bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–06–21
sixty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
  2. Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
  3. Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.
  4. Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
  5. Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.
  6. Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
  7. The role of energy deficit in autophagy failure in Parkinson's disease.
  8. Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
  9. Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
  10. NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
  11. SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
  12. Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.
  13. Drosophila Myc ameliorates defects in mitochondrial homeostasis and muscle maturation caused by Metaxin-2 deficiency.
  14. Miro1 mutations disrupt cellular calcium homeostasis via dysregulation of mitochondria-ER-contact-sites, rendering iPSC-derived neurons more susceptible to lipid peroxidation.
  15. Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells.
  16. Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.
  17. Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.
  18. Limiting neurodegeneration in ALS: A phosphatase paves the way.
  19. Mass spectrometry proteomics for studying mitostasis.
  20. [Advances in the molecular genetics of nuclear gene mutations causing pediatric mitochondrial cardiomyopathy].
  21. Structural evolution of the MTCH family of mitochondrial insertases.
  22. Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
  23. Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.
  24. Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
  25. Mitochondrial Dynamics in Cellular Senescence: Mechanisms, Context Dependence, and Therapeutic Potential.
  26. Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
  27. Protocol update to: Protocol for rapid manipulation of mitochondrial morphology in living cells using inducible counter mitochondrial morphology.
  28. Multi-layered Regulatory Mechanisms and Translational Implications of Mitochondrial Redox Imbalance in Aging Stem Cells.
  29. Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.
  30. The leaked mitochondrial DNA activated the cGAS-STING signaling pathway and exacerbated the motor dysfunction in mice caused by MPTP.
  31. Mitofusins are required for specialized mitochondrial morphology and function of rod photoreceptor cells.
  32. Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
  33. Structural Basis for Stepwise Substrate Transport and Disease Phenotypic Heterogeneity of the Mitochondrial ADP/ATP Carrier.
  34. From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.
  35. Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
  36. Navigating a crowded developing brain leaves neurons with broken DNA.
  37. Decoding common and rare noncoding variant effects across cellular and developmental contexts.
  38. 3D skeletal muscle model recapitulating the myostatin knockout phenotypic and mitochondrial metabolic features.
  39. Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.
  40. Rethinking mitochondrial metabolism: Intraindividual variability meets population constraints.
  41. An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
  42. Cardiolipin remodelling in mitochondrial therapeutics: translational evidence chains from elamipretide to emerging strategies.
  43. Inferring accumulation times of mitochondrial DNA deletion mutants from cross-sectional single-cell data: methodological framework and validation.
  44. Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.
  45. Epigenetic lockdown of type I interferon sensing and signalling in human pluripotent cells.
  46. Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
  47. The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
  48. Efficient prime editing in vivo and in vitro using lipid nanoparticles.
  49. Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex.
  50. iSCORE-PD: an isogenic stem cell collection to research Parkinson's disease.
  51. Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.
  52. An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial Ca2⁺-Sensing Mechanism for ATP Synthase Regulation.
  53. Vacuolar H+-ATPase Preserves Cardiolipin Homeostasis Through the Lysosomal-Mitochondrial Axis to Restrain Cardiac Aging.
  54. Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing.
  55. Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.
  56. NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition.
  57. Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
  58. Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.
  59. Pediatric hereditary optic neuropathies in the United Arab Emirates.
  60. In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant.
  61. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  62. Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.
  63. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
  64. Fragmentation of Long Reads Enables Reliable Mitogenome Assembly From Whole-Genome Amplification Data With Pervasive Palindromic Reads.
  65. Electron transfer between complexes III and IV in S. cerevisiae mitochondrial membranes.
  1. Front Cell Dev Biol. 2026 ;14 1872916
    Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
    Nahid A Khan, Ruben Torregrosa-Muñumer.
      
    Keywords:  cell fate regulation; metabolic signaling; mitochondria; mitochondrial disease; mitochondrial dynamics; mitochondrial quality control; mitochondrial therapy; redox metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1872916
  2. EMBO Mol Med. 2026 Jun 17.
    Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
    Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.
      Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.
    DOI:  https://doi.org/10.1038/s44321-026-00471-z
  3. Kidney Int Rep. 2026 Jul;11(7): 106578
    Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.
    Daniel R Schecter, Rory J Tinker, Patrick O'Connell, Jiuhong Pang, Simon SzeKing Lee, Meltem Ece Kars, Aysegul Guvenek, Michael Preuss, Yuval Itan, Eva Morava, Tamas Kozicz, Michio Hirano, Ali Naini, Jaya Ganesh.
       Introduction: Pathogenic mitochondrial DNA (mtDNA) variants cause multisystem disease, yet their contribution to kidney disease remains incompletely characterized, partly because of exclusion of the mitochondrial genome from genetic studies.
    Methods: We evaluated mtDNA variation in 27,747 participants from the Mount Sinai Million Health Discoveries Program (MSM), an ancestrally diverse biobank with whole-exome sequencing and linked electronic health records (EHR). mtDNA variants were identified using MitoVerse and classified with MITOMAP. Kidney disease was defined using renal PheCodes for glomerular disease (GU_580) and renal failure (GU_582). Previous mitochondrial diagnoses were ascertained from EHR to identify undiagnosed individuals. Associations were adjusted for age, self-reported gender, and ancestry, with genotype-phenotype review.
    Results: Among 3935 individuals with kidney disease, 45 carried clinically associated mtDNA variants, 42 of whom had no previous clinical mitochondrial diagnosis. mtDNA variants were enriched among individuals with kidney disease and associated with increased odds of renal involvement (odds ratio [OR] = 1.72). Associations were strongest for chronic kidney disease (CKD; GU_582.2; OR = 1.55) and renal failure (GU_582; OR = 1.53). Among undiagnosed carriers, genotype-phenotype review identified concordant manifestations in 14%, including mitochondrial CKD with hyperuricemia. Variant-level analysis identified enrichment of m.1630A>G in MT-TV (OR = 5.56), with additional variants showing trends. Both renal- and nonrenal-associated pathogenic mtDNA variants were observed.
    Conclusion: Pathogenic mtDNA variants are overrepresented among individuals with kidney disease, often without a known mitochondrial diagnosis. These findings support a contributory role for mtDNA in renal disease and highlight the value of mtDNA analysis into kidney disease research and clinical evaluation, particularly for identifying unrecognized mitochondrial disease with renal involvement.
    Keywords:  mitochondrial DNA; mitochondrial disease; population biobank; precision medicine; variant-level association
    DOI:  https://doi.org/10.1016/j.ekir.2026.106578
  4. Protein Sci. 2026 Jul;35(7): e70682
    Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.
    Nikita A Kvasov, Yury S Bykov.
      Mitochondria import the majority of their proteins from the cytosol, creating a fundamental challenge: precursor proteins must be synthesized, maintained in an import-competent state, and delivered to mitochondrial translocases without premature folding or aggregation. While mitochondrial protein import has been considered a post-translational process, growing evidence shows that a subset of mitochondrial proteins is synthesized in proximity to the organelle. We term this process co-translational targeting, or local translation. It may lead to direct structural coupling of protein synthesis and import, which we term co-translational translocation. New approaches, including selective ribosome profiling, proximity labeling, and RNA imaging, reveal that mitochondrial mRNA localization is highly dynamic and can be driven by both RNA-based and translation-dependent mechanisms. In contrast to the well-defined signal recognition particle pathway at the endoplasmic reticulum, mitochondrial targeting appears to rely on more flexible mechanisms shaped by nascent-chain properties, translation elongation, and coding-sequence features beyond the targeting signal. We discuss how these processes may support mitochondrial biogenesis and proteostasis while also creating vulnerabilities associated with ribosome stalling and precursor quality control. Together, recent findings position mitochondrial protein targeting as an integral part of cellular protein biogenesis and highlight key open questions in the coordination of translation and organelle function.
    Keywords:  NAC; chaperones; co‐translational import; mRNA localization; mitochondria; protein targeting; translation
    DOI:  https://doi.org/10.1002/pro.70682
  5. Cell Biosci. 2026 Jun 19.
    Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.
    Kexin Shi, Hao Liu, Hong Xu, Weina Shang, Liquan Wang, Chao Tong.
       BACKGROUND: Mitochondrial proteases are essential for mitochondrial protein import and constitute the core of the organelle's intrinsic protein quality control system. However, their physiological functions across tissues, as well as their influence on cytosolic proteostasis, remain incompletely understood.
    RESULTS: We generated loss- and gain-of-function alleles for 15 conserved mitochondrial proteases in Drosophila melanogaster to systematically dissect their in vivo functions. Disruption of specific proteases caused male sterility or organismal lethality, whereas tissue-specific knockouts in the eye, muscle, or fat body led to mitochondrial protein aggregates, structural defects, and age-dependent degeneration. Loss of UQCR-C1 or Afg3l2 robustly increased mitophagy, while overexpression of several proteases severely impaired muscle integrity. Loss of UQCR-C1, Mppa, or CG11771 promoted HTT72Q aggregation, and reducing UQCR-C1 or Afg3l2 markedly elevated cytosolic HTT72Q levels. Conversely, overexpressing Mppa-but with reduced efficacy in its disease-associated variants-suppressed HTT96Q aggregation and neuronal toxicity. Mppa forms a complex with UQCR-C1 to regulate mitochondrial pre-protein processing and import, indicating that enhancing mitochondrial protein import is sufficient to alleviate cytosolic proteotoxic stress caused by HTT polyglutamine (polyQ) proteins.
    CONCLUSIONS: This work establishes a comprehensive in vivo resource for mitochondrial protease functions and their roles in shaping cytosolic proteostasis.
    Keywords:   Drosophila ; Huntington disease (HTT) polyQ proteins; Mitochondria; Protease
    DOI:  https://doi.org/10.1186/s13578-026-01612-0
  6. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2530774123
    Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
    Marine Tessier, Zeinab Hamze, Nathalie Bonello-Palot, Nathalie Roeckel-Trévisiol, Nathalie Da Silva, Ilian Verlet, Natacha Broucqsault, Karine Bertaux, Emilien Delmont, Shahram Attarian, Marc Bartoli, Valérie Delague, Bernard L Schneider, Nathalie Bernard-Marissal.
      Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
    Keywords:  Charcot–Marie–Tooth disease; MFN2; endoplasmic reticulum; gene therapy; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2530774123
  7. Front Aging Neurosci. 2026 ;18 1846307
    The role of energy deficit in autophagy failure in Parkinson's disease.
    Mihajlo Bosnjak, Maja Misirkic Marjanovic, Milica Kosic, Milos Mandic, Ljubica Vucicevic, Verica Paunovic, Ljubica Harhaji-Trajkovic.
      Mitochondrial complex I dysfunction, ATP depletion, and impaired autophagy are key features of Parkinson's disease (PD), but their causal relationship remains unclear. Although energy stress induces autophagy, autophagy execution requires ATP. Available evidence suggests a biphasic effect of ATP depletion on autophagy in PD, with mild early energy decline promoting autophagy and more severe ATP loss, below a critical threshold, suppressing its completion. This mechanism may contribute to the accumulation of dysfunctional mitochondria and other undegraded cargo, creating a vicious cycle in which mitochondrial dysfunction, ATP decline, and autophagy failure progressively reinforce one another in PD. Here, we review current evidence linking cellular energy status to autophagic dysfunction in PD and discuss its pathogenic and therapeutic implications.
    Keywords:  ATP depletion; Parkinson’s disease; autophagy; mitochondrial dysfunction; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnagi.2026.1846307
  8. J Lipid Res. 2026 Jun 19. pii: S0022-2275(26)00109-4. [Epub ahead of print] 101083
    Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
    Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.
      The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans. Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
    Keywords:  Glycerophospholipids; membrane diversity; metabolic rewiring; mitochondria; phospholipids; phospholipids/biosynthesis; phospholipids/metabolism; phospholipids/trafficking
    DOI:  https://doi.org/10.1016/j.jlr.2026.101083
  9. Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]
    Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
    Amandine Grimm, Undine Lang, Anne Eckert.
      Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.
    Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
  10. Sci Adv. 2026 Jun 19. 12(25): eaec3505
    NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
    Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.
      Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.
    DOI:  https://doi.org/10.1126/sciadv.aec3505
  11. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123
    SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
    Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.
      Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.
    Keywords:  SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol
    DOI:  https://doi.org/10.1073/pnas.2612098123
  12. Nat Rev Cardiol. 2026 Jun 18.
    Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.
    Atsuko Imai-Okazaki, Liming Pei, Douglas C Wallace.
      Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopathy is caused by a dysfunction in mitochondrial oxidative phosphorylation due to pathogenic variants in either nDNA or the maternal mitochondrial DNA (mtDNA). Unlike contractile protein defects, which generally follow predictable Mendelian inheritance patterns, mitochondrial cardiomyopathy is genetically complex as a result of the distinctive characteristics of the mitochondrial genome, which influence patterns of maternal inheritance, heteroplasmy and tissue-specific variations in mtDNA variant load. Both single-gene nDNA and mtDNA variants can impair cardiac energetics, resulting in a wide clinical spectrum ranging from severe, childhood-onset to milder, adult-onset cardiomyopathy. Furthermore, the intricate metabolic demands of the heart mean that mitochondrial dysfunction can be influenced by a broad array of genetic and environmental modifiers. A greater recognition of these complexities and the integration of genomic sequencing, novel biomarkers and functional imaging have advanced diagnostic and therapeutic approaches. Emerging treatment strategies, such as metabolic supplementation, gene therapy and genome editing, are under investigation. In this Review, we synthesize the molecular and clinical landscape of mitochondrial cardiomyopathy, highlighting the ongoing challenges and prospects of precision medicine in this rapidly evolving field.
    DOI:  https://doi.org/10.1038/s41569-026-01301-y
  13. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2532562123
    Drosophila Myc ameliorates defects in mitochondrial homeostasis and muscle maturation caused by Metaxin-2 deficiency.
    Xinyi Shou, Xiaoyu Fan, Ling Li, Yina Ruan, Wei Li, Weina Shang, Jianhua Mao, Xiaojun Xie.
      Mitochondrial protein import machineries are essential for organelle homeostasis. Metaxin-2 (Mtx2) is an evolutionarily conserved component of the mitochondrial sorting and assembly machinery, and its mutations are associated with a progeroid syndrome, named mandibuloacral dysplasia associated to Mtx2 (MADaM). To investigate the pathologic mechanisms of MADaM, we developed Mtx2 genetic models in Drosophila. Mtx2 null mutants are lethal at a preadult stage, and this phenotype can be rescued by expression of either Drosophila Mtx2 (dMtx2) or its human ortholog, demonstrating functional conservation across species. Tissue-specific conditional knockout and transgene rescue experiments pinpoint muscle as a critical tissue requiring dMtx2 function. Loss of dMtx2 impairs myofibril assembly and induces structural and functional abnormalities in muscle mitochondria. Notably, Mtx2 deficiency significantly reduces the expression of myogenic, mitochondrial, and ribosomal proteins. Overexpression of Drosophila Myc, a master regulator of ribosome biogenesis and cell growth, successfully rescues the preadult lethality caused by dMtx2 deficiency, and partially restores sarcomere and mitochondrial defects. Our results reveal an interaction between Mtx2-related mitochondrial and ribosomal homeostasis, and elucidate potential Myc-dependent pharmaceutic mechanisms underlying MADaM pathologies.
    Keywords:  metaxin-2; mitochondria; muscle development; progeria
    DOI:  https://doi.org/10.1073/pnas.2532562123
  14. Neurobiol Dis. 2026 Jun 18. pii: S0969-9961(26)00237-8. [Epub ahead of print] 107492
    Miro1 mutations disrupt cellular calcium homeostasis via dysregulation of mitochondria-ER-contact-sites, rendering iPSC-derived neurons more susceptible to lipid peroxidation.
    Anna E Bartalis, Jack Genschmar, Julia C Fitzgerald, Andreas Hermann, Dajana Grossmann.
      The pathogenesis of Parkinson's disease is multifactorial, but disruption of calcium and iron is a common feature. The mitochondrial Rho GTPase Miro1 is a component of the mitochondrial-endoplasmic reticulum contact sites and a key regulator of calcium homeostasis. Heterozygous variants in the Miro1-encoding gene RHOT1 were identified in Parkinson's disease patients. Neurons harboring Parkinson's disease-associated variants show defects in mitochondrial calcium regulation and mitochondria-ER contact sites organization which we hypothesize to contribute to neuronal vulnerability. However, the exact mechanism is not fully understood. We systematically assessed the role of Miro1 and its different domains by using a set of isogenic lines with gene edited mutations S156A and K572R in PINK1/Parkin regulatory elements and the Parkinson's disease-associated mutation R272Q. This showed us a general role of Miro1 in the regulation of cellular calcium homeostasis and the regulation of mitochondrial-ER contact sites, but more importantly, a domain-specific involvement of local calcium distribution, impaired store operated calcium entry and vulnerability to ferroptosis. These findings indicate that Miro1-mutant specific impairments in cellular calcium handling contributes to neuronal vulnerability via mitochondria-ER contact sites and provides further insights in the mechanism how impaired regulation of Miro1 impacts neurons in the context of Parkinson's disease.
    Keywords:  Calcium; Ferroptosis; Lipid peroxidation; MERCS; Miro1; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2026.107492
  15. Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102959
    Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells.
    Vadim V Maximov, Nikita Shebanov, Natalia Nikitchina, Rachel Rapoport, Yehoshua Maor, Ivan Tarassov, Ophry Pines, Nina Entelis.
      Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables the introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. Forty-nine bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homologous to an ND4 site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the intended nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR-mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16 nt ND4 site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations, such as Leber's hereditary optic neuropathy (LHON)-associated mutations in the ND4 gene of mtDNA.
    Video Abstract:
    Keywords:  MT: oligonucleotides: therapies and applications; microhomology-mediated mtDNA editing; mitochondria; mitochondrial CRISPR; mitochondrial DNA delivery; mitochondrial genome editing
    DOI:  https://doi.org/10.1016/j.omtn.2026.102959
  16. Adv Sci (Weinh). 2026 Jun 16. e16501
    Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.
    Qingwen Zhao, Li Xie, Qianzhuo Wang, Shuying Dai, Bei Li, Yingjuan Zhang, Zhe Sun, Yue Gao.
      Brown and beige adipocytes dissipate energy as heat, yet effective strategies to enhance their mitochondrial efficiency remain limited. Here, we identify Agnuside (AGN) as a selective stabilizer of the complex I assembly factor NDUFAF6. AGN directly binds cytosolic NDUFAF6, suppresses its ubiquitination, prolongs its half-life, and facilitates mitochondrial import, thereby reinforcing complex I assembly and promoting coordinated stabilization of complexes III and IV within the respirasome, without altering complex II, complex V, or global mitochondrial biogenesis. Functionally, AGN exhibits a demand-dependent metabolic profile. Under basal conditions, AGN enhances mitochondrial oxidative efficiency without activating overt UCP1-dependent uncoupling. In contrast, cold exposure or chronic high-fat feeding markedly potentiates its thermogenic impact, as evidenced by improved mitochondrial ultrastructure, increased UCP1 abundance, and elevated energy expenditure in brown adipose tissue, with similar mitochondrial reinforcement observed in inguinal white adipose tissue under sustained metabolic stress. Importantly, thermoneutral Ucp1 knockdown does not abolish AGN-mediated enhancement of respiratory complex assembly and ATP production, whereas genetic ablation of Ndufaf6 eliminates these effects. Together, these findings establish AGN-NDUFAF6 stabilization as a key regulatory mechanism governing adipose mitochondrial efficiency and thermogenic responsiveness, and highlight assembly-factor targeting as a promising strategy to restore oxidative metabolism in metabolic dysfunction.
    Keywords:  NDUFAF6; agnuside; brown adipocytes; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1002/advs.202516501
  17. Transl Neurodegener. 2026 Jun 17. pii: 27. [Epub ahead of print]15(1):
    Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.
    Preethi Sheshadri, Maria Alicia Costa-Besada, Alessia Fisher, Szilvia Kiraly, Kritarth Singh, Ioanna Kourouzidou, Thomas S Blacker, Jialiu Zeng, Orian S Shirihai, Mark W Grinstaff, Michael R Duchen.
       BACKGROUND: Heterozygous mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson's disease (PD). The pathophysiological consequences of GBA1 mutations on dopaminergic neuronal function, especially their impact on lysosomal function, mitophagy, and mitochondrial bioenergetics, remain unclear.
    METHODS: Fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-PD were used in the study. Live-cell imaging was performed to measure lysosomal acidification, protease activity, mitochondrial membrane potential, and mitophagy. Mitochondrial morphology and autophagic vesicles were examined using transmission electron microscopy. Oxygen consumption rate was measured by Seahorse assay. V-ATPase assembly was quantified using fluorescence lifetime imaging with Förster resonance energy transfer (FLIM-FRET), and pharmacological interventions included rapamycin and acidic nanoparticles.
    RESULTS: GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired in GBA1 mutant dopaminergic neurons. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. Mechanistic target of rapamycin complex 1 (MTORC1) was constitutively phosphorylated and FLIM-FRET measurements confirmed impairment of lysosomal V-ATPase assembly, which was reversed by rapamycin treatment. Rapamycin and lysosome-targeting acidic nanoparticles rescued lysosomal pH and restored mitophagy, mitochondrial membrane potential and mitochondrial oxidative phosphorylation complex level in the GBA1 mutant dopaminergic neurons.
    CONCLUSIONS: We revealed a novel mechanistic link between GBA1 mutations and mitochondrial dysfunction, as the disruption of V-ATPase assembly driven by MTORC1 activation impairs lysosomal acidification. This causes impairment of mitophagy, leading to mitochondrial dysfunction, undermining dopaminergic cell function and fate. Pharmacological intervention with rapamycin or acidic nanoparticles restores lysosomal pH and rescue mitochondrial function, representing a novel therapeutic approach for GBA1-PD .
    Keywords:  Acidic nanoparticles; GBA1; Lysosomal pH; Lysosomes; MTORC1; Mitochondria; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-026-00559-z
  18. Neuron. 2026 Jun 17. pii: S0896-6273(26)00325-9. [Epub ahead of print]114(12): 2073-2075
    Limiting neurodegeneration in ALS: A phosphatase paves the way.
    Elena I Rugarli, Thomas Langer.
      Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.030
  19. Protein Sci. 2026 Jul;35(7): e70673
    Mass spectrometry proteomics for studying mitostasis.
    Lakshita Sharma, Sristi Chakroborty, Hirak Das, Silke Oeljeklaus, Julian Bender, Bettina Warscheid.
      Maintaining mitochondrial integrity and function is fundamental to cellular homeostasis. Cells rely on coordinated protein quality control (QC) systems-including intricate chaperone-protease networks, the ubiquitin-proteasome system, and cytosolic surveillance pathways-that together form a dynamic, cell-wide mitostasis network governing the import, folding, synthesis, and degradation of mitochondrial proteins. Disruption of mitochondrial homeostasis, for example, by impairing mitochondrial protein import, induces proteotoxic stress and contributes to human disease. Mass spectrometry (MS)-based proteomics has established itself as an indispensable method to dissect mitostasis at unprecedented depth by enabling systematic quantitative analysis of protein abundance, localization, interactions, stability, and dynamics. In this review, we highlight state-of-the-art MS technologies and multifaceted proteomics approaches used to study mitostasis on a proteome-wide level. These functional analysis approaches build on quantitative MS methods employing label-free, metabolic, and chemical labeling strategies, which allow precise tracking of proteome dynamics in response to different cellular conditions including stress. Spatial and interaction-based approaches, such as affinity purification-MS, proximity labeling, and complexome profiling, provide detailed insight into the organization and regulation of the complex mitochondrial organizing system, chaperone networks, and protein QC pathways. Furthermore, we discuss advanced methodologies such as nascent chain and dynamic proteomics strategies, which offer a proteome-wide comprehension of early stress responses and fast regulation. The skillful integration of temporal, spatial subcellular, interaction, nascent, and dynamic proteomics approaches now enables a systems-level assessment of mitostasis, paving the way for a holistic while nuanced understanding of this essential cellular process and the underlying molecular mechanisms.
    Keywords:  complexome profiling; dynamic SILAC; interactome analysis; mitochondria; nascent proteomics; protein import stress; proteome dynamics; proteostasis; proximity labeling; quantitative mass spectrometry
    DOI:  https://doi.org/10.1002/pro.70673
  20. Zhongguo Dang Dai Er Ke Za Zhi. 2026 Jun 15. pii: 1008-8830(2026)06-0772-08. [Epub ahead of print]28(6): 772-779
    [Advances in the molecular genetics of nuclear gene mutations causing pediatric mitochondrial cardiomyopathy].
    Zi-Wei Wang, Yu-Qi Wang, Chun-Li Wang.
      Mitochondrial cardiomyopathy (MCM) is a heterogeneous group of disorders characterized by abnormal myocardial structure and/or function caused by defects in genes encoding the oxidative phosphorylation chain. This review systematically summarizes molecular genetic advances regarding nuclear gene mutations associated with pediatric MCM, focusing on mutations affecting pathways including respiratory chain complex subunits and assembly factors, coenzyme Q10 biosynthesis, mitochondrial DNA maintenance and expression, lipid metabolism, iron-sulfur cluster metabolism, apoptosis regulation, and mitochondrial dynamics. These nuclear gene mutations contribute to myocardial pathological changes by disrupting key processes such as mitochondrial energy metabolism, membrane stability, and signal transduction. The review provides a theoretical basis for precise clinical diagnosis and the exploration of potential molecular targets in pediatric MCM.
    Keywords:  Child; Mitochondrial cardiomyopathy; Mutation; Nuclear gene; Oxidative phosphorylation
    DOI:  https://doi.org/10.7499/j.issn.1008-8830.2510107
  21. Sci Adv. 2026 Jun 19. 12(25): eaeh2957
    Structural evolution of the MTCH family of mitochondrial insertases.
    Taylor A Stevens, Zhilin Luo, Camryn Lee, Masami Hazu, Erini G Galatis, Alison J Inglis, Alina Guna, Rebecca M Voorhees.
      We demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. MTCH insertases are conserved across holozoa and have diverged from the solute carrier 25 transporters. The cryoelectron microscopy structure of the 33-kilodalton human MTCH2 revealed that evolution of its insertase activity required loss of a transmembrane helix, which created a lipid-accessible hydrophilic groove stabilized by its unique, structured C terminus. Mutational analyses showed that MTCH insertase activity is attenuated, while experimental structures and reconstitution of hyperactive mutants demonstrated that the hydrophobicity, charge, and size of the residues that line its groove regulated MTCH function. Leveraging the MTCH2 structure, we identified the plant OM insertase and proposed a universal mechanism for OM insertion across all kingdoms of life.
    DOI:  https://doi.org/10.1126/sciadv.aeh2957
  22. Stem Cell Res. 2026 Jun 18. pii: S1873-5061(26)00134-0. [Epub ahead of print]95 104038
    Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
    Gautam Sharma, Abhay Srivastava, Cheryl Rockman-Greenberg, Sanjiv Dhingra.
      MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) represents a multisystemic mitochondrial disease mainly triggered by heteroplasmic m.3243A > G mutation in mtDNA MT-TL1, the gene for tRNA^Leu(UUR). Here we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a female MELAS patient into induced pluripotent stem cells (iPSCs). This patient-specific iPSC line provides a valuable platform to investigate MELAS pathophysiology and screen therapeutic interventions targeting mitochondrial dysfunction in a genetically relevant context.
    DOI:  https://doi.org/10.1016/j.scr.2026.104038
  23. Physiol Behav. 2026 Jun 18. pii: S0031-9384(26)00211-8. [Epub ahead of print] 115427
    Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.
    Welington Henrique Justo Neto, Camila de Oliveira Ramos, Claudio Teodoro De Souza.
      Obesity is characterized not only by excessive adiposity but also by profound disturbances in cellular and systemic energy homeostasis. Metabolic inflexibility, defined as the impaired ability to adapt substrate utilization in response to nutrient availability and energetic demands, has emerged as a central feature of obesity-associated metabolic dysfunction. Increasing evidence suggests that mitochondrial remodeling represents an important mechanism linking obesity to tissue-specific metabolic alterations, systemic metabolic dysfunction, and insulin resistance. Across adipose tissue, skeletal muscle, and liver, obesity induces tissue-specific alterations in mitochondrial biogenesis, dynamics, oxidative metabolism, quality-control pathways, and redox signaling, ultimately disrupting substrate utilization and insulin signaling. Importantly, mitochondrial adaptations appear highly dynamic and context dependent, suggesting that certain responses may initially arise as compensatory mechanisms before becoming maladaptive during disease progression. In addition, translational differences between experimental models and humans contribute to the heterogeneity observed in obesity-associated mitochondrial phenotypes. Here, we integrate preclinical and clinical evidence to examine the molecular mechanisms underlying tissue-specific mitochondrial remodeling and its contribution to metabolic inflexibility. We further discuss how lifestyle, pharmacological, and surgical interventions modulate mitochondrial pathways involved in restoring metabolic flexibility and improving metabolic health. Collectively, this review highlights tissue-specific mitochondrial remodeling as a dynamic and context-dependent process linking obesity to metabolic inflexibility and impaired metabolic adaptability, while identifying mitochondrial plasticity as a promising therapeutic target.
    Keywords:  Adipose Tissue; Energy Metabolism; Insulin Resistance; Mitochondria; Muscle, Skeletal; Obesity
    DOI:  https://doi.org/10.1016/j.physbeh.2026.115427
  24. Annu Rev Genomics Hum Genet. 2026 Jun 15.
    Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
    Cameron Ryall, Patrick F Chinnery, Jelle van den Ameele.
      Heteroplasmy is the mixture of mutant and wild-type mitochondrial DNA (mtDNA) within each of our cells. Heteroplasmy levels in cells, tissues, and organisms change over time, thus contributing to mitochondrial disease, aging, and evolution. Germline and pedigree studies first revealed heteroplasmy shifts between generations and have long offered a window into the dynamics of mtDNA inheritance through single oocytes. Single-cell technologies are now uncovering similar mechanisms that operate in somatic tissues throughout life. Stochastic processes (relaxed replication and vegetative segregation, enhanced through genetic bottlenecks) generate cell-to-cell variation, while selection mechanisms such as intercellular competition, mitophagy, and preferential replication allow or drive directional shifts. Single-cell sequencing, mtDNA imaging, and genetic screening, combined with mtDNA-editing technology and heteroplasmic model systems, have transformed our ability to dissect these processes, revealing heteroplasmy dynamics at molecular resolution. These approaches are uncovering quantifiable principles governing heteroplasmy across cell types and life stages, transforming our understanding from descriptive observations to predictive mechanistic models and novel therapeutic avenues.
    DOI:  https://doi.org/10.1146/annurev-genom-120324-032239
  25. Aging Dis. 2026 Jun 05.
    Mitochondrial Dynamics in Cellular Senescence: Mechanisms, Context Dependence, and Therapeutic Potential.
    Dan Wu, Shihao Jiang, Chenyang Li, Xianqi Wang, Yuexiang Ma, Peiwen Wang, Yanan Xu, Heliang Fu, Qianmei Wang, Kuo Shen, Rui Zheng, Junjie Li.
      Mitochondria function as the primary energy centers of cells, and the dynamic equilibrium between their fission and fusion is essential for preserving cellular functional integrity and metabolic homeostasis. As research in cell biology has advanced, an imbalance in mitochondrial dynamics is tightly and bidirectionally linked to cellular aging. It not only contributes to aging-related functional decline but is also exacerbated by the senescent state itself, creating a vicious cycle that impacts key biological processes. Recent studies have demonstrated that the disruption of mitochondrial fission and fusion during aging, through mechanisms such as impaired cellular energy metabolism, increased oxidative stress, compromised mitophagy, and the induction of senescence-associated secretory phenotypes, collectively accelerates the functional decline of cells and organs. Nonetheless, many questions remain regarding the specific regulatory network of mitochondrial dynamics and its variations across different stages of aging. The aim of this review is to systematically elucidate the fundamental role of imbalances in mitochondrial dynamics in the context of cellular aging, along with its underlying molecular mechanisms. This review summarizes various intervention strategies targeting this process, including targeted therapies, small molecule regulators, stem cell therapy, lifestyle modifications, and innovative mitochondrial transplantation technology, whereas these approaches are still in experimental or early-stage development, and their translational potential requires further validation. The ultimate objective is to offer novel theoretical insights and potential therapeutic approaches for mitigating aging and associated diseases.
    DOI:  https://doi.org/10.14336/AD.2026.0323
  26. Nat Cell Biol. 2026 Jun 15.
    Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
    Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.
      Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
    DOI:  https://doi.org/10.1038/s41556-026-01991-z
  27. STAR Protoc. 2026 Jun 16. pii: S2666-1667(26)00288-1. [Epub ahead of print]7(3): 104635
    Protocol update to: Protocol for rapid manipulation of mitochondrial morphology in living cells using inducible counter mitochondrial morphology.
    Mayuko Kano, Naoko Onodera, Tomoto Ura, Satone Tanigaki, Teppei Nishino, Takafumi Miyamoto.
      Disruption of mitochondrial morphology occurs during various diseases, but the biological significance is not entirely clear. Here, we describe a detailed step-by-step protocol for a chemically inducible dimerization (CID) system-based synthetic protein device, termed inducible counter mitochondrial morphology (iCMM). This system allows artificial manipulation of mitochondrial morphology on a timescale of minutes in living mammalian cells. We also describe an AI-assisted image processing approach. For complete details on the use and execution of this protocol, please refer to Miyamoto et al.1 This protocol provides an updated version of the method described by Miyamoto et al.2.
    Keywords:  Cell Biology; Microscopy; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104635
  28. Free Radic Biol Med. 2026 Jun 18. pii: S0891-5849(26)00893-2. [Epub ahead of print]
    Multi-layered Regulatory Mechanisms and Translational Implications of Mitochondrial Redox Imbalance in Aging Stem Cells.
    Zi Ye, Shanshan Chen, Jiali Rui, Lumin Tang, Tianshi Wang, Qiuju Fan.
      Mitochondrial redox homeostasis is required for proper stem cell fate determination and tissue regeneration, and its dysregulation is a hallmark of aging-related stem cell dysfunction. This review systematically summarizes the multi-layered mechanisms by which aging-induced mitochondrial redox imbalance impairs stem cell identity, covering reactive oxygen species homeostasis, macromolecular metabolism, mitochondrial DNA integrity, mitochondrial dynamics, and the Sirtuin/forkhead box O (FoxO) signaling axis. We further highlight the context-specific metabolic features across different stem cell types and recent advances in targeted interventions to restore mitochondrial redox homeostasis, with a special focus on small molecule compounds with translational potential. This review further critically evaluates conflicting experimental evidence in current research, highlights major unresolved controversies and technical limitations in the field, providing a model that links mitochondrial redox status to epigenetic regulation for advancing both basic research and translational applications of mitochondrial redox-targeted interventions for stem cell aging.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.038
  29. Alzheimers Dement. 2026 Jun;22(6): e71594
    Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.
    Evelyn Pardo, Taylor Kim, Horst Wallrabe, Kristine E Zengeler, Vijay Kumar Sagar, Garnett Mingledorff, Xuehan Sun, Ammasi Periasamy, John R Lukens, George S Bloom, Andrés Norambuena.
       INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.
    METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.
    RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.
    DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.
    Keywords:  Alzheimer's disease; NADPH; PS19; brain metabolism; endocytosis; mitochondria; tau spreading
    DOI:  https://doi.org/10.1002/alz.71594
  30. Exp Neurol. 2026 Jun 13. pii: S0014-4886(26)00241-4. [Epub ahead of print]404 115876
    The leaked mitochondrial DNA activated the cGAS-STING signaling pathway and exacerbated the motor dysfunction in mice caused by MPTP.
    Guangyao Zhu, Xuanjie Yu, Yi Guo, Liting Yang, Qianhui Yang, Wangyuan Xu, Jingwen Yang, Ruyi Zhang, Li Lin, Changhan Ouyang, Lijun Zhang.
      Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide, outpacing even the rate of population aging. The Global Burden of Disease Study estimated that more than 10 million individuals were affected in 2020, a figure projected to double by 2040. Pathologically, PD is characterised by the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Although early mechanistic work centred on gross anatomical changes and neuronal injury, converging evidence now positions neuroinflammation as an early and causal driver of DA neurodegeneration across the entire PD continuum. While cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent innate immune signaling has been implicated in several neurodegenerative disorders, its contribution to PD has remained undefined. Here, using complementary in vitro and in vivo PD models, we demonstrate that mitochondrial stress triggers mitochondrial DNA (mtDNA) leakage into the cytosol, thereby activating the cGAS-STING pathway and precipitating SNcDA neuronal loss and overt motor dysfunction. Genetic knockdown of STING markedly attenuated DA neuronal demise and preserved motor performance, identifying STING-mediated neuroinflammation as a critical mediator of DAergic neurodegeneration in MPTP-induced motor deficits. Collectively, our data indicate that selective inhibition of the cGAS-STING inflammatory cascade robustly mitigates MPTP-induced nigrostriatal DA neurodegeneration and motor deficits in mice, and nominate this pathway as a tractable therapeutic target for disease-modifying intervention in PD.
    Keywords:  Motor dysfunction; Parkinsons disease; Substantia nigra pars compacta; cGAS-STING
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115876
  31. Front Cell Dev Biol. 2026 ;14 1724328
    Mitofusins are required for specialized mitochondrial morphology and function of rod photoreceptor cells.
    Michael Landowski, Ryo Hagimori, Purnima Gogoi, Pawan K Shahi, Kazuya Oikawa, Vijesh J Bhute, Gillian J McLellan, Sakae Ikeda, Ken-Ichi Yamada, Bikash R Pattnaik, Tetsuya Takimoto, Akihiro Ikeda.
      Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion within each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, as well as their relationship to photoreceptor function, remain incompletely understood. Here, we investigated the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in rod photoreceptor cells. Rod-specific ablation of MFN1 and MFN2 resulted in near-complete and uniform mitochondrial fragmentation by 1 month of age, indicating that mitochondrial fusion is required for the development and maintenance of photoreceptor cell-specific mitochondrial architecture. At this stage, the layer structures of the retina examined by light microscopy appeared largely unaffected. Despite the absence of overt structural degeneration, electroretinography revealed early functional impairment, including reduced a-wave amplitudes and attenuation of the c-wave, indicating compromised rod photoreceptor activity and disrupted photoreceptor-RPE interactions. This was followed by progressive photoreceptor cell degeneration observed at 2 and 3 months of age. MFN1/2 ablation was also associated with changes in proteins involved in glycolysis, oxidative phosphorylation, and β-oxidation, along with activation of cellular stress pathways, including ER stress and the unfolded protein response. While total retinal ATP levels were only modestly reduced at early stages, these findings are consistent with alterations in metabolic homeostasis. Together, our findings demonstrate that MFN1 and MFN2 are required for specialized mitochondrial architecture in rod photoreceptor cells, and that their loss is associated with molecular remodeling and early functional deficits, preceding progressive degeneration.
    Keywords:  metabolic alteration; mitochondria; morphology; retina; rod photoreceptor cells
    DOI:  https://doi.org/10.3389/fcell.2026.1724328
  32. Neurotherapeutics. 2026 Jun 15. pii: S1878-7479(26)00115-7. [Epub ahead of print]23(4): e00945
    Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
    Anthony C T Cheung, Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.
      We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic POLG variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p < 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p < 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.
    Keywords:  DNA polymerase gamma; Deoxynucleoside; Mitochondrial DNA depletion disorder; Mitochondrial disorder; POLG
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00945
  33. J Chem Inf Model. 2026 Jun 17.
    Structural Basis for Stepwise Substrate Transport and Disease Phenotypic Heterogeneity of the Mitochondrial ADP/ATP Carrier.
    Shihao Yao, Xiao He, Qiuzi Yi, Qinghai Zhang, Min-Xin Guan.
      The mitochondrial ADP/ATP carrier (AAC) is essential for cellular energy metabolism and responsible for exchanging ADP for ATP across the inner mitochondrial membrane. However, the precise molecular determinants of substrate binding and the mechanisms underlying the phenotypic heterogeneity of AAC-related diseases remain poorly understood. Here, we combined AlphaFold3 predictions, molecular dynamics simulations, and experimental validation to identify and characterize a previously unrecognized ADP-binding site in AAC (site S2), which is distinct from the canonical bottom site (site S1). AlphaFold3 predictions on AAC variants with disrupted site S1 consistently placed ADP at site S2, interacting with residues R188, K92, and K96, a finding that was independently corroborated by our prior MD simulations. Systematic mutagenesis and functional analysis revealed distinct roles for site S2 residues: R188 serves as the primary phosphate-specific anchor; K92 and K96 facilitate initial recruitment and stabilization; and the aromatic ladder (Y187/Y191/F192/Y195) assists the conformational transition of ADP from anti to syn, a critical step enabling downward translocation. Functional characterization demonstrated that mutations in site S2 significantly impaired ADP transport and oxidative phosphorylation. Notably, the spatial distribution of AAC disease mutations correlates with this bipartite architecture: mild PEOA2-associated mutations cluster near site S2 and perturb the local conformation without abolishing binding, whereas lethal mutations cluster near site S1 and disrupt both ADP binding and structural integrity of the m-gate. Our findings provide new mechanistic insights into stepwise substrate transport and potential therapeutic targets for AAC-related diseases.
    DOI:  https://doi.org/10.1021/acs.jcim.6c01006
  34. Clin Transl Sci. 2026 Jun;19(6): e70634
    From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.
    Sydney Stern, Karryn Crisamore, John Patton, Robert Schuck, Michael Pacanowski.
      Primary mitochondrial diseases (PMDs) result from genetic variants in nuclear DNA and mitochondrial DNA which commonly lead to aberrant oxidative phosphorylation. The clinical complexity, often attributed to the underlying genetics, includes several distinct syndromes (e.g., Barth syndrome; Pearson syndrome; Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), some with overlapping symptoms. PMDs are highly heterogenous and affect multiple organs and tissues, prominently those with high energy demand such as muscle and neurologic tissues. Disease-modifying therapies for PMDs approved by the United States Food and Drug Administration are few and disease-specific, and treatment remains largely supportive in nature. The lack of robust biomarkers contributes to challenges associated with quantifying treatment responses in drug development. Recognizing this area of critical need, we sought to understand the landscape of molecular biomarkers that may inform treatment response, support clinical trials, and may be useful for regulatory decision-making. In this review, we assess the extent of evidence and challenges for each biomarker. We propose considerations for future biomarker development to measure treatment response and facilitate early drug development in PMDs by guiding dose selection and trial enrichment.
    DOI:  https://doi.org/10.1111/cts.70634
  35. Biochem Pharmacol. 2026 Jun 16. pii: S0006-2952(26)00508-3. [Epub ahead of print]251(Pt 2): 118170
    Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
    Lin Xie, Li-Hong Wu, Xin-Cheng Ni, Jiang-Nan Zhang.
      Mitochondrial Lon protease 1 (LONP1) is an ATP-dependent protease involved in mitochondrial protein quality control, mitochondrial DNA (mtDNA) maintenance, and stress adaptation. Beyond this canonical role, accumulating evidence links LONP1 to metabolic rewiring, inflammatory signaling, immune-cell polarization, and disease-associated mitochondrial dysfunction. Recent human LONP1 cryo-electron microscopy (cryo-EM) structures have revealed nucleotide- and substrate-dependent conformational states, including fold-sensing intermediates, pore-loop rearrangements, and catalytic-site organization, providing a structural framework for substrate processing and state-dependent ligandability. Functionally, LONP1 regulates the turnover or stability of metabolic enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and aconitase 2 (ACO2), thereby influencing carbon flux, epigenetic regulation, and immune-related metabolic programs. LONP1 deficiency or dysfunction can promote mitochondrial stress responses, including mtDNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-dependent inflammation, with implications for aging, pulmonary fibrosis, developmental disorders such as cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome, and organ injury. Conversely, increased LONP1 activity or expression has been associated with tumor progression, desmoplastic remodeling, ferroptosis resistance, and viral pathogenesis in selected models, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coxsackievirus B3 (CVB3). Pharmacological studies, including activators, dual-target inhibitors, and bortezomib-bound structural complexes, support the potential ligandability of LONP1 but also highlight unresolved issues in selectivity, target engagement, mitochondrial toxicity, and context-dependent therapeutic windows. This review summarizes current structural, mechanistic, and pharmacological evidence for LONP1 as a context-dependent immunometabolic regulatory node and discusses limitations and open questions that must be addressed before clinical translation.
    Keywords:  Enzyme activators; Immunity; LONP1protease; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1016/j.bcp.2026.118170
  36. Nature. 2026 Jun 17.
    Navigating a crowded developing brain leaves neurons with broken DNA.
    Monica D Manam, Christopher A Walsh.
      
    Keywords:  Cell biology; Developmental biology; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-01705-3
  37. Nat Genet. 2026 Jun 15.
    Decoding common and rare noncoding variant effects across cellular and developmental contexts.
    Andrew R Marderstein, Soumya Kundu, Evin M Padhi, Salil Deshpande, Austin Wang, Esther Robb, Ying Sun, Chang M Yun, Diego Pomales-Matos, Yilin Xie, Serena H Chang, Iris M Chin, Aayushi J Shah, Zachary A Gardell, M Ryan Corces, Daniel Nachun, Selin Jessa, Anshul Kundaje, Stephen B Montgomery.
      Interpreting how noncoding variants act in specific cell types across human development is a major challenge. Here we generated 3 billion predictions from deep learning sequence models of chromatin accessibility across diverse fetal and adult cellular contexts. These prioritized functional variants and revealed a dichotomy: common variants are more cell-type-specific, whereas ultra-rare variants had larger and broader effects across cell types, with the strongest evidence of purifying selection in fetal neurons. Leveraging these insights, we developed FLARE (Functional Lasso Analysis of Regulatory Evolution), which integrates evolutionary constraint to prioritize noncoding variants with extreme regulatory effects. FLARE provided a general framework for studying regulatory variation, from de novo mutations in childhood disorders to rare variants underlying outlier adult brain expression and common variants enriched for schizophrenia heritability. Together, these results demonstrate how integrating single-cell chromatin accessibility, population genetics and deep learning can identify regulatory variants that influence human development and disease.
    DOI:  https://doi.org/10.1038/s41588-026-02619-6
  38. Physiol Rep. 2026 Jun;14(12): e70947
    3D skeletal muscle model recapitulating the myostatin knockout phenotypic and mitochondrial metabolic features.
    Barbara Vernus, Elodie Jublanc, Béatrice Chabi, Laurence Pessemesse, Zacharie Cheng-Boivin, Benoit J Gentil, Anne Bonnieu, Christelle Koechlin-Ramonatxo, Bénédicte Goustard.
      3D cell culture, using a variety of bioengineering techniques, enables muscle cells to be cultured in more structural and functional biomimetic conditions than 2D cell culture. Here, we tested the ability of an engineered 3D skeletal muscle model to recapitulate in vivo metabolic muscle response. First, C2C12 myoblasts in 3D cultures showed improved myogenesis, attested by increased differentiation time, myotube formation, and gene expression of differentiated muscle markers. At the functional level, the 3D muscle culture displayed contractile properties and proper mitochondrial respiration. Second, to highlight the interest of such system we used primary myoblasts derived from myostatin knockout (Mstn-/-) mice. When compared to control wild-types 3D myotubes, 3D myotubes made from Mstn-/- myoblasts exhibit a hypertrophic phenotype associated with a decrease mitochondrial oxygen consumption, consistent with the skeletal muscle characteristics of Mstn-/- mice. Our findings show that 3D primary myotubes retain their in vivo phenotype in culture. This provides a useful framework for studying the underlying mechanisms of a various genetic muscle diseases, as well as for screening therapeutic drugs.
    Keywords:  3D skeletal muscle; mitochondrial respiration; murine myoblasts/myotubes; myogenic differentiation; myostatin deficiency
    DOI:  https://doi.org/10.14814/phy2.70947
  39. Nat Commun. 2026 Jun 17.
    Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.
    Na Geng, Taiwei Chen, Hao Li, Shan Lu, Yuehong Wang, Ling Gao, Donald M Bers, Xiyuan Lu.
      Heart failure (HF) is a growing global health burden characterized by impaired cardiac contractility and progressive remodeling, driven in part by disrupted Ca2+ handling and mitochondrial dysfunction. However, the molecular mechanisms coordinating these processes remain incompletely understood. Here we showed that OPA3 was decreased in both human and murine HF. Cardiomyocyte-specific deletion of Opa3 in male mice led to the progressive dilated cardiomyopathy (DCM), accompanied by impaired myocardial function, calcium cycling and mitochondria function. Mechanistically, OPA3 forms multimers that are required for its interaction with phospholamban (PLN), thereby maintaining sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and Ca2+ handling. OPA3 is localized to the mitochondrial outer membrane, and its absence impaired mitochondrial function. Cardiomyocyte-specific overexpression of Opa3 improved cardiac dysfunction in both pressure overload- and doxorubicin-induced HF models. Our data define a critical role of OPA3-PLN-SERCA2a axis that regulates both mitochondria and SR function, representing a potential therapeutic target for HF.
    DOI:  https://doi.org/10.1038/s41467-026-73991-4
  40. Trends Genet. 2026 Jun 18. pii: S0168-9525(26)00138-1. [Epub ahead of print]
    Rethinking mitochondrial metabolism: Intraindividual variability meets population constraints.
    José L Cabrera-Alarcón, José A Enríquez.
      Recent advances integrating high-resolution 3D structures with population genetics and comparative evolutionary analyses indicate that mitochondrial DNA (mtDNA) acts as a primary evolutionary engine driving nuclear coadaptation. This process reflects a trade-off between individual heterozygosity and mtDNA-driven variability, which together expand the mitonuclear haplotype pool within species.
    Keywords:  OxPhos; mitonuclear evolution
    DOI:  https://doi.org/10.1016/j.tig.2026.05.011
  41. Mol Cell. 2026 Jun 18. pii: S1097-2765(26)00322-9. [Epub ahead of print]86(12): 2237-2239
    An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
    Haruka Ozaki, Nobunari Sasaki, Shunsuke Kitajima.
      In this issue of Molecular Cell, Sohn et al.1 explore how endogenous dsRNAs influence organismal aging and identify an unexpected function of the aminoacyl-tRNA synthetase FARS-1/FARSA in regulating mitochondrial dsRNA homeostasis to balance longevity and innate immunity.
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.016
  42. Front Physiol. 2026 ;17 1813119
    Cardiolipin remodelling in mitochondrial therapeutics: translational evidence chains from elamipretide to emerging strategies.
    Ke Di, Yusheng Hu, Hechen Sun, Tianwei Meng, Tingquan Han, Rui Qie.
      Mitochondrial therapeutics have repeatedly fallen short of disease modification, in part because inner-membrane architecture constrains both molecular access and the reversibility of bioenergetic failure. Cardiolipin (CL), the signature phospholipid of the inner mitochondrial membrane, provides a mechanistically cohesive axis that links membrane mechanics to cristae organisation, respiratory-chain supercomplex stability and redox vulnerability. This Review summarises how CL biosynthesis and remodelling shape tissue-specific lipid species and how pathological remodelling can amplify oxidative injury. The MLCL: CL ratio is discussed as a rare lipid biomarker with direct interpretability for diagnosis, stratification and target engagement. Clinical evidence for CL-targeting stabilisers is evaluated to delineate settings in which structural support yields functional benefit and those in which organ-level remodelling limits translation despite improved respiration. Emerging approaches that improve tissue distribution, modulate membrane phase behaviour or rebalance upstream lipid flux are considered alongside trial designs that couple target-proximal readouts to patient-relevant endpoints, paving the way for precision medicine in mitochondrial lipodystrophies.
    Keywords:  cardiolipin; cardiolipin remodelling; elamipretide; inner mitochondrial membrane; target engagement
    DOI:  https://doi.org/10.3389/fphys.2026.1813119
  43. NPJ Aging. 2026 Jun 16. pii: 83. [Epub ahead of print]12(1):
    Inferring accumulation times of mitochondrial DNA deletion mutants from cross-sectional single-cell data: methodological framework and validation.
    Axel Kowald, Thomas B L Kirkwood.
      The accumulation of mitochondrial DNA (mtDNA) deletion mutants in post-mitotic cells is a hallmark of mammalian ageing and a key contributor to tissue decline in skeletal muscle and neurons. A transcription-coupled replication model predicts that deletions affecting a negative feedback mechanism gain a selective replication advantage, leading to relatively short accumulation times for mutant takeover. However, these accumulation times are experimentally inaccessible since single-cell measurements are destructive. Here, we present a framework to infer such accumulation times from cross-sectional single-cell RNA sequencing (scRNAseq) data, exploiting the fact that mtDNA deletions are also reflected at the transcript level. To establish feasibility, we generated synthetic datasets using two stochastic models of the mitochondrial life cycle and used these as a gold standard. We then applied the Moran process, a stochastic birth-death model, to calculate distributions of accumulation times and to extract key parameters. The Moran model reproduced the distributions obtained from stochastic simulations with high fidelity across different assumptions about mitochondrial regulation. Fitting the model to synthetic data, successfully recovered mutation probability, selection advantage, and the fraction of advantageous mutants. These results establish a methodological framework for quantifying mtDNA mutant dynamics from single-cell transcriptomic data and provide a foundation for analysing large experimental datasets in ageing research.
    DOI:  https://doi.org/10.1038/s41514-026-00431-4
  44. Nat Commun. 2026 06 17. pii: 5359. [Epub ahead of print]17(1):
    Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.
    Ulrike B Hendgen-Cotta, Anna Roth, Christine Beuck, Daniel Messiha, Stephan Settelmeier, Shah Bahrullah Shah, Sebastian Korste, Kenny Bravo-Rodriguez, Mike Blueggel, Feyza Cansiz, Luiza Martins Nascentes Melo, Jonas Roesler, Sven W Meckelmann, Oliver J Schmitz, Farnusch Kaschani, Markus Kaiser, Sonja Esfeld, Omar El Bounkari, Jürgen Bernhagen, Sophie Brameyer, Kirsten Jung, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Matthias Totzeck, Thomas Minor, Michael Ehrmann, Alpaslan Tasdogan, Peter Bayer, Tienush Rassaf.
      Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence-function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-73993-2
  45. Nat Commun. 2026 Jun 16.
    Epigenetic lockdown of type I interferon sensing and signalling in human pluripotent cells.
    James H Holt, Rocio Enriquez-Gasca, Rachel P Wilson, Elena G Bochukova, Pierre V Maillard, Helen M Rowe.
      The Human Silencing Hub (HUSH) complex safeguards genome integrity in human somatic cells, repressing transposable elements and regulating type I interferon (IFN-I) induction. Here, we use depletion of MPP8 in human induced pluripotent stem cells (iPSCs) as a tool to investigate epigenetic control of the IFN-I system in early development. We confirmed that human iPSCs display an attenuated IFN-I pathway, whereas iPSC-derived neural progenitor cells (NPCs) respond robustly to IFN-I pathway agonists. We found that, in iPSCs, depletion of MPP8 was sufficient to induce expression of young LINE-1 elements and genes linked to the IFN-I system including double-stranded RNA sensors and interferon-stimulated genes (ISGs). ISG upregulation occurred without IFN-I signalling, suggesting that, in contrast to differentiated cells, this ISG regulation is uncoupled from nucleic acid sensing specifically in early development. Chromatin profiling confirmed MPP8 enrichment at HUSH-regulated ISGs and revealed a bimodal binding profile of MPP8 to both ISGs and non-ISGs, the latter largely driven by young LINE-1 elements. We propose that shutdown of the IFN-I system in pluripotent stem cells is essential to prevent lethality from unwarranted self-nucleic acid sensing. This shutdown is achieved through a triple-layer of epigenetic lockdown targeting ligands, sensors, and effectors across the IFN-I pathway.
    DOI:  https://doi.org/10.1038/s41467-026-74147-0
  46. Clin Chim Acta. 2026 Jun 13. pii: S0009-8981(26)00354-2. [Epub ahead of print]591 121172
    Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
    Jiaqi Hu, Tongling Liufu, Cong Li, Qijin Zhao, Meng Yu, Yun Yuan, Li Quan, Zhixing Chen, Zhaoxia Wang.
       OBJECTIVES: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder driven by mutations in mitochondrial or nuclear DNA, involving an altered NADH/NAD+-associated redox metabolism as a key pathological mechanism. The traditional metabolomic analyses in MELAS face sensitivity and sample volume limitations, particularly for carboxylic acid metabolites. This study employed a recently established diazo-carboxyl/hydroxylamine-ketone double-click derivatization (DQmB-HA) mass spectrometry method to overcome these barriers, enabling highly sensitive quantification of NADH/NAD+-related serum metabolites in minimal sample volumes.
    METHODS: Using DQmB-HA mass spectrometry, we analyzed lactate, pyruvate, β-hydroxybutyrate, acetoacetate, α-hydroxybutyrate, and malate in 5-μL serum samples from each of the MELAS patients (n = 70), healthy controls (n = 29), and CPEO patients (n = 17). Individual metabolite levels were quantified, and the lactate/pyruvate ratio and β-hydroxybutyrate/acetoacetate ratio were used as surrogate indicators of cytoplasmic and mitochondrial NADH/NAD+ redox states, respectively. Following this, analyses were performed to assess between-group differences in these indicators and to determine their correlations with disease duration.
    RESULTS: MELAS patients exhibited significantly elevated lactate, β-hydroxybutyrate, α-hydroxybutyrate, and malate levels, together with increased lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios compared with healthy controls. Among the evaluated biomarkers, the lactate/pyruvate ratio achieved the highest diagnostic performance (AUC = 0.993, 95% CI = 0.979-1.000), followed by lactate (AUC = 0.976) and β-hydroxybutyrate (AUC = 0.864). Although the β-hydroxybutyrate/acetoacetate ratio showed high sensitivity (95.7%), its overall diagnostic accuracy was limited by lower specificity. However, none of these serum markers show a significant correlation with the disease duration course in MELAS patients. Relative to MELAS, lower concentrations of α-hydroxybutyrate (p < 0.001) and malate (p = 0.026) and elevated lactate/pyruvate ratio (p < 0.001) were observed in CPEO.
    CONCLUSION: The DQmB-HA method enabled high-sensitivity metabolomic profiling in low-volume clinical samples and revealed broad alterations in metabolites and metabolite ratios associated with NADH/NAD + -related redox metabolism in MELAS, providing a useful framework for metabolomic screening in mitochondrial diseases.
    Keywords:  MELAS; Metabolic dysfunction; Mitochondrial disease; NADH/NAD(+) ratio
    DOI:  https://doi.org/10.1016/j.cca.2026.121172
  47. Cell Metab. 2026 Jun 15. pii: S1550-4131(26)00193-2. [Epub ahead of print]
    The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
    Luigi Ferrucci, Stefano Donega, Allison B Herman, Rafael de Cabo, Myriam Gorospe.
      Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis. The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.
    Keywords:  extracellular matrix; hypoperfusion; mitochondrial dysfunction; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.008
  48. Nat Nanotechnol. 2026 Jun 15.
    Efficient prime editing in vivo and in vitro using lipid nanoparticles.
    Allen Y Jiang, Ana Cristian, Dominique L Brooks, Emily R Feierman, Paul Z Chen, Madelynn N Whittaker, Sarah E Pierce, Holt A Sakai, Hongyu Chen, Dangliang Liu, Peyton B Randolph, Angus H Li, Alvin Hsu, Serena O Omo-Lamai, Y Allen Tao, Benista Owusu-Amo, Xiao Wang, Xiao Wang, Kiran Musunuru, David R Liu.
      Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become a preferred method for gene editing in animals and patients, its application to complex, three-component prime editing systems has yielded low editing efficiencies. Here we developed a systematic prime editing LNP (PE-LNP) optimization platform that addresses key bottlenecks in cargo design that limit editing efficiency. This generalizable workflow yielded PE-LNPs that can achieve 49% average in vivo prime editing in the bulk mouse liver with a single dose of 2 mg kg-1. We applied our workflow to the correction of PAH R408W, a cause of phenylketonuria, in a mouse model and achieved prime editing efficiencies and serum phenylalanine levels anticipated to be curative. We also show that PE-LNPs minimize off-target editing compared with DNA delivery methods, induce only transient elevation of liver enzymes and can be dosed repeatedly to improve editing efficiencies. These PE-LNP systems provide an attractive alternative to viral delivery by offering transient expression that minimizes off-target editing, no observed long-term toxicity and high levels of non-viral in vivo liver prime editing.
    DOI:  https://doi.org/10.1038/s41565-026-02200-6
  49. Cell Death Dis. 2026 Jun 19.
    Frontotemporal dementia associated CHCHD10V57E mutation aggravates tau pathology via disrupting the CHCHD10-Rab7A-TBC1D15 complex.
    Jie Sheng, Jing Yan, Yan Xu, Xingyu Xu, Xuemei Zhang, Anqi Wang, Buhui Liu, Jun Ma, Xiuying Duan, Heng Zhou, Wei Liu.
      Frontotemporal dementia (FTD), a neurodegenerative disorder characterized by early-onset cognitive decline, includes two major pathologic types: FTD-Tau and FTD-TDP. Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) encodes a mitochondrial protein, and the CHCHD10V57E variant is a novel mutation clinically identified in FTD patients. The role of CHCHD10 mutants in the pathogenesis of FTD-TDP has been largely reported. However, whether CHCHD10 variants impact the FTD-tau pathology or tau-mediated neurodegeneration is not clear. Here, we generated CHCHD10V57E mutant Drosophila and mammalian cell culture models on a human R406W tau or 0N4R tau expressing background. We discovered that the CHCHD10V57E mutation aggravates retinal degeneration, climbing defects, and short lifespan in tauR406W Drosophila. Additionally, the CHCHD10V57E mutation promotes synaptic integrity defects, increases secretion of total and phosphorylated tau, and induces cytotoxicity in tau-overexpressing mammalian cell culture models. Further studies indicated that localization of the endogenous and wild-type CHCHD10, as well as the V57E mutant, includes the mitochondrial inner and outer membranes. Furthermore, we showed that phosphorylated tau accumulates within the endo-lysosomal system of the CHCHD10V57E-expressing flies and mammalian cells. Depletion of endosomal protein Rab7A partially attenuates neurodegeneration, reduces total and phosphorylated tau secretion, and diminishes cytotoxicity in tauopathy models expressing CHCHD10V57E. Mechanistically, we presented evidence that the CHCHD10-Rab7A-TBC1D15 complex maintains Rab7A in an inactive state. By contrast, CHCHD10V57E expression dissociates the protein complex, resulting in Rab7A activation. Taken together, our study proposes a model whereby the FTD-associated CHCHD10V57E mutation modulates the activation process of Rab7A, resulting in promoting the development of tau pathologies.
    DOI:  https://doi.org/10.1038/s41419-026-08983-9
  50. Nat Commun. 2026 Jun 17.
    iSCORE-PD: an isogenic stem cell collection to research Parkinson's disease.
    Oriol Busquets, Hanqin Li, Khaja Mohieddin Syed, Pilar Alvarez Jerez, Jesse Dunnack, Riana Lo Bu, Yogendra Verma, Gabriella R Pangilinan, Annika Martin, Jannes Straub, YuXin Du, Vivien M Simon, Steven Poser, Zipporiah Bush, Jessica Diaz, Atehsa Sahagun, Jianpu Gao, Samantha Hong, Dena G Hernandez, Kristin S Levine, Nathalie Pochet, Ezgi O Booth, Marco Blanchette, Helen S Bateup, Donald C Rio, Cornelis Blauwendraat, Dirk Hockemeyer, Frank Soldner.
      Genome-edited human pluripotent stem cells (hPSCs) provide a powerful platform to study complex diseases such as Parkinson's disease (PD). Here, we describe iSCORE-PD, an isogenic collection of 65 genome-edited hPSC lines carrying disease-causing or high-risk variants in 11 PD-linked genes (SNCA, PRKN, PINK1, DJ1/PARK7, LRRK2, ATP13A2, FBXO7, DNAJC6, SYNJ1, VPS13C, and GBA1). All lines are derived from a well-characterized female hESC line and subjected to extensive quality control. Whole-genome sequencing reveals that genetic variation between lines, largely confined to non-coding regions, is minimal relative to inter-individual differences in patient-derived hiPSCs, with most variation arising from random mutations acquired during cell culture rather than genome-editing-induced off-target effects. Including multiple independently derived clones per mutation can control for this random genetic drift. Our systematic approach ensures high quality of this publicly available iSCORE-PD resource, highlights the advantages of prime editing over conventional CRISPR/Cas9 methods, and establishes best practices for generating disease-modeling hPSC collections.
    DOI:  https://doi.org/10.1038/s41467-026-74355-8
  51. Brain Commun. 2026 ;8(3): fcag200
    Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.
    Cristina Domínguez-González, Caterina Garone, Andrés Nascimento, Yuanjun Ma, Nada Boudiaf, Richard Kim, Susan VanMeter, Marcus Brunnert, Michio Hirano.
      Thymidine kinase 2 deficiency (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial disease, resulting in progressive myopathy, respiratory insufficiency and increased risk of early death. Doxecitine and doxribtimine represents the first approved treatment for thymidine kinase 2 deficiency in the USA and the EU; previously, management was restricted to supportive care. The overall understanding of the natural history of thymidine kinase 2 deficiency is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with thymidine kinase 2 deficiency as part of one of the largest international datasets to date. Data from individuals with thymidine kinase 2 deficiency identified through the review of published literature and a retrospective chart review study (NCT05017818) were pooled with pretreatment data from patients later treated with pyrimidine nucleos(t)ides (NCT03701568; NCT03845712; NCT05017818; company-supported Expanded Access Programs). Subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, regain and use of ventilatory and feeding support. In total, 257 patients were included in the study. Most patients [n = 199 (77.4%)] had an age of symptom onset ≤12 years, while 49 (19.1%) had an age of symptom onset >12 years; age of onset was missing for 9 (3.5%). Kaplan-Meier survival analyses estimated that the median time (95% confidence interval) from symptom onset to death was 2.6 (1.3, 6.4) years with age of symptom onset ≤12 years and 24.0 (16.0, not applicable) years with age of symptom onset >12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset ≤12 years [61/75 patients (81.3%) lost ≥1 motor milestone]. Spontaneous regain of lost motor milestones was rare [3/71 patients (4.2%), all with age of symptom onset ≤12 years]. Use of ventilatory support was observed for both subgroups [81/199 patients (40.7%) with age of symptom onset ≤12 years (missing data, n = 73); 23/49 patients (46.9%) with age of symptom onset >12 years (missing data, n = 11)]. Use of feeding tube support was also reported [28/199 patients (14.1%) with age of symptom onset ≤12 years (missing data, n = 121); 4/49 patients (8.2%) with age of symptom onset >12 years (missing data, n = 21)]. This study confirms the severe disease burden and high mortality associated with thymidine kinase 2 deficiency, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.
    Keywords:  mitochondrial myopathy; motor milestones; natural history; survival; thymidine kinase 2 deficiency
    DOI:  https://doi.org/10.1093/braincomms/fcag200
  52. J Mol Biol. 2026 Jun 18. pii: S0022-2836(26)00284-6. [Epub ahead of print] 169911
    An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial Ca2⁺-Sensing Mechanism for ATP Synthase Regulation.
    Sergey V Ivanov, Roman V Uzhachenko, Sergei P Budko, Anil Shanker, Sanika S Chirwa, Alla V Ivanova.
      Mitochondrial ATP synthase (mATPS) has the capacity to regulate the permeability transition pore (mPTP) during Ca2⁺ fluctuations. Dysregulation of this mechanism is implicated in neurodegenerative and other diseases; however, the endogenous mechanisms that couple calcium sensing to mATPS function remain poorly defined. We recently demonstrated that loss of TUSC2, a mitochondrial Ca2⁺-binding protein, leads to mitochondrial Ca2⁺ overload and sustained mPTP opening. The oligomycin sensitivity-conferring protein (OSCP), a regulatory subunit of mATPS, responds to Ca2⁺ and oxidative stress, positioning it as a potential integrator of bioenergetic and stress signals. With age, the ability of OSCP to maintain regulatory interactions and resist stress-induced conformational perturbations declines, contributing to multiple pathologies. Here, we combine AI-assisted structural modeling with phylogenetic analysis to nominate TUSC2 as a previously unrecognized candidate OSCP-interacting partner. Across evolution-from basal eukaryotes to higher metazoans-TUSC2 exhibits near-invariant conservation of its central Ca2⁺-binding motif (CBM), in contrast to pronounced divergence of its N-terminal region. AlphaFold3 modeling provides a structural framework for this conservation, predicting Ca2⁺-dependent engagement of the CBM with a conserved C-terminal region of OSCP with established regulatory function. The predicted interface is preserved across phylogenetically distant species, indicating co-conservation of interacting surfaces. The model further suggests coordinated engagement of Ca2⁺ and a second metal ion by TUSC2 and OSCP, as well as accommodation of a nucleotide. The deep conservation of these features across eukaryotes is consistent with a functionally constrained, Ca2⁺-sensing regulatory role for TUSC2 in mATPS function, with potential implications for mPTP regulation.
    Keywords:  AlphaFold structural modeling; OSCP (ATP5PO); TUSC2 (FUS1); aging; calcium-binding motif; evolutionary conservation; metal ion coordination; mitochondrial ATP synthase; mitochondrial permeability transition pore (mPTP); oxidative stress
    DOI:  https://doi.org/10.1016/j.jmb.2026.169911
  53. Circulation. 2026 Jun 17.
    Vacuolar H+-ATPase Preserves Cardiolipin Homeostasis Through the Lysosomal-Mitochondrial Axis to Restrain Cardiac Aging.
    Hongtao Tie, Mengqian Hou, Yumeng Li, Min Pan, Dietbert Neumann, Ruimin Liu, Jun Zhang, Martijn F Hoes, Miranda Nabben, Jan F C Glatz, Xi Li, Xin Wu, Joost J F P Luiken, Shujin Wang.
       BACKGROUND: Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)-mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function.
    METHODS: To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, (co)immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 (Crsl1) knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people.
    RESULTS: Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase-mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide-dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans.
    CONCLUSIONS: Augmenting v-ATPase-mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.
    Keywords:  aged heart; cardiolipin metabolism; cardiolipin synthase 1; lysosomal acidification; mitochondrial homeostasis; vacuolar H+-ATPase
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.078376
  54. Genome Biol. 2026 Jun 15. pii: 194. [Epub ahead of print]27(1):
    Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing.
    Undiagnosed Diseases Network
       BACKGROUND: Native long-read DNA sequencing simultaneously captures genetic variants and epigenetic modifications from single molecules, but preserving molecular length and base modifications currently depends on cold-chain infrastructure that limits access to well-resourced settings.
    RESULTS: We demonstrate that ensilication, the encapsulation of DNA within silica matrices, preserves DNA at ambient temperature for 30 days with sequencing performance equivalent to conventional - 80 °C freezing. Across three Genome-in-a-Bottle reference genomes, ensilicated and frozen samples show no significant differences in read length (N50 ~ 8,000-11,000 bp), variant-calling accuracy, or genome-wide CpG methylation. Single-read methylation calls benchmarked against an independent bisulfite-sequencing reference confirm that ensilication introduces no detectable bias, with per-read accuracy differing by less than 0.4% between preservation conditions. Ensilicated DNA tolerates repeated handling better than frozen samples and maintains fragment integrity under accelerated weathering. In two patients with rare genetic disorders, ambient-preserved DNA resolves a de novo variant in the segmentally duplicated GTF2I locus and detects methylation patterns consistent with KDM2A-related disorder.
    CONCLUSIONS: Ensilication enables diagnostic-quality native long-read sequencing without cold-chain infrastructure, supporting ambient storage and transport while preserving both sequence and methylation information.
    DOI:  https://doi.org/10.1186/s13059-026-04137-4
  55. Cell Commun Signal. 2026 Jun 13.
    Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.
    Lei Liu, Saiteng Wu, Lei Zhang, Li Zhong, Rui Guo.
      Cardiovascular disease remains the leading cause of global mortality, with mitochondrial dysfunction playing a central pathogenic role. Post-translational modifications act as fundamental regulators of mitochondrial quality control. Yet, how mitochondrial post-translational modifications integrate stress signals to direct cell fate among diverse regulated cell death pathways in cardiovascular disease remains incompletely understood. This review proposes a conceptual framework in which mitochondrial post-translational modifications act as the master conductors of an integrated network linking mitochondrial homeostasis to cellular demise. We first outline the pivotal roles of mitochondrial quality control in cardiovascular disease and detail their precise mechanisms governed by mitochondrial post-translational modifications over each process. We then delineate how mitochondrial post-translational modifications critically regulate the initiation and execution of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, evaluating their distinct contributions to cardiovascular pathophysiology. Furthermore, we highlight the extensive crosstalk and convergence among these death modalities at the mitochondrial level, emphasizing the role of mitochondrial post-translational modification signatures in amplifying death signals or triggering modality switching. By synthesizing recent discoveries, this work connects dynamic protein-level modifications to cell fate outcomes, offering a theoretical basis for future therapeutic strategies aimed at rebalancing the network of mitochondrial post-translational modifications to combat heart failure and other cardiovascular diseases.
    Keywords:  Cardiovascular disease; Cell death; Dynamic equilibrium.; Mmitochondrial quality control; Post-translational modifications
    DOI:  https://doi.org/10.1186/s12964-026-03002-y
  56. Sci Adv. 2026 Jun 19. 12(25): eadt2527
    NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition.
    Kateryna Murlanova, Ksenia Novototskaya-Vlasova, Shovgi Huseynov, Olga Pletnikova, Rebecca D Howell, Yan Jouroukhin, Dong Won Kim, Adrian Eddy-Sulaiman Jenson, Juhyun Lee, Cheng Qin, Stephen R Thompson, Vikyath Saraf, Michael J Morales, Eduardo Cortes Gomez, Russell L Margolis, Frederick C Nucifora, Spencer R Rosario, Andrew A Pieper, Henry G Withers, Samir Haj-Dahmane, Juhyun Kim, Mikhail V Pletnikov.
      The basic helix-loop-helix transcription factor neuronal PAS (Per, Arnt, Sim) domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways and is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction under several neuropsychiatric conditions, but the underlying brain cell type-specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondrial bioenergetics in astrocytes in the mouse brain. Selective deletion of Npas3 in mature astrocytes decreases expression of mitochondrial glutamate carrier 2 involved in glutamate oxidation, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit reduces intrinsic excitability, dendritic spine density, and excitatory synaptic transmission of medial prefrontal cortex (mPFC) pyramidal neurons. Mice with Npas3-deficient mPFC astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondrial bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.
    DOI:  https://doi.org/10.1126/sciadv.adt2527
  57. CNS Neurosci Ther. 2026 Jun;32(6): e70997
    Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
    Zimeng He, Huafang Jiang, Tongyue Li, Yang Liu, Ying Zou, Chaolong Xu, Zhimei Liu, Danmin Shen, Ruoyu Duan, Minhan Song, Yunxi Zhang, Zixuan Zhang, Mingxi Sun, Rui Shen, Hong Xue, Fang Fang.
       AIM: To systematically characterize the phenotypic spectrum, neuroimaging features, heteroplasmy-phenotype correlation, and prognosis of the m.10191 T > C mutation.
    METHODS: We collected and analyzed data from 52 patients (14 newly recruited; 38 from literature). Phenotypes were pre-classified as Leigh syndrome (LS), Leigh-like syndrome (LLS), MELAS/LS overlap syndrome, and MELAS-like syndrome. Neuroimaging data were subjected to statistical analysis to explore inter-lesional associations and lesion-symptom correlations. Heteroplasmy level underwent k-means clustering and latent class analysis (LCA) to define data-driven subgroups and model genotype-phenotype correlations. Prognostic factors were evaluated through Bayesian logistic regression, and survival analysis was conducted.
    RESULTS: The cohort exhibited phenotypic heterogeneity, dominated by LS (46.2%). Key features included epilepsy, developmental delay, and dystonia. Globus pallidus involvement frequently co-occurred with midbrain and pontine lesions. Heteroplasmy level differed significantly across phenotypes. LCA identified three classes corresponding to clinical phenotypes. High heteroplasmy level, medullary involvement, and severe hyperlactatemia were associated with disease progression. Survival analysis indicated a 5 year survival rate of 80.0%, with high heteroplasmy level, hypotonia, and cerebellar lesions predicting poorer survival.
    INTERPRETATION: The m.10191 T > C mutation is linked to a continuous clinical spectrum correlated with heteroplasmy level. Specific clinical and neuroimaging features serve as valuable biomarkers for phenotypic classification and prognostic assessment.
    Keywords:   MT‐ND3 ; complex I deficiency; leigh syndrome; m.10191 T > C; mitochondrial encephalomyopathy with lactate acidosis and stroke‐like episodes (MELAS)
    DOI:  https://doi.org/10.1002/cns.70997
  58. Brain Commun. 2026 ;8(3): fcag201
    Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.
    Michio Hirano, Caterina Garone, Richard Haas, Carmen Paradas, Fernando Scaglia, Irene Rebollo Mesa, Carl Chiang, Anny-Odile Colson, Susan VanMeter, Cristina Domínguez-González.
      Thymidine kinase 2 deficiency (TK2d) (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial myopathy caused by TK2 variants, leading to mitochondrial DNA depletion and/or multiple deletions. People with thymidine kinase 2 deficiency experience progressive myopathy, bulbar weakness and respiratory insufficiency, often losing the ability to walk, eat and breathe independently. Doxecitine and doxribtimine represents the first approved treatment for patients with thymidine kinase 2 deficiency with age of symptom onset ≤12 years by the US Food and Drug Administration and the European Medicines Agency; previously, disease management was limited to supportive care. We investigated the efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Patients treated with pyrimidine nucleos(t)ides were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) studies and company-supported Expanded Access Programs. Untreated patients were pooled from literature reviews and a retrospective chart review study (NCT05017818). Patient subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). The primary outcome was survival in 50th-percentile matched pairs of treated and untreated patients. Other outcomes included status of developmental motor milestones, ventilatory and feeding tube support, and safety. In total, 218 patients were included (treated: 104; untreated: 114). Baseline demographics and characteristics were comparable between subgroups. Most patients had an age of symptom onset ≤12 years [treated: 82/104 (78.8%); untreated: 93/114 (81.6%)]. In the age-of-symptom-onset-≤12-years subgroup, restricted mean survival time (95% confidence interval) was 29.2 (28.2, 30.3) years over the 30 years after symptom onset for treated patients and 14.4 (11.1, 17.6) years for untreated patients. Loss of ≥1 acquired motor milestone was more frequent before treatment start than after. Substantially more patients regained ≥1 lost motor milestone after treatment start than before. Ventilatory and feeding support were used across all age-of-symptom-onset subgroups, but some patients reduced or discontinued support after starting treatment and fewer patients initiated support after treatment start than before. Most treatment-emergent adverse events (TEAEs) did not lead to discontinuation. The most frequent TEAE was diarrhoea [43/50 patients (86.0%)], which was generally mild or moderate and resolved with dose reduction. Serious TEAEs occurred in 28/50 patients (56.0%); few were considered to be drug related [4/50 (8.0%)]. In total, 3/67 patients (4.5%) experienced a fatal serious TEAE, which were not considered to be drug related. These findings indicate that pyrimidine nucleos(t)ide therapy improves survival and functional outcomes in people with thymidine kinase 2 deficiency, especially those with age of symptom onset ≤12 years, and has an acceptable safety profile.
    Keywords:  mitochondrial myopathy; pyrimidine nucleos(t)ide therapy; survival; thymidine kinase 2 deficiency; treatment efficacy
    DOI:  https://doi.org/10.1093/braincomms/fcag201
  59. Ophthalmic Genet. 2026 Jun 16. 1-6
    Pediatric hereditary optic neuropathies in the United Arab Emirates.
    Arif O Khan.
       PURPOSE: To characterize outpatient pediatric hereditary optic neuropathies in the United Arab Emirates.
    METHODS: Retrospective case series (2016-2023, inclusive).
    RESULTS: Thirteen probands were identified (nine males). Thirty-eight percent (5/13) had extraocular symptoms at the time of presentation (e.g. hearing loss or developmental delay). For the remaining 62% (8/13) who reported only visual symptoms at presentation, half (4/8) were subsequently diagnosed with extraocular findings (e.g. hearing loss or neurological regression). The single most common genetic diagnosis was heterozygous OPA1 variant (31%, 4/13). The remaining 69% (9/13) harbored pathogenic variants in nine different genes that were monoallelic (ATP1A3, NR2F1, PTCH1) or biallelic (ACO2, BTD, GALC, OPA1, WFS1, POLR3B). For these nine cases, two had treatable metabolic disease that had not been previously recognized before the presentation for visual loss (BTD, GALC). No pathogenic variant was recurrent in the series.
    DISCUSSION: Although private heterozygous OPA1 variant (dominant optic atrophy) was the single most frequent genotype in this cohort, non-OPA1-related cases were more common, genetically heterogenous, and often autosomal recessive. Children with hereditary optic neuropathy should be evaluated for actionable extraocular features such as hearing loss and undiagnosed metabolic disease as they are not infrequent and best addressed at an earlier age.
    Keywords:  OPA1; Optic neuropathy; United Arab Emirates; pediatric; recessive
    DOI:  https://doi.org/10.1080/13816810.2026.2674280
  60. Mol Ther Adv. 2026 Jun 11. 34(2): 201760
    In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant.
    Megan K Gautier, Kaitlyn King, Yongseok Han, Hooda Said, Mohamad-Gabriel Alameh, Xiao Wang, Xinying Hong, Kiran Musunuru, Rebecca C Ahrens-Nicklas.
      Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. Patients are unable to convert the amino acid phenylalanine (Phe) into tyrosine (Tyr), leading to neurotoxic Phe accumulation. Chronically elevated Phe results in intellectual disability, psychiatric disorders, motor impairments, and epilepsy in affected children. Although there are interventions that focus on reducing plasma Phe levels, no curative therapies exist for PKU. Utilizing an adenine base editor (ABE), we demonstrate efficient in vivo corrective editing of hepatocytes in humanized PKU mice homozygous for the common P281L (c.842C>T) variant of PAH. Delivery of the ABE via lipid nanoparticles (LNPs) at four weeks of age resulted in significant reductions in Phe levels in plasma and cortex, as well as increases in cerebral amino acid and neurotransmitter concentrations. Behavioral assessment post-treatment revealed improvements in abnormal motor phenotypes. These data provide increased support for the viability of ABE-based therapeutics as a durable treatment for patients with monogenic metabolic disorders.
    Keywords:  PAH; PKU; base editing; in vivo gene therapy; inborn error of metabolism; lipid nanoparticle; mRNA; neurotransmitter; phenylalanine; rotarod
    DOI:  https://doi.org/10.1016/j.omta.2026.201760
  61. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
    Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.
      Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  62. Mol Genet Genomic Med. 2026 Jun;14(6): e70253
    Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.
    Ling Li, Xiu Chen, Hua Li, Kai Guo, Ting Zhang, Mingyi Ma, Songhua Zhao.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, which disrupt thymidine metabolism. This study aimed to characterize a novel homozygous TYMP variant and provide insights into its potential structural and functional consequences through bioinformatic analyses.
    METHODS: We identified a homozygous TYMP variant (c.131G>C, p.R44P) in a proband with MNGIE using whole-exome sequencing and Sanger sequencing. Computational structural analyses and molecular modeling were performed to predict the impact of the R44P substitution on thymidine phosphorylase (TP) stability, homodimerization, catalytic activity, and substrate binding.
    RESULTS: The homozygous TYMP c.131G>C variant was confirmed in the proband. Computational analyses suggested that the p.R44P substitution may destabilize TP and potentially impair homodimerization. Molecular modeling further predicted altered thymidine binding and disrupted active-site geometry. These predicted perturbations are hypothesized to contribute to defective nucleotide metabolism, thymidine accumulation, and deoxynucleotide triphosphate pool imbalance, which may ultimately result in mitochondrial genomic instability manifesting as mitochondrial DNA deletions and depletion.
    CONCLUSION: Our findings report the TYMP c.131G>C variant in a homozygous configuration, extending beyond a recently described compound heterozygous case. The bioinformatic predictions support the classification of this variant as likely pathogenic in MNGIE, though functional studies are warranted to validate these findings.
    Keywords:   TYMP ; MNGIE; missense variant; nucleotide homeostasis; whole‐exome sequencing
    DOI:  https://doi.org/10.1002/mgg3.70253
  63. Cell Metab. 2026 Jun 17. pii: S1550-4131(26)00240-8. [Epub ahead of print]
    Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
    Yan Huang, Biao Hu, Ya Liu, Ling-Qi Xie, Yu Dai, Yu-Ze An, Xin-Yi Peng, Ya-Lun Cheng, Yi-Fan Guo, Wei-Hong Kuang, Yao Xiao, Xin Chen, Yong-Jun Zheng, Gen-Qing Xie, Jian-Ping Wang, Hui Peng, Xiang-Hang Luo.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.014
  64. Mol Ecol Resour. 2026 Jul;26(5): e70165
    Fragmentation of Long Reads Enables Reliable Mitogenome Assembly From Whole-Genome Amplification Data With Pervasive Palindromic Reads.
    Matteo Vecchi, Bartłomiej Surmacz, Ingemar K Jönsson, Daniel Stec.
      Whole genome amplification (WGA), and in particular multiple displacement amplification (MDA), has become a key technique for genomic sequencing of microscopic organisms, yet it introduces artefacts such as palindromic (inverted chimeric) reads that may compromise downstream analyses. We assessed how pervasive palindromic reads generated by MDA impact the assembly of tardigrade (Acutuncus giovanniniae and A. mecnuffi) mitogenomes sequenced with Oxford Nanopore technology. We show that the MDA produces a high proportion of palindromic reads, often exceeding one-third of mitochondrial reads and frequently exhibiting complex multi-inversion structures. These artefacts severely impair long-read assembly, leading to low success rates and inconsistent genome reconstruction. To solve this issue, a strategy based on in silico fragmentation of long reads into short, high-quality fragments, followed by short-read assembly, consistently produced complete and accurate circularised mitochondrial genomes. Our results demonstrate that palindromic read formation can be, in some cases, a limitation of MDA coupled with long-read sequencing, but this issue can be mitigated through read fragmentation. This approach provides a simple, robust and scalable solution for mitogenome assembly from data heavily affected by amplification artefacts, particularly in microscopic taxa where whole genome amplification is often unavoidable.
    Keywords:  Acutuncus; chimeric sequences; long reads; mitochondria; nanopore; tardigrades
    DOI:  https://doi.org/10.1111/1755-0998.70165
  65. FEBS Lett. 2026 Jun 16.
    Electron transfer between complexes III and IV in S. cerevisiae mitochondrial membranes.
    Ana Paula Lobez, Mikael Oliveberg, Peter Brzezinski.
      Mitochondrial oxidative phosphorylation relies on cytochrome c transferring electrons between complexes III and IV. Earlier studies using detergent-purified complex III-IV supercomplexes from S. cerevisiae showed that this transfer is limited by two-dimensional cytochrome c diffusion. This study investigates this process in membrane-embedded mitoplasts. The results show that membrane embedment shifts the rate-limiting step from cytochrome c-mediated electron transfer to the catalytic activity of the supercomplex itself. Up to a cytochrome c : supercomplex ratio of unity, turnover increases sharply regardless of ionic strength. At higher ratios, the rate levels out at 15-20 s-1, indicating that the process is no longer limited by salinity-dependent electron transfer, but rather by the catalytic capacity of complex IV.
    Keywords:  cytochrome bc1; cytochrome c oxidase; electrochemical gradient; electron transfer; energy conversion; membrane protein; proton transfer; respiratory chain; respiratory supercomplex
    DOI:  https://doi.org/10.1002/1873-3468.70382
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