochondria-GFP). Dual-labeled mitochondria in untreated hASM cells exhibited ~10% non-overlap between the two fluorescence signals, indicating presence of damaged (depolarized) mitochondria in homeostatic conditions. Dose- and time-dependent treatment with the mitochondrial uncoupler FCCP induced loss of membrane potential, confirmed by TMRM, and resulted in a marked reduction in fluorescence overlap, volume of intact mitochondria and increased mitochondrial fragmentation. Complementary analysis using the redox-sensitive reporter pMitoTimer was performed, where a shift in fluorescence signal from green to red is indicative of increased mitochondrial oxidative stress and rate of mitochondrial turnover. Together, these findings validate the dual-labeling strategy as a quantitative method to distinguish intact from damaged mitochondria in situ and as a useful tool for studying mitochondrial quality control, potentially translatable to various cell and disease models.
    Keywords:  Confocal Imaging; Depolarization; Mitochondria; Mitochondrial Damage; Mitochondrial Membrane Potential
    DOI:  https://doi.org/10.1152/ajpcell.00033.2026
  23. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2523913123
    Diffusive spreading across dynamic mitochondrial network architectures.
    Keaton B Holt, Camryn Zurita, Lizzy Teryoshin, Samantha C Lewis, Elena F Koslover.
      In eukaryotic cells, mitochondria form networks that range from highly fused interconnected structures to fragmented populations of individual organelles that undergo transient interactions. These structures can be described as temporal networks of physical units, whose dynamic topology is determined by fusion, fission, and motion of the mitochondria through intracellular space. The heterogeneity of the mitochondrial population is governed by diffusive transport and interunit exchange of proteins, lipids, ions, and RNA within these networks. We present a unifying framework for the dispersion of material within temporal networks of spatially embedded units that span across a broad connectivity range. Specifically, we consider filling of the networks with a locally produced but globally consumed material, demonstrating that the steady-state content is determined by the balance of timescales for spatial encounter between clusters, local fusion, fission, and diffusive transport within a cluster. As the connectivity increases, filling behavior transitions from three-dimensional spread through a "social network" limited by cluster interactions to low-dimensional transport through a largely stationary "physical network" limited by material diffusivity. We extract parameters for mitochondrial networks in three human cell lines, demonstrating that different cells can access both the social and the physical network regimes. These results provide a quantitative basis for predicting the homogenization of biomolecules through a mitochondrial population. Our framework unifies a variety of temporal network structures into an overarching theory for transport through populations of interacting and interconnected units.
    Keywords:  intracellular transport; mitochondria; networks; organelle dynamics; temporal networks
    DOI:  https://doi.org/10.1073/pnas.2523913123
  24. Nat Commun. 2026 Apr 09.
    Molecular pathogenesis and gene therapy-based intervention of GTPBP3-related mitochondrial disease.
    Yong Zhang, Shi-Ying Yao, Jing Li, Tingting Yu, Hao Liu, Nanlin Zhu, Gui-Xin Peng, Wen-Qiang Zheng, Chun-Rui Ma, En-Duo Wang, Cui Song, Xiao-Long Zhou.
      Mitochondrial transfer RNA (mt-tRNA) modification determines organelle translation and function. GTPBP3 and MTO1 catalyze 5-taurinomethyluridine (τm5U) modification at wobble uridine of five mt-tRNAs. τm5U hypomodification causes mitochondrial encephalomyopathy, but the underlying pathogenesis and intervention strategy due to GTPBP3 mutations are lacking. In this study, we identify two genetic variants (c.689 A > C (p.Q230P) and c.1120 A > G (p.N374D)) of GTPBP3 in a Chinese proband with metabolic disorders and multisystem dysfunction. Mechanistically, Q230P and N374D mutations induce protein multimerization/aggregation, protease degradation, decreased GTPase activity, and tRNA modification to varying degrees, affecting mitochondrial translation, respiration, dynamics, and function. Homozygous N374D mutations in mice cause embryonic lethality; homozygous E230P or compound heterozygous E230P/N374D knock-in mice develop cardiac and muscular dysfunction due to altered mitochondrial translation. Mitochondrial dysfunction and pathology are efficiently reversed by virus-mediated GTPBP3 expression in cells and animals. This study provides valuable insights into the etiology of and promising intervention strategies for GTPBP3-related diseases.
    DOI:  https://doi.org/10.1038/s41467-026-71750-z
  25. J Clin Invest. 2026 Apr 09. pii: e194989. [Epub ahead of print]
    Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.
    Wahyu Handoko Wibowo Darsono, Yeongran Hwang, Erica Valencia, Leonardo Tejo Gunawan, Seung Jae Hyeon, Hoon Ryu, Thor D Stein, Mi-Yoon Chang, Noviana Wulansari, Sang-Hun Lee.
      Loss-of-function mutations in DNAJC6, encoding the co-chaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson's disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell-derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a pro-inflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein-induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.
    Keywords:  Clinical Research; Neuroscience; Parkinson disease
    DOI:  https://doi.org/10.1172/JCI194989
  26. Circ Res. 2026 Apr 10. 138(8): e326984
    Mitochondrial Transfer: From Bench to Bedside.
    Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.
      Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.
    Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984
  27. Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217
    Exercise induces sex-specific assembly of mitochondrial supercomplexes.
    Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.
      The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.
    Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117217
  28. Circ Res. 2026 Apr 10. 138(8): e327357
    Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease.
    Erjola Rapushi, Anubhav Aryal, Tianyuan Yang, Zhixin Li, Xiaohong Wang, Guo-Chang Fan.
      Mitochondria-derived vesicles (MDVs) and mitochondrial extracellular vesicles (mitoEVs) represent 2 related extensions of mitochondrial dynamics that link organelle maintenance to communication within and between cells. MDVs are small vesicles that bud directly from mitochondria, selectively packaging components of the outer membrane, inner membrane, or matrix. They serve as a localized quality control mechanism that removes oxidized or damaged material without engaging the entire mitophagic machinery. After budding, MDVs typically enter the endolysosomal pathway, where they can fuse with late endosomes or lysosomes for cargo degradation. A subset of MDVs also targets other organelles, particularly peroxisomes, contributing to organelle crosstalk, lipid metabolism, and redox balance. By contrast, mitoEVs released into the extracellular space contain intact functional mitochondria, mitochondrial contents (proteins, DNAs/RNAs, lipids, and so on), and nonmitochondrial cargo (ie, mRNAs, noncoding RNAs, and so on), which can be transferred to recipient cells and subsequently induce either pathogenic or beneficial outcomes. Therefore, mitoEVs have been implicated in metabolic cooperation, immune regulation, tissue remodeling, and aging. Accordingly, this review summarizes recent progress on the diverse mechanisms for the biogenesis of MDVs and mitoEVs, as well as available protocols for their isolation. The roles of MDVs and mitoEVs in mediating mitochondrial quality/quantity control and multiple layers of crosstalk between intracellular organelles and different cell types in health and disease are highlighted. Last, mitoEV-mediated pathogenic effects and therapeutic potential in cardiovascular disease are also discussed.
    Keywords:  cardiovascular diseases; extracellular vesicles; lipid metabolism; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327357
  29. BMC Pediatr. 2026 Apr 09.
    Novel NDUFV1 variant in progressive cavitating leukodystrophy with microcephaly: a case report.
    Lu Xiaowei, Wang Hong, Li Hong, Wu Bo, Yu Xiaoli.
       BACKGROUND: Progressive cavitating leukoencephalopathy (PCL) is a rare mitochondrial neurodegenerative disorder primarily caused by mitochondrial respiratory chain complex Ⅰ deficiency, with NDUFV1 identified as a major pathogenic gene. Typical phenotypes associated with NDUFV1-related PCL include motor regression, dystonia, cognitive impairment, and limb weakness, while microcephaly is extremely rare. The c.749T > A (p.Val250Glu) variant in NDUFV1 has not been documented previously, and its clinical significance remains undetermined. This report describes a case of PCL associated with this novel variant and microcephaly, aiming to investigate the correlation between genotype and phenotype.
    CASE PRESENTATION: A 17-month-old male infant of Chinese ethnicity was admitted to the hospital for assessment of motor skill regression. Physical examination revealed a head circumference of 45.5 cm (below the 3rd percentile for age and sex), hypertonia, and positive pyramidal tract signs. Laboratory tests showed elevated blood lactate levels. Neuroimaging revealed widespread, symmetrical, patchy abnormal signals accompanied by cavitation in the bilateral cerebral white matter, extending to involve the corpus callosum, brainstem, cerebellum, and upper cervical spinal cord. Genetic testing identified compound heterozygous NDUFV1 variants: c.749T>A (p.Val250Glu, paternal, previously unreported) and c.365C>T (p.Pro122Leu, maternal). The analysis of mitochondrial respiratory chain enzyme activity in skin fibroblasts revealed a deficiency in complex I. The patient received oral cocktail therapy combined with rehabilitation training and was followed up for over two years, showing improvements in motor, language, and cognitive functions, normalization of blood lactate levels, and reduction of abnormal MRI signals post-treatment.
    CONCLUSION: Our study describes a case of NDUFV1-associated PCL caused by a novel compound heterozygous variant. This finding expands both the mutational spectrum of NDUFV1 and the phenotypic spectrum of PCL. It thus contributes significantly to the understanding of genotype-phenotype correlations in this disorder. Importantly, it highlights the need for early recognition of clinical features such as developmental delay, motor regression, and microcephaly, followed by diagnostic and therapeutic steps including prompt genetic testing, timely diagnosis, and appropriate intervention, all essential to improve patient outcomes and slow disease progression.
    Keywords:   NDUFV1 ; Case report; Mitochondrial complex I deficiency; Progressive cavitating leukoencephalopathy
    DOI:  https://doi.org/10.1186/s12887-026-06858-8
  30. Circ Res. 2026 Apr 10. 138(8): e326986
    Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
    Yajun Wang, Rong Tian.
      Mitochondria are important organelles for metabolic homeostasis, cell fate, and survival. Emerging evidence suggests that mitochondria are not confined to the cells. Intercellular mitochondrial transfer (IMT) is increasingly recognized between a variety of cells, including major cell types in the cardiovascular system. Observations made by coculture systems, genetic lineage-tracing approaches, and animal models indicate that mitochondria can be transferred between cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, cardiac macrophages, and mesenchymal stromal cells. IMT has also been reported between a remote organ, for example, adipose tissue, and the heart, suggesting that mitochondrial trafficking can mediate communications not only between individual cells but also across organs. Two principal modes of IMT are reported. One involves directed, contact-dependent trafficking of mitochondria through membranous contacts or nanotubes. The other relies on the release of mitochondria, either packaged in membrane-bound vesicles or as free mitochondria, into the extracellular space followed by import into the acceptor cells. Consequences of IMT can be beneficial or detrimental depending on the cell type and the conditions under which the IMT occurs. Mechanisms underlying the transfer or its consequences are not fully understood, however. The role of IMT in cardiovascular health is, therefore, interpreted with certain assumptions. In this review, we first summarize the evidence of IMT in the cardiovascular system and the observed functional outcome. We then aim to identify the knowledge gaps and critical questions to be addressed, followed by a discussion of challenges and opportunities to advance the field.
    Keywords:  cardiovascular system; cell communication; extracellular vesicles; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326986
  31. bioRxiv. 2026 Mar 30. pii: 2026.03.27.714765. [Epub ahead of print]
    Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
    Meagan S Kingren, Daniel G Sadler, Elijah Bolin, Izak Harville, James Sikes, Renny Lan, Elisabet Børsheim, Craig Porter.
       Background: Carnitine plays an obligatory role in energetics owing to its role in the translocation of long-chain fatty acids into the mitochondrion for oxidation. Here, we determined the metabolic and behavioral consequences of systemic carnitine deficiency (SCD) in mice.
    Methods: Female C57BL/6J mice were randomized to receive normal drinking water (control, n = 8) or drinking water supplemented with mildronate 4g.L-1 (mildronate, n = 8) for 21 days. Body composition was assessed at baseline and post treatment. Metabolic and behavioral phenotyping was performed continuously over 72 hours following 14 days of control or mildronate treatment. Stable isotope were used to assess whole-body substrate oxidation. Carnitine subfractions were quantified in skeletal muscle and liver, as was mitochondrial respiratory function. Liver and muscle samples also underwent proteomic analysis.
    Results: Mildronate treatment depleted total carnitine in muscle and liver by ∼97% ( P < 0.001) and ∼90% ( P < 0.001), respectively. Carnitine depletion was accompanied by lower total energy expenditure ( P = 0.01), attributable to lower voluntary wheel running ( P = 0.01). Oxidation rates of palmitate ( P < 0.01) but not octanoate were lower whereas rates of glucose oxidation were greater in carnitine depleted mice ( P < 0.01). Mitochondrial respiratory capacity was unaltered by carnitine deficiency. Carnitine deficiency remodeled muscle and liver proteomes to support lipid oxidation and energy production.
    Summary: In mice, carnitine deficiency is characterized by decreased long-chain fatty acid oxidation despite preserved mitochondrial respiratory capacity. Carnitine deficiency resulted in lower voluntary exercise and a concomitant reduction in energy expenditure.
    DOI:  https://doi.org/10.64898/2026.03.27.714765
  32. Cell Genom. 2026 Apr 08. pii: S2666-979X(26)00057-1. [Epub ahead of print]6(4): 101195
    A unified ACSF3-mtFAS model linking mitochondrial energy metabolism to human anthropometric evolution.
    Sara Tucci.
      We here propose a mitochondria-centered reinterpretation of the ACSF3 regulatory variant reported by Zhang et al., integrating advances in mitochondrial fatty acid synthesis and ACSF3-deficient models to link subcellular control of oxidative efficiency with organismal traits such as basal metabolic rate, height, and systemic growth regulation in humans.
    DOI:  https://doi.org/10.1016/j.xgen.2026.101195
  33. Front Physiol. 2026 ;17 1774714
    Recalibrating cell fate: targeting the mitochondrial signaling hub with natural active compounds to inhibit regulated cell death in diabetic kidney disease.
    Yinzhong Dai, Chenguang Wu, Jiaying Zheng, Keqin Zhao, Shimei Hua, Jianing Sun, Han Zhu, Jun Luo, Junwei Shi, Lu Han, Lifan Wang, Peng Liu.
      Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The progression of DKD is closely related to various cell death (RCD) pathways such as apoptosis, pyroptosis and ferroptosis. Although historically viewed as distinct events, we propose that mitochondria function as the central hub integrating hyperglycemic, lipotoxic, and pro-inflammatory insults. We delineate how initial hyperglycemic and hemodynamic insults compromise mitochondrial quality control, triggering a vicious cycle: dysfunctional mitochondria release ROS and damage-associated molecular patterns to initiate regulated cell death and inflammation, which in turn further impairs mitochondrial bioenergetics, thereby amplifying diabetic kidney injury. Mechanistically, mitochondrial outer membrane permeabilization triggers intrinsic apoptosis, while the cytosolic leakage of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) primes the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to drive pyroptosis. In parallel, organelle-level metabolic and redox instabilities fuel the lipid peroxidation characteristic of ferroptosis. We highlight the sophisticated crosstalk within this network, such as the Caspase-3/Gasdermin E switch, arguing that these pathways function as a network of molecular crosstalk and functional interdependence with distinct spatiotemporal dynamics, rather than a singular execution program. Regarding therapeutic interventions, we summarize preclinical evidence for natural active compounds like berberine and quercetin. These phytochemicals act as network-level modulators of mitochondrial targets to restore cellular homeostasis. Finally, we critically address the "translational gap" posed by poor oral bioavailability and lack of human target validation. We also explore emerging biophysical concepts, such as liquid-liquid phase separation, as a speculative yet novel frontier for organizing pathological metabolic signals. Therefore, disrupting this mitochondrial feedback loop, when coupled with advanced delivery strategies, represents a strategic therapeutic avenue to arrest DKD progression.
    Keywords:  apoptosis; diabetic kidney disease; ferroptosis; mitochondria; phytochemicals; pyroptosis; regulated cell death
    DOI:  https://doi.org/10.3389/fphys.2026.1774714
  34. Front Immunol. 2026 ;17 1716906
    Mitochondrial transplantation for osteoarthritis: from molecular mechanisms to clinical translation.
    Ying Liu, Yang Liu, Na Zhang, Haizhuan An, Liangyu Mi, Yanan Gao, Ke Xu.
      Osteoarthritis (OA) is the most prevalent chronic degenerative joint disorder worldwide, characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and impaired mobility. Growing evidence has established mitochondrial dysfunction-including impaired oxidative phosphorylation (OXPHOS), excessive reactive oxygen species (ROS) generation, disrupted mitochondrial dynamics, and dysregulated mitophagy-as an early and pivotal driver of OA pathogenesis. These bioenergetic failures not only disrupt chondrocyte metabolism but also amplify inflammation, matrix degradation, and cell death. In recent years, mitochondrial transplantation has emerged as a revolutionary therapeutic paradigm, aiming to restore cellular homeostasis by delivering functional mitochondria into damaged chondrocytes. This review systematically summarizes the molecular mechanisms of mitochondrial dysfunction in OA and highlights three major therapeutic strategies: (1) cell-based approaches, particularly mesenchymal stem cell (MSC)-mediated mitochondrial transfer via tunneling nanotubes (TNTs) or extracellular vesicles (EVs); (2) cell-free approaches, utilizing purified mitochondria or MitoEVs for direct transplantation; and (3) engineered mitochondrial transplantation, integrating bioengineering, nanotechnology, and genetic modification to enhance mitochondrial quality, delivery efficiency, and therapeutic persistence. We further discuss opportunities and challenges in clinical translation, including standardization of mitochondrial preparation, optimization of delivery systems, immunological safety, and regulatory classification. Collectively, mitochondrial transplantation represents a disruptive strategy that directly addresses the bioenergetic collapse of chondrocytes and offers a promising avenue for disease-modifying therapy in OA. Future advances in mechanistic elucidation, technological optimization, and multicenter clinical trials will be crucial to transform "mitochondrial medicine" from experimental concept to clinical reality.
    Keywords:  extracellular vesicles; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; osteoarthritis; oxidative phosphorylation; regenerative medicine; stem cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1716906
  35. Biochemistry. 2026 Apr 06.
    Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
    Ashwini Kumar, Emmanouil Zacharioudakis.
      Mitochondria are increasingly recognized as signaling organelles that coordinate cell-fate decisions during stress. Because outer mitochondrial membrane (OMM) proteins are exposed to the cytosol, they are prominent substrates for ubiquitination, a dynamic post-translational modification that encodes information through diverse chain architectures and linkage types. In this review, we examine how ubiquitination of OMM proteins functions as a molecular switch that integrates mitochondrial stress signals and engages three major, often antagonistic, stress-response mechanisms: mitophagy, cell death, and innate immune signaling. We highlight an emerging concept that a stress-responsive "ubiquitin code" is written on OMM substrates, in which pathway selection is coordinated by the identity of ubiquitinated OMM proteins together with the linkage type and branching of attached polyubiquitin chains. We provide an updated overview of the E3 ubiquitin ligases and deubiquitinases (DUBs) that write and erase this code and summarize ubiquitin linkage types reported on key OMM substrates across these pathways. For mitophagy, we cover both PARKIN-dependent and PARKIN-independent mechanisms mediated by other E3 ligases and counteracted by DUBs. For innate immunity, we discuss how ubiquitination of OMM proteins regulates the MDA5/RIG-I-MAVS axis and NF-κB signaling. For cell death, we describe how ubiquitination of anti- and pro-apoptotic BCL-2 family proteins can either lower or increase the threshold for the induction of apoptosis. We also highlight the newfound role of PARKIN to drive apoptosis through a BAX/BAK-independent mechanism. Finally, we discuss therapeutic opportunities to reprogram OMM ubiquitination by targeting E3 ligases or DUBs directly, or by using PROTAC- and DUBTAC-based strategies.
    Keywords:  E3 ubiquitin ligases; apoptosis; deubiquitinases; innate immune signaling; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1021/acs.biochem.6c00007
  36. Nature. 2026 Apr 08.
    Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders.
    Joachim De Jonghe, Hyung Chul Kim, Ayanfeoluwa Adedeji, Elsa Leitão, Ruebena Dawes, Christina M Kajba, Benjamin Cogné, Yuyang Chen, Alexander J M Blakes, Cas Simons, Rocio Rius, Javeria R Alvi, Florence Amblard, Christina Austin-Tse, Sarah Baer, Elsa V Balton, Pierre Blanc, Daniel G Calame, Charles Coutton, Chloe A Cunningham, Nitsuh Dargie, Katrina M Dipple, Haowei Du, Salima El Chehadeh, Ian Glass, Joseph G Gleeson, Olivier Grunewald, Paul Gueguen, Radu Harbuz, Marie-Line Jacquemont, Richard J Leventer, Pierre Marijon, Olfa Messaoud, Tipu Sultan, Christel Thauvin, Catherine Vincent-Delorme, Elif Yilmaz Gulec, Julien Thevenon, Rodrigo Mendez, Daniel G MacArthur, Christel Depienne, Caroline Nava, Nicola Whiffin, Gregory M Findlay.
      Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome3. ReNU syndrome variants disrupt spliceosome function and alter 5' splice site selection1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants' effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development.
    DOI:  https://doi.org/10.1038/s41586-026-10334-9
  37. Chem Commun (Camb). 2026 Apr 07.
    Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
    Zixuan Zhao, Hongling Li, Lijun Li, Jinping Liu, Qi Ai, Xin Wen, Baoxiang Gao.
      Mitochondrial autophagy (mitophagy) is pivotal for mitochondrial quality control and intracellular homeostasis. However, real-time visualization of mitochondrial inner membrane viscosity - a key biophysical parameter of mitophagy - remains challenging. To address this, a silicon rhodamine (SiR)-based dual-modal imaging probe was developed, enabling reliable real-time monitoring of mitophagic processes and providing novel insights into mitochondrial remodeling during autophagy.
    DOI:  https://doi.org/10.1039/d6cc00586a
  38. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  39. J Cell Mol Med. 2026 Apr;30(7): e71132
    DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
    Chul Hong Park, Donghyuk Shin, Kwang Chul Chung.
      Parkinson's disease (PD) is characterised by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of α-synuclein. Mitochondrial dysfunction and impaired protein degradation pathways are thought to play critical roles in PD progression, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of α-synuclein has been shown to promote its aggregation, underscoring its potential role in disease progression. Parkin, an E3 ubiquitin ligase, is widely regarded as a pleiotropic neuroprotective protein that modulates the mitochondrial quality control, as well as metabolic turnover and the accumulation of α-synuclein. Death-associated protein kinase 1 (DAPK1), which is involved in the regulation of apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 has been implicated in Alzheimer's disease through its role in tau aggregation and amyloid-β production, our findings suggest that DAPK1 may also influence PD-related pathways by phosphorylating parkin at Ser136 and Ser198. This phosphorylation promotes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localised E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. Given the neuroprotective role of parkin, its reduction increases the vulnerability of neurons to 6-hydroxydopamine-induced toxicity, potentially contributing to decreased neuronal survival. Together, these findings suggest that DAPK1 functions as a previously unrecognised modulator of parkin and could potentially influence PD-related neurodegenerative processes. This pathway may provide a mechanistic link between mitochondrial dysfunction, α-synuclein pathology and neuronal cell death.
    Keywords:  6‐OHDA; DAPK1; MITOL; neuronal toxicity; parkin; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.1111/jcmm.71132
  40. Chemphyschem. 2026 Apr 14. 27(7): e202500782
    Decoding the Heterodimer Stability of Pro-Apoptotic Effectors via Multiscale Simulations: Mutational Insights Into Mitochondrial Signaling.
    Pratyush Pani, Anvesha Shree, Malay Kumar Rana.
      The BCL-2 protein family plays a central role in regulating mitochondrial apoptosis, with Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated X protein (BAX) acting as key effectors that oligomerize to disrupt the outer mitochondrial membrane. While the mechanisms behind their homo-oligomerization are well studied, much less is known about their heterodimer. In this work, we explored how specific point mutations at the BAK-BAX interface affect the heterodimer's structure, dynamics, and energetics. Using DUET, we identified stabilizing and destabilizing mutations from both subunits, which were then subjected to 1 μs molecular dynamics simulations. Across multiple structural metrics, the L78D mutation in BAK consistently appeared to enhance rigidity and compactness, while the D68I mutation in BAX led to increased flexibility and conformational drift. Steered MD shows that BAK-L78D strengthens the BAK-BAX interface, resisting separation, whereas BAX-D68I weakens it, leading to faster dissociation. Markov state modeling with Kullback-Leibler divergence indicates that BAK-L78D mirrors wild-type dynamics, while BAX-D68I deviates across key slow motions. Alchemical free energy calculations further delineates the cost of transformation from one amino acid to the other in case of both the mutations. Together, these results highlight BAK-L78D as a stabilizing mutation and BAX-D68I as a destabilizing variant that modulates complex integrity.
    Keywords:  BAK; BAX; COM; DUET; MSM
    DOI:  https://doi.org/10.1002/cphc.202500782
  41. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 305-311
    Leber Hereditary Optic Neuropathy in the Elderly: A Case Report.
    Haoran Li, Jonathan Micieli.
       Introduction: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder typically affecting young males, with rare reports of late-onset disease. Among the three primary LHON mutations, m.14484T>C is generally associated with a relatively favorable visual prognosis. However, the disease in elderly patients carrying this mutation remains poorly characterized. This case represents the oldest reported patient to date with LHON due to the m.14484T>C mutation.
    Case Presentation: An 89-year-old man presented with a 4-month history of painless, bilateral vision loss. The patient had a 30-pack-year smoking history and daily alcohol intake but no family history of vision loss. His best-corrected visual acuity was counting fingers at 1 foot in both eyes, with color vision loss and bilateral elevated hyperemic optic disks. OCT demonstrated relatively preserved GCIPL thickness and pRNFL elevation, and visual fields showed diffuse loss. MRI of the brain and orbits was unremarkable. Laboratory evaluation, including serum B12, was normal. Genetic testing revealed the m.14484T>C mutation in mitochondrial DNA, confirming the diagnosis of LHON. At 3-month follow-up, fundus exam showed mild disk pallor bilaterally, reduced pRNFL elevation, diffuse GCIPL thinning, and stable vision and visual field.
    Conclusion: This case represents the oldest reported patient to date with LHON due to the m.14484T>C mutation. Despite the mutation's typical association with better visual outcomes, the patient experienced progressive vision loss with no recovery. This case underscores the importance of considering LHON in elderly patients with bilateral optic neuropathy and highlights the potential impact of age and environmental exposures on disease expression and prognosis.
    Keywords:  Late onset; Leber hereditary optic neuropathy; m.14484T>c
    DOI:  https://doi.org/10.1159/000551146
  42. Genes Dis. 2026 Jul;13(4): 101856
    Mitochondrial transplantation in lung diseases: From mechanisms to application prospects.
    Haoneng Wu, Qiuran Zhao, Ying Zhao, Jinguang Bai, Junxi Pan, Songling Huang.
      Mitochondria are double-membrane organelles in eukaryotic cells, which play an important role in energy metabolism, cell cycle and apoptosis. Therefore, mitochondrial abnormalities can affect various physiological and pathological processes. Extensive research over a long period of time has shown that mitochondrial dysfunction is considered a hallmark of several diseases, including cardiovascular diseases, neurodegenerative diseases, respiratory diseases, and even cancer. Mitochondrial transplantation has emerged in recent years as a novel approach for treating mitochondria-related diseases. This therapy involves transferring viable, functionally intact mitochondria into cells or tissues, either directly or indirectly, to replace dysfunctional mitochondria and restore mitochondrial function, thereby achieving therapeutic goals. Research has indicated that mitochondrial transplantation can alleviate the progression of lung diseases and improve disease outcomes. In this review, we explore the mechanisms underlying mitochondrial dysfunction in lung disease and the potential application of mitochondrial transplantation in the treatment of lung disease.
    Keywords:  Lung disease; Mitochondrial dysfunction; Mitochondrial transplantation; Oxidative stress; Respiratory system
    DOI:  https://doi.org/10.1016/j.gendis.2025.101856
  43. Alzheimers Dement. 2026 Apr;22(4): e71306
    TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.
    Neil V Yang, Shaowei Wang, Boyang Li, Jeffrey Simms, Linsey Dinh, Annie Huang, Jacob H Oei, Hussein N Yassine, Ronald M Krauss.
       INTRODUCTION: While the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease (AD), the role of translocase of outer mitochondrial membrane 40 (TOMM40)-an adjacent gene involved in mitochondrial protein import-is not known.
    METHODS: Human brain tissue, human induced pluripotent stem cell-derived neurons (iNeurons), and mice were used for study of gene expression, cholesterol metabolism, mitochondrial function, and animal cognition.
    RESULTS: Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. In human iNeurons, TOMM40 knockdown (KD) disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of liver X receptor beta (NR1H2), upregulation of APOE and low-density lipoprotein receptor (LDLR), and increased cellular cholesterol and amyloid beta (Aβ)42 independent of APOE ε4. Consistently, Tomm40 KD in mice induced increased brain cholesterol, Aβ42 content, and impaired memory.
    DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function.
    Keywords:  Alzheimer's disease; apolipoprotein E; cholesterol metabolism; mitochondria; mitochondria–endoplasmic reticulum contact sites; translocase of outer mitochondrial membrane 40
    DOI:  https://doi.org/10.1002/alz.71306
  44. MedComm (2020). 2026 Apr;7(4): e70713
    Single-Cell and Spatial Omics: Methods and Applications.
    Xiaoping Cen, Xiaolan Huang, Enjin Deng, Xue Gong, Na Tan, Jifeng Ye, Yin Wang, Roland Eils, Qun Luo, Yixue Li, Fangfang Qu.
      Single-cell and spatial omics have revolutionized biomedical research by enabling high-resolution molecular profiling across cells and tissues, thereby overcoming key limitations of bulk sequencing and revealing unprecedented cellular heterogeneity and spatial organization central to development, homeostasis, and disease. Specifically, advances in high-throughput, subcellular, and multiomics profiling are promoting the field toward deeper insights. In parallel, computational progress, including generative artificial intelligence (AI) and foundation models, is developing rapidly for manipulating multimodal multiomics data. These advancements have been applied to diverse diseases and biological systems, facilitating innovative biomedical findings. However, a significant gap persists between rapid methodological advances and their systematic application for deciphering human biology and pathology. This review synthesizes recent breakthroughs in single-cell and spatial technologies and surveys computational methods, including AI-driven approaches, foundation models, and multi-omics integration algorithms for both single-cell and spatial analyses. We then summarize representative applications across major human organ systems in health and disease, highlighting opportunities for biomarker discovery, therapeutic target identification, and precision medicine. Finally, we discuss current challenges and future directions for bridging technological innovation with robust biomedical discovery and translational impact. This review provides a vital guide for researchers in the field, offering critical insights for accelerating the translation of single-cell and spatial omics.
    Keywords:  artificial intelligence; foundation models; multi‐omics integration; precision medicine; single‐cell omics; spatial omics
    DOI:  https://doi.org/10.1002/mco2.70713
  45. FEBS J. 2026 Apr 07.
    Identifying targeting signals and distinct localization-based roles of yeast aldehyde dehydrogenase Hfd1.
    Yuta Konishi, Haruka Sakaue, Hironori Takeda, Toshiya Endo.
      Hfd1 is a yeast fatty aldehyde dehydrogenase that catalyzes the oxidation of long-chain aliphatic aldehydes and localizes to membranes in multiple organelles, including mitochondria, the endoplasmic reticulum (ER), and lipid droplets. Here, we identified the segments of Hfd1 responsible for this multiple-organelle targeting and generated variants that localize exclusively to mitochondria, the ER, or the cytosol. These Hfd1 variants allowed us to reveal the relationship between the subcellular localization and the function of Hfd1 in coenzyme Q biosynthesis and sphingolipid metabolism. The catalytic N-terminal domain of Hfd1, when exposed to the cytosol, is sufficient to support coenzyme Q biosynthesis regardless of whether Hfd1 has an anchor or is anchored to either the mitochondrial or ER membranes. Furthermore, Hfd1 contributes to the mitigation of reactive oxygen species and to the oxidation of hexadecanal and hexadecenal, which may be important for efficient mitochondrial protein transport and/or quality control in cooperation with Ubx2 and the TOM complex.
    Keywords:  ER; Hfd1; TOM complex; Ubx2; mitochondria
    DOI:  https://doi.org/10.1111/febs.70536
  46. Pharmacol Res. 2026 Apr 07. pii: S1043-6618(26)00103-9. [Epub ahead of print] 108188
    Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
    Kuan-Hao Tsui, Shih-Hsuan Cheng, Boyang Wang, Pei-Hsuan Lin, Emmanuel Naveen Raj, Li-Te Lin, Renin Chang, Zhi-Hong Wen, Andy P Tsai, Chia-Jung Li.
      Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+/sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.
    Keywords:  Aging; Metabolism; Mitochondrial quality control; Mitophagy; Translational biomarkers
    DOI:  https://doi.org/10.1016/j.phrs.2026.108188
  47. Autophagy. 2026 Apr 08.
    In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
    Yufei Huang, Tianyu Zheng, Xiaofeng Sun, Ruoxi Wang, Shujun Cai.
      Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understood. Here, we studied the in situ architecture of forming mitophagosomes in the developing Drosophila intestine by combining cryo-electron tomography (cryo-ET), serialized on-grid lift-in sectioning for tomography (SOLIST), cryo-focused ion beam (cryo-FIB) milling, and volume electron microscopy. Our data reveal that the endoplasmic reticulum (ER) forms continuous membrane connections with the phagophore during mitophagosome formation. In Vps13D mutant enterocytes, stalled mitochondrial phagophore membrane expansion is associated with an accumulation of persistent ER-phagophore membrane continuities. Together, our findings support a model in which the ER can establish direct membrane continuity with the phagophore to facilitate rapid mitophagosome formation. AbbreviationAPF: after puparium formation; BLTP: bridge-like lipid transfer protein; CCS: cleaning cross-section; cryo-ET: cryo-electron tomography; cryo-FIB: cryo-focused ion beam; CTF: contrast transfer function; ER: endoplasmic reticulum; HPF: high-pressure freezing; mitolysosome: autolysosome containing a mitochondrion; mitophagophore: mitochondrial phagophore; mitophagy: selective mitochondrial clearance by autophagy; NGS: normal goat serum; OMM: outer mitochondrial membrane; OsO4: osmium tetroxide; PB: phosphate buffer; PBSTx: PBS containing 0.3% (w:t) Triton X-100; RCS: regular cross-section; RT: room temperature; RT-FIB-SEM: room-temperature focused ion beam scanning electron microscopy; SOLIST: serialized on-grid lift-in sectioning for tomography; TLD: Through-the-Lens Detector.
    Keywords:  Cryo-ET; Cryo-FIB; Drosophila; Vps13D; mitochondria; mitophagy; serial cryo-lift-out
    DOI:  https://doi.org/10.1080/15548627.2026.2657543
  48. Circ Res. 2026 Apr 10. 138(8): e326985
    Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
    Xi Fang, Åsa B Gustafsson.
      Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.
    Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
  49. bioRxiv. 2026 Mar 15. pii: 2026.03.12.711365. [Epub ahead of print]
    Correction of a recurrent pathogenic variant in methylmalonic acidemia using adenine base editing.
    Elena M Kahn, Hooda Said, Ping Qu, Mohamad-Gabriel Alameh, Xiao Wang, Kiran Musunuru, Rebecca C Ahrens-Nicklas.
      Methylmalonic acidemia (MMA) is a recessive genetic disease caused by variants in the MMUT (mitochondrial enzyme methylmalonyl-CoA mutase) gene or by defects in transport or metabolism of MMUT cofactor (5' deoxyadenosylcobalamin), including variants in the MMAB gene. For the most recurrent pathogenic MMAB variant, c.556C>T (R186W), we identified a corrective editing strategy using adenine base editing. Deploying an adenine base editor mRNA and optimized hybrid guide RNA with lipid nanoparticles, we observed efficient in vitro corrective editing of the variant to wild-type, with minimized bystander editing and off-target editing in hepatocytes. These observations lay the groundwork for a gene editing therapy for patients with MMA resulting from at least one copy of the MMAB c.556C>T (R186W) variant, as well as a platform of similar therapies for patients with MMA caused by other variants amenable to adenine base editing.
    DOI:  https://doi.org/10.64898/2026.03.12.711365
  50. Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488
    Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
    Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.
      Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.
    Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite
    DOI:  https://doi.org/10.1016/j.canlet.2026.218488
  51. Sci Rep. 2026 Apr 04.
    Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice.
    Aldo Vorkapich, Arshi Mustafa, Amanda L Flores-Torres, Konstantinos S Zarbalis, Cecilia Giulivi.
      WDFY3/ALFY is an adaptor protein involved in selective autophagy. Loss of Wdfy3 in mice causes severe deficits in neuronal health, and pathogenic mutations in WDFY3 are associated with neurodevelopmental disorders in humans. As impaired autophagy is increasingly implicated in Parkinson's disease (PD) and other neurodegenerative disorders, we investigated whether Wdfy3 haploinsufficiency produces early molecular and cellular signatures of neurodegeneration in Wdfy3+/lacZ mice, given that these diseases often exhibit presymptomatic alterations preceding overt clinical manifestations. Cortical tissue from 3-month-old presymptomatic mice showed significant proteomic overlap with both patient-derived PD cell lines and human brain proteomic datasets, particularly from the substantia nigra, underscoring the translational relevance of this model. Consistent with disease progression, immunofluorescence analyses of the cortex and substantia nigra from 14-month-old mice revealed significant dysregulation of multiple markers associated with neurodegeneration. Together, these findings demonstrate that impaired autophagy resulting from reduced Wdfy3 expression recapitulates key features of neurodegenerative disease at both early and later stages. By providing a platform to investigate presymptomatic pathogenic mechanisms, this model may inform the development and testing of future diagnostic and therapeutic strategies aimed at preserving neuronal health.
    Keywords:  Autophagy; Biomarkers; Mitochondrial dysfunction; Mouse model; Neurodegeneration; Parkinson’s disease; Proteomics
    DOI:  https://doi.org/10.1038/s41598-026-43314-0
  52. Cell Mol Gastroenterol Hepatol. 2026 Apr 07. pii: S2352-345X(26)00060-3. [Epub ahead of print] 101782
    IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.
    Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Courtney Worrell, Jasmine Cruz, No'ad Shanas, Alena Klochkova, Travis H Bordner, John M Crespo, Annie D Fuller, B S William-Nazario-Lugo, Grace Davis, Hailey Golden, Andres J Klein-Szanto, Tatiana A Karakasheva, Adam Karami, John W Elrod, Gary W Falk, Zachary Wilmer Reichenbach, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.
       BACKGROUND & AIMS: Metabolic and mitochondrial dysfunction have recently been implicated in eosinophilic esophagitis (EoE) pathogenesis. However, there is a need to define the influence of EoE-associated inflammatory cues upon mitochondrial biology, mechanisms mediating these effects, and the clinical significance of mitochondrial alterations in EoE.
    METHODS: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes stimulated with EoE-relevant cytokines. Mitochondrial mediators were assessed via qRT-PCR and western blotting. Metabolism, mitochondrial membrane potential, and apoptosis were measured. Mitochondrial DNA (mtDNA)-encoded genes, ND1 and ND6 were assessed by qPCR in DNA from culture media and circulating nucleic acids from human serum samples. Effects of JAK inhibitor ruxolitinib or genetic inhibition of STAT3 or STAT6 on mitochondria were assessed in vitro.
    RESULTS: We identified evidence of increased mitochondria in esophageal mucosa of EoE patients and mice with EoE-like inflammation. IL-13 consistently induced mitochondrial accumulation in esophageal keratinocytes in vitro and this response was associated with increased expression of mediators of mitochondrial biogenesis, fusion, and mitophagy. IL-13 suppressed mitochondrial respiration and ATP production, without impacting membrane polarization or apoptosis. Active EoE patients exhibited elevated serum mtDNA levels and upregulation of mediators of mtDNA-associated inflammatory signaling. Increased mitochondrial mass and accumulation of extracellular mtDNA in IL-13-treated esophageal keratinocytes were dependent on JAK/STAT signaling.
    CONCLUSIONS: We identify IL-13 as a mediator of increased mitochondrial mass in EoE through JAK/STAT signaling. We further demonstrate that IL-13 promotes accumulation of extracellular mtDNA and that circulating mtDNA is elevated in EoE patients.
    Keywords:  Eosinophilic esophagitis; Interleukin-13; JAK/STAT pathway; mitochondria
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101782
  53. Sci Adv. 2026 Apr 10. 12(15): eadz9095
    RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response.
    Lizhen Zhu, Li Lin, Tuan Qi, Geng Li, Zhixing Liang, Jiancheng Yu, Yifan Fu, Yue Peng, Xing Chang.
      B cells are crucial for adaptive immunity, orchestrating humoral responses by producing antibodies essential for pathogen clearance. Here, we show that Poly(rC) binding protein 1 (Pcbp1), a multifunctional RNA binding protein, is a key regulator of antibody production in B cells. Pcbp1 deficiency in B cells resulted in significant reductions in immunoglobulin M expression at steady state and compromised differentiation of germinal center B cells and production of high-affinity antibodies upon immunization. These effects were caused by defective mitochondrial integrity in Pcbp1-deficient B cells, including impaired mitochondrial electron transport chain complex I and elevated mitochondrial reactive oxygen species production. Mechanistically, Pcbp1 binds to the 3' untranslated region of Fdxr messenger RNA to promote its expression, thereby supporting iron-sulfur cluster biogenesis, the assembly of mitochondrial complex I, and other Fdxr-dependent processes. Our findings reveal a previously unidentified role for Pcbp1 in regulating mitochondrial function, protein synthesis, and antibody responses in B cells, providing insight into posttranscriptional regulation and mitochondrial functions in adaptive immunity.
    DOI:  https://doi.org/10.1126/sciadv.adz9095
  54. Ophthalmic Genet. 2026 Apr 09. 1-4
    Novel heterozygous UCHL1 variant causing severe optic atrophy and vision loss.
    Natalie S Lee, Clare L Fraser, Zornitza Stark, Kate Ahmad.
       INTRODUCTION: Heterozygous UCHL1 variants have recently been associated with an autosomal dominant neurodegenerative disease characterized by spastic ataxia, optic atrophy and neuropathy.
    METHODS: We describe two individuals from a single family who presented with optic atrophy and progressive vision loss, without demonstrable spasticity, ataxia or peripheral neuropathy.
    RESULTS: Genetic testing revealed a novel pathogenic UCHL1 variant accounting for the two individuals' phenotype.
    DISCUSSION: Our findings highlight the significant phenotypic variability related to heterozygous UCHL1-related disease. Clinicians should consider UCHL1 variants in individuals presenting with multigenerational optic atrophy even in the absence of multisystem features.
    Keywords:  Optic atrophy; UCHL1; autosomal dominant
    DOI:  https://doi.org/10.1080/13816810.2026.2655887
  55. Ageing Res Rev. 2026 Apr 08. pii: S1568-1637(26)00125-X. [Epub ahead of print] 103133
    Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.
    Xiaolan Ran, Mei Wang, Juan Huang, Nanyu Kuang, Peng Tian, Jingjing Wu, Fei Feng, Yong Luo, Nanqu Huang.
      One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.
    Keywords:  Alternative splicing; Alzheimer's disease; Neurodegenerative diseases; Parkinson's disease; Splicing factors; Therapeutics
    DOI:  https://doi.org/10.1016/j.arr.2026.103133
  56. Acta Pharmacol Sin. 2026 Apr 09.
    ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
    Xiao-Ou Hou, Miao Wang, Rong Deng, Yi-Fan Lu, Jin-Ru Zhang, Li Ren, Jing Chen, Chun-Feng Liu, Ya-Ping Yang, Li-Fang Hu.
      Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H2S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H2S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.
    Keywords:  ADT-OH; Parkinson’s disease; cGAS-STING; microglia; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.1038/s41401-026-01789-7
  57. JAMA Ophthalmol. 2026 Apr 09.
    Clinical and Genetic Spectrum of ACO2-Linked Dominant Optic Atrophy.
    Cléis Beaulieu, Aymane Bouzidi, Valérie Desquiret-Dumas, Xavier Dieu, Rahul Makam, Neringa Jurkute, Catherine Vignal, Manon Philibert, Sylvie Odent, Xavier Zanlonghi, Marie Latypov, Eloi Debourdeau, Béatrice Bocquet, Raihane Yahia, Linda Pons, Frédéric Pollet Villard, Luc Jeanjean, Sarah Verrecchia, Caroline Froment, Camille Engel, Céline Poirsier, Carl Arndt, Hélène Dollfus, Philippe Gohier, Majida Charif, Marc Ferré, Delphine Prunier-Mirebeau, Isabelle Meunier, Patrick Yu-Wai-Man, Patrizia Amati-Bonneau, Guy Lenaers, Vasily Smirnov.
       Importance: Aconitase 2 (ACO2) gene variants are one of the most frequent causes of dominant optic atrophy (DOA). However, the associated phenotypes and genotypes still lack proper characterization.
    Objective: To characterize the clinical and genetic spectrum of ACO2-related DOA and evaluate genotype-phenotype correlations.
    Design, Setting, and Participants: This was a retrospective case series to describe the ophthalmological examination of novel DOA cases with a heterozygous ACO2 variant. Data were collected from 13 reference centers in ophthalmology from France and Great Britain between January 2021 and September 2025. Included participants were those patients with OA and confirmed heterozygous or compound heterozygous ACO2 variants.
    Exposures: DOA cases with a heterozygous ACO2 variant.
    Main Outcomes and Measures: Positive molecular diagnosis for ACO2 variants by next-generation sequencing, clinical examination including age at diagnosis, sex, best-corrected visual acuity (BCVA), retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness, visual field mean deviation (MD), and fundus examination.
    Results: Data for 55 patients (median [IQR] age at diagnosis for 45 patients, 24 [8-51] years; 33 male [67%]) from 37 families with ACO2 variants were compiled. Analyses were conducted on 49 patients who were strictly heterozygous or compound heterozygous with the c.220C>G benign variant. Clinical data disclosed a high variability of severity, from pauci-symptomatic up to legal blindness. Median BCVA was 0.46 logMAR (Snellen equivalent, 20/63; IQR 0.00-0.89; n = 45). Four patients exhibited retinal abnormalities: 3 displayed a foveopathy, and 1 had retinitis pigmentosa. There were 12 previously unreported variants (to the authors' knowledge), including the deletion of ACO2 exon 9. No correlation between BCVA and sex, age at diagnosis (Spearman ρ = -0.19; 95% CI, -0.45 to 0.07), or variant type (Kruskal-Wallis test P =.33) was found, but there was a correlation between BCVA and RNFL (Spearman ρ = -0.74; 95% CI, -0.85 to -0.54), GCL (Spearman ρ = -0.60; 95% CI, -0.79 to -0.30), and MD (Spearman ρ = -0.65; 95% CI, -0.89 to -0.31). RNFL correlated with GCL (Spearman ρ = 0.69; 95% CI, 0.42-0.87) and MD (Spearman ρ = 0.57; 95% CI, 0.14-0.85); age at diagnosis correlated with GCL (Spearman ρ = -0.37; 95% CI, -0.63 to -0.03).
    Conclusions and Relevance: Results of this case series reveal the high clinical heterogeneity among patients with ACO2-related DOA and demonstrated that some of these patients can also exhibit retinal abnormalities. In addition, there was a deletion of an entire ACO2 exon, emphasizing the potential importance of searching for large genomic rearrangements in patients without a molecular diagnosis. These findings support further studies to explain clinical variability, as no genotype-phenotype correlation was encountered.
    DOI:  https://doi.org/10.1001/jamaophthalmol.2026.0634
  58. Circ Res. 2026 Apr 10. 138(8): e326988
    Rethinking Mitochondria: The Extracellular Dimension.
    Laura Pena-Couso, Magdalena Makuch, Jose Angel Nicolas-Avila.
      Mitochondria are essential organelles that transform the energy contained in metabolic substrates into ATP while supporting numerous cellular processes. Traditionally regarded as strictly intracellular, growing evidence now demonstrates that mitochondria and mitochondria-derived components can also be released into the extracellular space, giving rise to extracellular mitochondria. extracellular mitochondria display remarkable heterogeneity, ranging from intact organelles to individual molecular components, free to vesicle-encapsulated structures, and with functional states spanning from severely damaged to metabolically active. Their release is mediated by tightly regulated mechanisms in both living and dying cells, and is influenced by cellular stress, activation state, and pathways that control mitochondrial selection, compartmentalization, trafficking, and extrusion. Extracellular release fulfills multiple functions across the organism, including quality control, modulation of cellular identity, inflammatory signaling, and functional support of recipient cells. In the cardiovascular system, extracellular mitochondria contribute to both homeostasis and disease progression. This review summarizes current knowledge of extracellular mitochondria forms, mechanisms of release, and pathophysiological relevance, and highlights their emerging potential as therapeutic targets in cardiovascular pathophysiology and beyond.
    Keywords:  cardiovascular system; extracellular space; homeostasis; mitochondria; organelles
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326988
  59. Reprod Biomed Online. 2026 Jan 12. pii: S1472-6483(26)00005-2. [Epub ahead of print]52(6): 105464
    Public support for mitochondrial donation: an Australian knowledge and attitudes study.
    Ezra Kneebone, Zachary Russell, Ainsley J Newson, Chris Degeling, Karinne Ludlow, Narelle Warren, Catherine Mills.
       RESEARCH QUESTION: What does the Australian public know about mitochondrial donation and think about its potential clinical implementation?
    DESIGN: 1042 people aged ≥18 years living in Australia completed an online anonymous survey between October and December 2022. Participants were recruited through a market research company. The survey included multiple choice and Likert-scale questions gauging respondents' knowledge and attitudes. Bivariate analysis investigated differences in support for mitochondrial donation based on different sociodemographic groups.
    RESULTS: Just 19% of respondents had ever heard of mitochondrial donation prior to participation (n = 202). The average level of agreement with the statement 'If the clinical trial proves mitochondrial donation is safe, I support it becoming available in Australia' was 3.36 out of a possible 4, indicating agreement. Significant differences in the average agreement level were reported across the different 'prior use of assisted reproductive technology', 'sexual orientation', 'genetic condition' and 'mitochondrial disease' groups; however, the average level of agreement in each group was consistently >3.
    CONCLUSIONS: The findings indicate broad public support for the clinical implementation of mitochondrial donation in Australia, provided that clinical trials demonstrate its safety. Although these results may not extrapolate directly to other contexts, they may guide other jurisdictions in considering their position towards mitochondrial donation.
    Keywords:  Assisted reproductive technology; Mitochondrial diseases; Mitochondrial replacement techniques; Public opinion
    DOI:  https://doi.org/10.1016/j.rbmo.2026.105464
  60. Ageing Res Rev. 2026 Apr 07. pii: S1568-1637(26)00123-6. [Epub ahead of print] 103131
    Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
    Linbo Peng, Kexin Wang, Limin Wu, Lei Yao, Bin Shen, Jian Li.
      Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.
    Keywords:  Calcium homeostasis; Degenerative musculoskeletal diseases; ER–mitochondria crosstalk; Mitochondria-associated ER membranes; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.arr.2026.103131
  61. Biochim Biophys Acta Mol Cell Res. 2026 Apr 08. pii: S0167-4889(26)00043-1. [Epub ahead of print] 120146
    Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.
    Yuqiao Xu, Xing Gao, Shenhui Xu, Lele Jian, Jiankkuan Shi, Yuanlin Zhao, Yuying Wang, Ying Yang, Yuan Yuan, Qiulong Dai, Qian Zhang, Jing Li, Lijun Zhang.
      Perilipin 5 (Plin5) is a lipid droplet-associated protein that regulates lipid hydrolysis and mitochondrial oxidative metabolism, and is highly expressed in skeletal muscle. Its role in skeletal muscle glucose metabolism and its relevance to mitochondrial myopathy (MM) remain unclear. We used Plin5-knockout (Plin5-KO) mice in exhaustive swimming tests to assess endurance and anaerobic exercise capacity. Glucose uptake was measured using 2-NBDG; glucose, lactate, NADH/NAD+ ratio, and fatty acid oxidation (FAO) rate were determined with commercial kits. Mitochondrial ultrastructure was evaluated via electron microscopy, and immunoblotting was used to assess proteins related to glucose-lipid metabolism. Muscle biopsies from 26 patients with mitochondrial myopathy were examined morphologically and for Plin5 expression by immunohistochemistry. Plin5-KO mice showed impaired anaerobic capacity, markedly reduced glycogen storage (especially after-exercise), increased lactate production, and reduced AKT phosphorylation, indicating insulin resistance. Mechanistically, Plin5 deficiency promoted excessive FAO, worsened mitochondrial damage, and elevated the NADH/NAD+ ratio, shifting glucose metabolism toward anaerobic glycolysis with excess lactate output. In contrast, Plin5 overexpression improved insulin sensitivity and reduced FAO in skeletal muscle cells. In MM patients, Plin5 expression in skeletal muscle tended to be negatively associated with blood lactate levels. These findings indicate that Plin5 may play a crucial role in improving glycolipid metabolism and protecting mitochondrial function by enhancing glycogen storage and reducing excessive FAO in skeletal muscle cells.
    Keywords:  Insulin resistance; Lactate; Mitochondrial dysfunction; Myopathy; NADH/NAD+; Perilipin 5
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120146
  62. bioRxiv. 2026 Apr 02. pii: 2026.03.31.713900. [Epub ahead of print]
    Mapping the mammalian dark metabolome by in vivo isotope tracing.
    Michael R MacArthur, Justine Raeber, Wenyun Lu, Hantao Qiang, Amelia V Schueppert, Lucas B Ayres, Ricardo A Cordova, Michael D Neinast, Edmundo Leiva, Vanha N Pham, Jenna E AbuSalim, Connor S R Jankowski, Laith Z Samarah, Asael Roichman, Christian G Peace, Daniil G Ivanov, Gianna L Renzo, Anna M Oschmann, Julien F Ayroles, Sarah J Mitchell, Xi Xing, Kellen Olszewski, Hahn Kim, Joshua D Rabinowitz, Michael A Skinnider.
      Despite decades of biochemical study, a comprehensive map of the mammalian metabolome remains elusive. Mass spectrometry-based metabolomics detects thousands of small molecule-associated signals in mammalian tissues, but it is currently unclear how many of these reflect products of endogenous metabolism. Here, we leverage systematic in vivo isotope tracing to infer the biosynthetic origins of unidentified metabolites. We administered 26 different isotopically labelled nutrients to mice, measured circulating and tissue metabolite labelling by mass spectrometry, and developed a statistical framework to infer the number of carbon atoms incorporated from each of these precursors into more than 4,000 putative metabolites. We show this information can be harnessed for biosynthesis-aware structure elucidation using a multimodal AI model that co-embeds isotopic labelling patterns with chemical structures. This approach revealed several previously unrecognized families of mammalian metabolites, including cysteine-derived alkylthiazolidines, dithioacetal mercapturic acid derivatives, short-chain N-acyltaurines, acylglycyltaurines, and N-oxidized taurines. It further uncovered a family of mevalonate-derived isoprenoid metabolites that includes 2,3-dihydrofarnesoic acid, which is markedly depleted in both mouse and human aging. Age-related depletion of these isoprenoids is driven by impaired coenzyme A synthesis. Our work establishes the biosynthetic precursors for thousands of unidentified metabolites and reveals multiple previously unrecognized branches of mammalian metabolism.
    DOI:  https://doi.org/10.64898/2026.03.31.713900
  63. J Transl Med. 2026 Apr 10.
    Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
    Chengqian Teng, Jianjie Wei, Yixiao Zhu, Andi Chen, Xiaohui Chen.
       BACKGROUND: Neonatal brain injury, including hypoxic-ischemic encephalopathy, preterm brain injury, and neonatal infectious brain injury, remains a major cause of death and long-term neurodevelopmental disability worldwide. The immature brain is highly dependent on oxidative metabolism yet particularly vulnerable to energy failure and oxidative stress, placing mitochondria at the core of injury cascades. By integrating disturbances in energy production, redox balance, calcium homeostasis, and cell death signaling, mitochondrial dysfunction is increasingly recognized as a unifying driver of diverse neonatal brain injury phenotypes.
    MAIN BODY: This narrative review synthesizes current knowledge on the main clinical forms of neonatal brain injury and their developmental context, alongside an overview of mitochondrial physiology in neural cells, including the regulation of bioenergetics, reactive oxygen species, calcium signaling, mitochondrial dynamics, and inter‑organelle communication. It critically examines how mitochondrial dysfunction contributes to injury across hypoxic-ischemic, preterm, and infectious or inflammatory insults, emphasizing links between impaired oxidative phosphorylation, excessive oxidative and nitrosative stress, calcium overload with pathological opening of the mitochondrial permeability transition pore, activation of apoptosis and regulated necrosis, disrupted mitochondrial fusion-fission balance and biogenesis, and defective mitophagy and mitochondrial quality control. These mitochondrial disturbances precipitate acute neuronal and oligodendroglial injury and hinder the long-term maturation and connectivity of neural circuits. Finally, we review emerging mitochondria‑targeted neuroprotective strategies, focusing on approaches that enhance mitochondrial biogenesis, reduce mitochondrial oxidative stress, and target mitochondrial dynamics to restore mitochondrial homeostasis and improve cellular resilience in the immature brain.
    CONCLUSION: By linking specific patterns of mitochondrial dysfunction to distinct forms and stages of neonatal brain injury, this review provides a mechanistic framework for identifying high‑risk infants, refining pathophysiological understanding, and guiding the rational development of mitochondria‑targeted interventions aimed at improving neurological outcomes in vulnerable newborns.
    Keywords:  Energy metabolism; Hypoxic–ischemic encephalopathy; Mitochondrial dynamics and mitophagy; Mitochondrial dysfunction; Mitochondria‑targeted therapy; Neonatal brain injury; Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1186/s12967-026-08104-2
  64. J Neuromuscul Dis. 2026 Apr 07. 22143602261433223
    Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.
    Gulcin Akinci, Javid Sardarzada, Haluk Topaloglu.
       BACKGROUND: Thymidine kinase 2 (TK2) deficiency is an ultra-rare, severe mitochondrial myopathy caused by pathogenic variants in TK2 and characterized by a wide range of ages at onset. The infantile form, presenting before 2 years of age, is the most rapidly progressive and is associated with a high risk of early mortality. We describe the clinical outcomes of early nucleoside therapy in a series of children with infantile-onset TK2 deficiency.
    METHODS: We retrospectively reviewed four children with genetically confirmed infantile-onset TK2 deficiency treated with oral deoxycytidine/deoxythymidine (dC/dT) through an Early Access Program at two centers. Dosing was escalated to 800 mg/kg/day as tolerated. Patients were followed at baseline, Month 1, and regular intervals thereafter. Outcomes included neurological examinations, eight motor milestones, and respiratory and feeding support. Safety laboratory results, neuroimaging, and biopsy findings were reviewed.
    RESULTS: Treatment began at 19-24 months (median duration 26 months; range: 4-81). All presented within the first year with hypotonia, motor regression, and respiratory and/or bulbar involvement. Two required invasive ventilation and three required tube feeding before therapy. After dC/dT initiation, all improved with no further milestone loss. Three achieved independent ambulation and stair climbing; the fourth, at 4 months of therapy, has begun unassisted walking. Both tracheostomized patients were weaned from ventilation, and enteral feeding was discontinued in all three within 1-6 months. Only mild dose-related diarrhea occurred in one patient.
    CONCLUSION: Early nucleoside therapy halts disease progression and restores motor function in infantile-onset TK2 deficiency, the most severe form of the disease.
    Keywords:  infantile-onset; mitochondrial myopathy; mtDNA depletion syndrome; nucleoside therapy; thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1177/22143602261433223
  65. Cell Death Discov. 2026 Apr 09.
    Glycosylation-driven necroptosis in retinal degeneration: dual rescue by AAV8 gene therapy and RIPK1 inhibition.
    Jia-Ying Chien, Peng Yeong Woon, Hsien-Yang Tsai, Mei-Ling Peng, Shi-Huang Lee, Siu-Fung Chau, Yu-Chen Chen, Wai-Man Cheang, Ching-Yen Tsai, Shun-Ping Huang.
      Glycosylation defects are increasingly implicated across neurodegenerative diseases, yet the mechanism by which perturbed O-mannosylation drives neuronal death-and how to reverse it-remains unclear. Here we show that a disease-associated POMGnT1 L120R mutation produces widespread retinal neurodegeneration by coupling metabolic collapse to necroptosis. In mice harboring the human POMGnT1 L120R allele and in POMGnT1-knockout human RPE cells, hypoglycosylation of key substrates (α-dystroglycan and ENO1) coincides with strengthened SAG-ENO1 interaction, reduced glycolytic capacity, ATP shortfall, Golgi fragmentation, tight-junction failure, and robust activation of the RIPK1/RIPK3/MLKL cascade; notably, degeneration proceeds with minimal apoptotic signatures. Two orthogonal interventions-AAV8-mediated POMGnT1 gene augmentation and pharmacologic RIPK1 inhibition (RIPA-56)-each suppress necroptotic signaling, restore barrier integrity, and rescue visual function in vivo. These data define a glycosylation-metabolism-necroptosis axis that generalizes beyond a single gene or tissue and motivate a mutation-independent therapeutic blueprint: repair the upstream glycosylation deficit and/or block the downstream necroptotic execution pathway. Our findings position O-mannosylation homeostasis as a tractable control point for neuroprotection and nominate combined gene-augmentation and kinase-inhibition strategies for glycosylation-linked neurodegeneration.
    DOI:  https://doi.org/10.1038/s41420-026-03098-8
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