bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–05–31
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Cholesterol in Mitochondrial Diseases-Friend or Foe?
  2. A transport-independent role for SLC25A12 in mitochondrial stress signalling.
  3. Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
  4. Mitochondrial drivers of stem cell aging and inflammaging.
  5. Mitochondrial extracellular vesicles between pathology and regeneration.
  6. A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
  7. NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
  8. Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
  9. Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
  10. A multilayered stress-response circuit: The mammalian mitochondrial UPR.
  11. MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
  12. Organ formation in early human embryos captured in spatial cell atlas.
  13. Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
  14. Transmembrane domain switching controls PINK1 import and fate in mitochondria.
  15. OPA1 Requires ATP Synthase Activity and Oligomerization to Mitigate Prion-Induced Mitochondrial Dysfunction, Oxidative Stress, and Neuronal Apoptosis.
  16. Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
  17. Mitochondrial activity promotes neutrophil degranulation and endothelial dysfunction in systemic infections.
  18. African swine fever virus B66L drives extracellular mitochondrial release to promote systemic inflammation in mice.
  19. Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
  20. MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
  1. Int J Mol Sci. 2026 May 13. pii: 4353. [Epub ahead of print]27(10):
    Cholesterol in Mitochondrial Diseases-Friend or Foe?
    Mila Taylor, Michal Halicki, Paul Chazot.
      Serving as central signalling organelles and hubs of metabolism, mitochondria are essential for cellular homeostasis. Mitochondrial disease can arise from mutations to nuclear or mitochondrial DNA, which result in disruptions to normal mitochondrial function. This generates a suite of rare disorders which are multi-system and often fatal. Variable tissue distribution of mitochondria, alongside a high degree of heterogeneity in associated phenotype, has resulted in an inadequate understanding and characterisation of mitochondrial disease. Addressing this issue is therefore crucial for better clinical management and patient outcomes. Cholesterol dyshomeostasis is a potential pathological hallmark of numerous mitochondrial diseases. Cholesterol is an essential lipid and bioactive compound involved in numerous mitochondrial and cellular processes. A growing number of studies have reported perturbations to cholesterol biosynthesis, cholesterol import, and cholesterol ratios in cell and animal models and individuals with mitochondrial disease, suggesting it could be a unifying feature of these disparate and variable disorders. This review summarises the current experimental evidence for the role of cholesterol dyshomeostasis in mitochondrial disease. It will further discuss reports of statin intolerance, generally attributed to off-target action on mitochondrial structures, in the context of this evidence. Ultimately, the necessity of further integrative clinical and experimental studies exploring the potential of cholesterol dyshomeostasis as a pathological hallmark of mitochondrial disease will be highlighted.
    Keywords:  cholesterol; dyshomeostasis; lipid; mitochondria; statin
    DOI:  https://doi.org/10.3390/ijms27104353
  2. Nat Cell Biol. 2026 May 27.
    A transport-independent role for SLC25A12 in mitochondrial stress signalling.
    Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.
      Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-01973-1
  3. Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]
    Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
    Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.
      The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.
    Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
  4. NPJ Aging. 2026 May 28.
    Mitochondrial drivers of stem cell aging and inflammaging.
    Jhommara Bautista, Andrés López-Cortés.
      Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.
    DOI:  https://doi.org/10.1038/s41514-026-00422-5
  5. Neural Regen Res. 2026 May 14.
    Mitochondrial extracellular vesicles between pathology and regeneration.
    Paola Margutti, Silvia Zamboni.
      Mitochondria are central regulators of cellular energy production, metabolic homeostasis, and stress responses, and their dysfunction represents a critical hallmark of neurodegenerative and neuroinflammatory diseases. To preserve mitochondrial integrity, cells rely on an intricate mitochondrial quality control system encompassing mitochondrial dynamics, mitophagy, biogenesis, and vesicle-mediated pathways. Emerging evidence highlights the pivotal role of mitochondria-derived vesicles as vehicles for trafficking mitochondrial components within cells, thereby contributing significantly to intracellular communication and mitochondrial quality control. In parallel, mitochondrial extracellular vesicles have been identified as dynamic mediators of intercellular communication, enabling the transfer of mitochondrial proteins, lipids, and even mitochondrial DNA between cells. Mitochondria-derived vesicles selectively remove damaged mitochondrial components and coordinate intracellular stress responses, whereas mitochondrial extracellular vesicles can transfer mitochondrial material, including proteins, mitochondrial DNA, and even intact mitochondria, between cells, thereby modulating inflammation, immune activation, and cellular bioenergetics. Interestingly, mitochondrial extracellular vesicles play a dual, context-dependent role: they can exacerbate pathology when carrying damaged or dysfunctional mitochondrial cargo, or promote cellular resilience when delivering healthy, functional mitochondrial components. Likewise, extracellular vesicles derived from mesenchymal stem cells, including larger extracellular vesicle populations capable of transferring functional mitochondria, are emerging as promising cell-free therapeutic candidates with the potential to restore mitochondrial function and promote tissue repair across multiple diseases, including neurodegenerative disorders. Collectively, these insights establish mitochondrial vesicular trafficking as a transformative frontier for diagnostic innovation, biomarker development, and novel therapeutic strategies in neurodegenerative and mitochondria-related central nervous system disorders. Implications for the field include: the recognition of mitochondrial vesicular pathways as fundamental regulators of central nervous system homeostasis highlights their crucial roles in sustaining neuronal function, cellular resilience, and overall brain health. When enriched with dysfunctional mitochondrial cargo, mitochondrial extracellular vesicles are emerging as key contributors to the etiopathogenesis of neurodegenerative and neuroinflammatory diseases, thereby driving disease initiation and progression. In parallel, their ability to reflect mitochondrial status positions mitochondrial extracellular vesicles - particularly those containing mitochondrial DNA and mitochondrial proteins - as promising biomarkers for monitoring mitochondrial stress, disease activity, and therapeutic response. At the translational level, advancing mitochondrial extracellular vesicles and mitochondrial vesicular pathways as therapeutic tools opens new opportunities to restore mitochondrial integrity, modulate neuroinflammation, and potentially modify disease trajectories. The objectives of this review are to: (1) delineate the mechanisms of mitochondrial dysfunction and mitochondrial quality control failure in neurodegenerative and neuroinflammatory diseases; (2) comprehensively characterize the biogenesis, trafficking pathways, and functional roles of mitochondria-derived vesicles; (3) evaluate experimental and clinical evidence supporting the role of mitochondrial extracellular vesicles as mediators of neuroimmune communication and mitochondrial transfer; (4) critically assess the therapeutic potential of mesenchymal stem cell-derived mitochondrial extracellular vesicles.
    Keywords:  autophagy; extracellular vesicles; lysosome; mesenchymal stem cells; mitochondria; mitochondrial damage-associated molecular patterns; mitochondrial transfer; mitophagy; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00964
  6. Int J Mol Sci. 2026 May 14. pii: 4387. [Epub ahead of print]27(10):
    A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
    Yung Wu, Hongyun Tang.
      Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPRmt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPRmt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPRmt.
    Keywords:  Caenorhabditis elegans; GLDI-8; electron transport chain dysfunction; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27104387
  7. Autophagy. 2026 May 24. 1-19
    NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
    Jie Cui, Shifeng Ren, Bingjie Wang, Nan Zhang, Shanshan Zhu, Yajun Zhang, Xiangqing Qi, Weixue Meng, Liwei Shao, Shan Gao, Lijie Xing, Zengjun Li, Xiaodong Mu.
      The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.
    Keywords:  Cellular senescence; cytoskeleton; innate immunity; mechanical stress; mitochondrial damage; mitophagy dysfunction
    DOI:  https://doi.org/10.1080/15548627.2026.2677181
  8. Cell Death Differ. 2026 May 27.
    Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
    Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.
      Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-026-01769-8
  9. Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]
    Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
    Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.
      Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.
    Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
  10. FEBS J. 2026 May 29.
    A multilayered stress-response circuit: The mammalian mitochondrial UPR.
    Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.
      Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.
    Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.1111/febs.70607
  11. Neurol Sci. 2026 May 26. pii: 521. [Epub ahead of print]47(6):
    MNGIE with TYMP and POLG variants presenting as decade-long capsule retention: A case report.
    Yuan Xia, Yufen She, Ruiqi Zhao, Yan Zhang.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem mitochondrial disorder caused by thymidine phosphorylase (TYMP) deficiency, leading to toxic nucleoside accumulation and mitochondrial DNA instability. Pathogenic variants in POLG, encoding mitochondrial DNA polymerase γ, have been associated with overlapping mitochondrial syndromes. However, the coexistence of TYMP-related MNGIE and a concurrent heterozygous POLG variant has not been reported.
    CASE PRESENTATION: A 57-year-old woman presented with a 10-year history of recurrent dizziness, chronic diarrhea, and 20 kg weight loss. Laboratory investigations revealed chronic anemia, hypoproteinemia, and positivity for anti-centromere protein B and anti-mitochondrial M2 antibodies. Abdominal CT revealed multiple small-bowel diverticula, splenomegaly, and a retained capsule endoscope, whereas brain MRI showed diffuse white-matter hyperintensities. Electromyography showed sensorimotor neuropathy, and neurological examination revealed bilateral ptosis, ophthalmoplegia, and distal weakness. Whole-exome sequencing confirmed a homozygous TYMP variant (c.708C>A, p.Phe236Leu) and a heterozygous POLG variant (c.1781 T>C, p.Leu594Pro). Surgical removal of the retained capsule together with supportive therapy, including enteral nutrition and coenzyme Q10, resulted in clinical improvement. To our knowledge, this is the first reported case of MNGIE with a homozygous TYMP variant and a concurrent heterozygous POLG variant.
    CONCLUSION: While the homozygous TYMP variant provides the primary molecular basis for the diagnosis, the concurrent heterozygous POLG variant may represent a potential phenotypic modifier. This case expands the genotypic context of MNGIE and highlights the importance of early genetic testing and multidisciplinary management in patients with unexplained gastrointestinal and neurological manifestations.
    Keywords:  Capsule endoscopy; Mitochondrial disease; Mitochondrial neurogastrointestinal encephalomyopathy; POLG; TYMP
    DOI:  https://doi.org/10.1007/s10072-026-09131-z
  12. Nature. 2026 May 27.
    Organ formation in early human embryos captured in spatial cell atlas.
    Varun K A Sreenivasan, Malte Spielmann.
      
    Keywords:  Developmental biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01416-9
  13. EMBO J. 2026 May 27.
    Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
    Tanveer Ahmed, Hui Zhang, Ghulam M Mushraf, Yongzhang Pan, Zeyu Zhang, Zhenzhu Sun, Mengran Yin, Xueting Xu, Xinyu Wu, Yin Gao, Yan Li, Peizhi Li, Liang Ding, Qiang Zhang, Runxia Lin, Khair Ullah, Yinghua Huang, Bushra Mirza, Yifeng Huang, Abdul Sammad, Xiangqian Kong, Dajiang Qin, Miguel A Esteban, Lulu Wang, Baoming Qin.
      The electron transport chain (ETC) is essential for NAD+ regeneration and proliferation. While many cell types tolerate ETC inhibition when pyruvate or aspartate is supplied, pluripotent stem cells (PSCs) enter a reversible paused state even at abundant pyruvate levels. Here, we show that ETC inhibition triggers severe NADH reductive stress in mouse embryonic stem cells (mESCs), driven mainly by threonine dehydrogenase (TDH). TDH-derived NADH establishes a metabolic environment that disfavors cells with compromised mitochondrial function, maintains inhibition of pyruvate dehydrogenase (PDH), and is associated with increased genomic and epigenetic stability at the cellular population level. ETC inhibition similarly induces pausing in early mouse embryos and in human pluripotent stem cells (hPSCs). In hPSCs, combined inhibition of the one-carbon metabolism enzymes serine hydroxymethyltransferase (SHMT1/2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) effectively reduced reductive stress and rescued the paused phenotype. Together, these findings support a model in which limited mitochondrial redox adaptability represents a conserved metabolic feature of pluripotent stem cells and in which NADH reductive stress is associated with genomic and epigenetic stability.
    DOI:  https://doi.org/10.1038/s44318-026-00784-2
  14. EMBO J. 2026 May 26.
    Transmembrane domain switching controls PINK1 import and fate in mitochondria.
    James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.
      Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.
    DOI:  https://doi.org/10.1038/s44318-026-00789-x
  15. Mol Neurobiol. 2026 May 23. pii: 647. [Epub ahead of print]63(1):
    OPA1 Requires ATP Synthase Activity and Oligomerization to Mitigate Prion-Induced Mitochondrial Dysfunction, Oxidative Stress, and Neuronal Apoptosis.
    Wei Wu, Xixi Zhang, Mingyue Jiang, Deming Zhao, Lifeng Yang, Ning Ma.
      Prion diseases are lethal neurodegenerative disorders marked by mitochondrial impairment, oxidative stress, and neuronal apoptosis. Our previous work identified optic atrophy protein 1 (OPA1) as a promising point of intervention, yet the underlying mechanisms are poorly understood. In the present work, we showed that OPA1-mediated protection depends on ATP synthase activity and oligomerization. In N2a cells, PrP106-126 exposure reduced the protein expression levels of OPA1 and key ATP synthase subunits, including the catalytic subunit ATP5A and the oligomerization-associated subunit ATP5k, whereas OPA1 overexpression attenuated this downregulation. Additionally, OPA1 overexpression preserved mitochondrial morphology and cristae structure, alleviated mitochondrial dysfunction, limited oxidative stress, and suppressed mitochondria-dependent apoptotic signaling. Importantly, these protective effects were abolished by pharmacological inhibition of ATP synthase or genetic silencing of ATP5k. Collectively, these results demonstrate that ATP synthase activity and oligomerization are indispensable for OPA1-mediated protection against prion-induced mitochondrial dysfunction, oxidative stress, and neuronal apoptosis, thereby providing novel mechanistic insights and identifying avenues for therapeutic intervention in prion diseases.
    Keywords:  ATP synthase activity and oligomerization; Mitochondrial dysfunction; Neuronal apoptosis; OPA1; Oxidative stress; Prion diseases
    DOI:  https://doi.org/10.1007/s12035-026-05960-3
  16. Neurol Genet. 2026 Jun;12(3): e200394
    Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    Gianpaolo Cicala, Elisa Rolleri, Beatrice Berti, Marco Luigetti, Nicola Forcina, Marianna Villa, Anna Capasso, Chiara Arpaia, Martina Malaspina, Fabiana Fattori, Luca Bosco, Guido Primiano, Antonio Novelli, Teresa Rizza, Enrico Bertini, Marika Pane, Eugenio Mercuri.
       Objectives: Variants in COA7 (cytochrome c oxidase assembly factor 7) are a rare cause of mitochondrial disease, with limited clinical descriptions and phenotypic variability. We describe 2 siblings carrying compound heterozygous COA7 variants, one of which (c.457C>T; p.Leu153Phe) is novel. Both presented with early-onset, slowly progressive axonal sensorimotor neuropathy, with differences in severity and associated features.
    Methods: Patients were identified based on clinical presentation and evaluated through longitudinal neurologic, neurophysiologic, genetic, biochemical, and neuroimaging assessments.
    Results: The elder brother developed symptoms at age 12, including muscle cramps, tremors, and falls, whereas the sister showed motor impairment with difficulty walking and running from age 5, along with more prominent cerebellar involvement. Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother. Nerve conduction studies demonstrated axonal sensorimotor polyneuropathy. Genetic analysis identified 2 compound heterozygous COA7 variants. Skin biopsy revealed reduced mitochondrial complex IV activity. Brain MRI findings were unremarkable in both siblings.
    Discussion: These cases expand the clinical spectrum of COA7-related disorders and illustrate the potential for intrafamilial phenotypic variability. The identification of a novel variant and extended clinical follow-up provide further insight into the features associated with COA7 variants.
    DOI:  https://doi.org/10.1212/NXG.0000000000200394
  17. EMBO Mol Med. 2026 May 27.
    Mitochondrial activity promotes neutrophil degranulation and endothelial dysfunction in systemic infections.
    Przemysław Zakrzewski, Christopher M Rice, Claire Naveh, Isaac Dowell, Kathryn Fleming, Aravind V Ramesh, Rachel Jones, Pedro L Moura, Drinalda Cela, Sarah Groves, Stephanie Fletcher-Jones, Yohance Victory, Mainga Bhima, Stefan Ebmeier, Laura Carey, Matthew Butler, Simon C Satchell, Ase Berg, Nadia Palolite, James Nyirenda, Watipenge Nyasulu, Isabel Zgambo, Charalampos Attipa, Linda Wooldridge, Andrew D Davidson, Aubrey Cunnington, Christopher A Moxon, Borko Amulic.
      Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulation of mitochondrial pathways, which was accompanied by increased rates of mitochondrial respiration and was linked to neutrophil immaturity. Malaria induced mitochondrial fusion and networking, while sepsis was associated with mitochondrial biogenesis. Immature neutrophils in both infections produced elevated levels of mitochondrial ROS, which enhanced release of primary and secondary granules via reorganization of cortical actin. Our study provides a mechanistic explanation for the hyperinflammatory nature of immature neutrophils and points to pharmacological scavenging of mitochondrial ROS as a potential therapeutic strategy to reduce endothelial damage in severe inflammation.
    DOI:  https://doi.org/10.1038/s44321-026-00453-1
  18. Nat Commun. 2026 May 27.
    African swine fever virus B66L drives extracellular mitochondrial release to promote systemic inflammation in mice.
    Lulu Lin, Zeyuan Hu, Gang Xing, Fei Wang, Jiajun Wu, Jialu Bao, Renlong Fang, Yalan Zhong, Yahui Li, Jian Li, Jiyong Zhou, Boli Hu.
      Systemic inflammation is a hallmark of viral infection, but the upstream signals that initiate it remain poorly defined. Here we show that extracellular mitochondria act as inflammatory mediators during infection by vesicular stomatitis virus, influenza A virus, rabies virus, herpes simplex virus 1 and African swine fever virus (ASFV). In ASFV-infected primary porcine alveolar macrophages, the viral protein B66L promotes the capture of damaged mitochondria by autophagosomes while blocking their fusion with lysosomes, causing mitochondria to accumulate outside cells. Extracellular mitochondria are detected in the serum and bronchoalveolar lavage fluid of mice expressing B66L and in the serum of ASFV-infected pigs. Purified extracellular mitochondria trigger inflammatory cytokine production through cGAS-STING signalling and contribute to lung injury in mice. These findings identify virus-associated extracellular mitochondrial release as a pro-inflammatory mechanism during infection.
    DOI:  https://doi.org/10.1038/s41467-026-73537-8
  19. BMC Bioinformatics. 2026 May 25.
    Mito_Plot: open-source pipeline for quantification and visualization of mitochondrial DNA heteroplasmy.
    Kohta Nakamura, Naoyuki Matsumoto, Yasushi Okazaki.
       BACKGROUND: Mitochondrial DNA heteroplasmy plays a crucial role in mitochondrial function, aging, and a wide range of human diseases. Recent advances in high-throughput sequencing have enabled large-scale detection of heteroplasmic variants; however, effective cohort-level integration, comparison, and visualization of Mutant Allele Frequency (MAF) values remain challenging. Existing tools often focus on single-sample visualization or require substantial manual preprocessing, limiting their scalability and usability for large cohorts. To address these challenges, we developed Mito_Plot, an open-source computational pipeline designed for standardized quantification and intuitive visualization of Mitochondrial DNA (mtDNA) heteroplasmy across multiple samples.
    RESULTS: Mito_Plot accepts standard mitochondrial VCF files and automatically calculates MAF based on allelic depth information. MAF data from multiple samples are aggregated into a unified matrix aligned by genomic position, enabling direct cross-sample comparison. The pipeline provides interactive two-dimensional circular plots that map MAF onto the mitochondrial genome with gene-level annotations, facilitating rapid identification of mutation hotspots and sample-specific patterns. In addition, Mito_Plot offers optional three-dimensional visualizations that enhance exploration of large cohorts by separating variant distributions across samples and genomic regions. Application of Mito_Plot to multi-sample mitochondrial sequencing datasets demonstrated robust handling of both variants with low and high MAF values, efficient processing of large cohorts, and improved interpretability compared with static or single-sample visualizations.
    CONCLUSIONS: Mito_Plot is a scalable, user-friendly software pipeline for cohort-scale quantification and visualization of mtDNA MAF. By integrating standardized MAF calculation with interactive 2D and 3D visualizations, Mito_Plot facilitates comprehensive exploration of mitochondrial variant landscapes across large datasets. The open-source and modular design of the software supports reproducible research and flexible integration into existing analysis workflows, making Mito_Plot a practical resource for mitochondrial genomics research and clinical investigations.
    Keywords:  Circular genome; Cohort-scale analysis; Data visualization; Mitochondrial DNA; Mitochondrial heteroplasmy; Variant analysis
    DOI:  https://doi.org/10.1186/s12859-026-06476-2
  20. Nanomedicine. 2026 May 25. pii: S1549-9634(26)00060-2. [Epub ahead of print]75 102959
    MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria.
    Nishad Keethedeth, Goutam Chandra, B Prakash Kumar, G Ganga Anand, Rajesh A Shenoi.
      Mitochondrial dysfunction is a key contributor to the pathogenesis of major neurodegenerative diseases such as Parkinson's disease. Targeted drug delivery to neuronal mitochondria is often limited by the inherent toxicity and inefficiency of drug carriers. Here we report the mitochondrial targeting ability of MitoPG, a novel nanocarrier based on dendritic polyglycerol (PG) conjugated with triphenylphosphonium (TPP+). Among a library of MitoPGs studied, MitoPG3 demonstrated superior mitochondrial localization and minimal cytotoxicity, without adverse effects on mitochondrial functions. Notably, it retained high mitochondrial targeting efficiency even under MPP+-induced mitochondrial dysfunction in neuronal cells. MitoPG 3 exhibited excellent blood brain permeability in vitro. To the best of our knowledge, this is the first report of a dendritic polymer-based nanocarrier with high mitochondrial localization and reduced toxicity and without impairing mitochondrial functions. These results highlight MitoPG as a safe and effective platform for delivering therapeutics to neuronal mitochondria, with the potential for clinical translation.
    Keywords:  Mitochondria targeting; Mitochondrial dysfunction; Polyglycerol; Targeted drug delivery; Triphenyl phosphonium
    DOI:  https://doi.org/10.1016/j.nano.2026.102959
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