bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–09–06
thirteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
  2. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  3. Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
  4. Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
  5. Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
  6. Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
  7. Airway administered artificial mitochondria-enriched nanovesicles for efficient and selective mitochondria transfer to intervene in pulmonary fibrosis.
  8. Horizontal mitochondrial transfer: an emerging field in cell biology.
  9. Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
  10. Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
  11. Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
  12. Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
  13. Mitochondria transfer research from cellular mechanisms to immune-inflammatory and translational frontiers: a bibliometric analysis from 2006 to 2026.
  1. J Inherit Metab Dis. 2026 Sep;49(5): e70247
    Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
    Lea Isermann, Aleksandra Trifunovic.
      Mitochondrial CLPP has emerged as an unusual therapeutic target because both increasing and decreasing its proteolytic activity can be beneficial, depending on the cellular and disease context. Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma. Conversely, reduced CLPP activity can preserve respiratory-chain components and promote adaptive metabolic and redox remodelling in selected models of mitochondrial disease, neurodegeneration and metabolic dysfunction, with emerging potential in ischaemia-reperfusion injury. These opposing outcomes reflect the broader role of CLPXP in controlling mitochondrial translation, respiratory-chain integrity and metabolism rather than acting simply as a general protein quality-control system. In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness.
    DOI:  https://doi.org/10.1002/jimd.70247
  2. Cell Rep. 2026 Aug 29. pii: S2211-1247(26)00927-7. [Epub ahead of print]45(9): 117849
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.
    Keywords:  CP: metabolism; NAD(+) metabolism; anemia; erythropoiesis; metabolism; mitochondria; post mitotic tissues; progeria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117849
  3. Mol Genet Metab. 2026 Aug 27. pii: S1096-7192(26)00530-5. [Epub ahead of print]149(1-2): 110247
    Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
    Merve Setenay Akyüzlüer Güneş, Merve Koç Yekedüz, Engin Köse, İlknur Sürücü Kara, Fatma Tuba Eminoğlu.
       BACKGROUND: Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort.
    MATERIALS AND METHODS: We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation.
    RESULTS: Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement.
    CONCLUSION: Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.
    Keywords:  Biotin; Carnitine; Coenzyme Q10; Primary mitochondrial disease; Riboflavin; Thiamine
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110247
  4. Psychophysiology. 2026 Sep;63(9): e70383
    Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
    Darshana Kapri, Gabriel Sturm, Catherine Kelly, Ke Bo, Cynthia C Liu, Tor D Wager, Michio Hirano, Caroline Trumpff, Martin Picard.
      Time perception-the subjective sense of how quickly or consistently time passes-shows striking variability across individuals, yet its physiological basis remains poorly understood. We hypothesized that internal clock speed and trial-to-trial variability in time perception would be linked to physiological and behavioral states. In a cohort of healthy adults (n = 59) and individuals carrying rare mitochondrial DNA mutations affecting mitochondrial energy transformation (n = 36), we explored the associations between time perception (time estimation and production) with measures of immune mitochondrial bioenergetics, blood catecholamines, working memory, and structural and functional neuroimaging. We found weak evidence suggesting that internal clock speed and time perception variability correlated with age and physiological metrics including resting energy expenditure, serum and urine norepinephrine levels, mood and fatigue, working memory performance, and neuroimaging measures of brain structure and function. Individuals with mitochondrial disorders and those with healthy mitochondria exhibited no main difference in time perception. However, they exhibited differential relations with physiological and neural variables, suggesting that mitochondria may moderate how specific processes influence time perception. These results provide a foundation for future studies to examine how cellular bioenergetics relate to time perception in humans.
    Keywords:  mitochondrial disease; norepinephrine; resting energy expenditure; time perception
    DOI:  https://doi.org/10.1111/psyp.70383
  5. Sci Adv. 2026 Sep 04. 12(36): eaef8132
    Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
    Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.
      Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef8132
  6. iScience. 2026 Sep 18. 29(9): 117230
    Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
    Stefania De Santis, Monica Rutigliano, Federica Simone, Letizia Larocca, Maria Laura Matrella, Martina Milella, Antonio Vavallo, Pasquale Ditonno, Nicola Marrano, Anna Mestice, Stefano Battaglia, Michele Battaglia, Antonio Moschetta, Peter Seibel, Elena Piccinin, Gaetano Villani.
      Antibiotics with off-target mitochondrial toxicity can impair host immunity, yet their impact on human adaptive immunity in vivo remains unclear. Because T cell activation and differentiation depend on mitochondrial metabolism, antibiotic-induced mitochondrial stress may alter T helper cell function. We investigated whether uridine and pyruvate (UP) supplementation modulates immune responses in patients receiving mitotoxic antibiotics. In a pilot observational study, 67 patients undergoing prophylactic antibiotic therapy received either antibiotics alone or antibiotics plus daily UP supplementation. Antibiotic exposure increased circulating growth differentiation factor-15 (GDF15), indicating mitochondrial stress, and altered T cell response. UP supplementation was associated with immune features consistent with preserved inflammatory competence, including a trend toward Th1 polarization. These findings suggest that mitotoxic antibiotics can influence human T cell programs and support the hypothesis that UP supplementation may preserve pro-inflammatory T cell responses during antibiotic therapy, representing a potential metabolic strategy to mitigate antibiotic-induced immunotoxicity.
    Keywords:  GDF15; OXPHOS; T cells; antibiotics; immunometabolism; mitochondria; pyruvate; uridine
    DOI:  https://doi.org/10.1016/j.isci.2026.117230
  7. Nat Commun. 2026 Aug 05. pii: 9412. [Epub ahead of print]17(1):
    Airway administered artificial mitochondria-enriched nanovesicles for efficient and selective mitochondria transfer to intervene in pulmonary fibrosis.
    Jinsong Zhang, Siying Fu, Jiawen Wang, Honghui Wu, Zhuoting Li, Ruyi Lin, Hao Sun, Seungho Choe, Yuhuan Kong, Donghang Xu, Jinqiang Wang, Zhen Gu, Jianqing Gao, Tianyuan Zhang.
      Mitochondrial transplantation is a promising therapeutic approach involving the transfer of exogenous mitochondria into diseased cells to restore impaired mitochondrial homeostasis. However, its clinical translation is severely limited by the lack of efficient methods for precise and potent mitochondria transfer. Inspired by natural mitochondria-containing vesicles, we develop mesenchymal stem cell-derived biomimetic nanovesicles with high mitochondrial loading capacity and augmented extracellular mitochondrial stability. These nanovesicles exhibit an ability to efficiently and selectively deliver mitochondrial cargo to injured cells, which is potentially ascribed to the specific interaction between very late antigen-5 on the nanovesicle surface and pathologically upregulated fibronectin on injured cells. In a mouse pulmonary fibrosis model, these nanovesicles successfully deliver healthy mitochondria to injured lung epithelial cells through airway administration, resulting in a significant reduction in fibrotic progression. This study introduces a design of mitochondria-enriched biomimetic nanovesicles for effective and targeted mitochondria transfer, offering a nanotechnology-based strategy to advance mitochondrial transplantation therapy.
    DOI:  https://doi.org/10.1038/s41467-026-76330-9
  8. Trends Cell Biol. 2026 Sep 04. pii: S0962-8924(26)00168-6. [Epub ahead of print]
    Horizontal mitochondrial transfer: an emerging field in cell biology.
    Michael V Berridge, Zuzana Nahacka, Katerina Komrskova, Minghao Zheng, Jiri Neuzil.
      The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.012
  9. Antioxid Redox Signal. 2026 Sep 02. 15230864261481794
    Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
    Huijia Zhang, Ying Chen, Junjie Jiang, Yarong Ding, Si Hu, Zhongzhi Zhou, Li Chen.
      Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  ESCRT complex; Rab GTPase; SPATA18/Mieap; TFEB; V-ATPase; autophagy; lysosomal membrane remodeling; mitochondrial microautophagy; mitochondrial quality control
    DOI:  https://doi.org/10.1177/15230864261481794
  10. Ann Hum Genet. 2026 Aug 30.
    Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
    Enchi Yuan, Ning Zhang, Haoyu He, Tao Zhang, Enze Chen, Qidi Zhang, Dongmei Ji.
       BACKGROUND: Variants in the MT-TI gene, which encodes mitochondrial transfer RNA for isoleucine, have been associated with neuromuscular, cardiac, auditory, renal, and metabolic disorders, but their clinical interpretation remains difficult.
    OBJECTIVE: To integrate clinical, familial, heteroplasmy, and functional evidence across the reported MT-TI variant spectrum and clarify its implications for variant interpretation and diagnosis.
    METHODS: We conducted a narrative review of reported MT-TI variants, with detailed comparison of seven representative variants and synthesis of phenotypic, familial, tissue-specific heteroplasmy, and functional findings.
    RESULTS: Evidence was derived mainly from case reports and small pedigrees. Heteroplasmy differed markedly among blood, skeletal muscle, and myocardium, indicating that blood may not represent variant loads in energy-demanding tissues. Reported values generally reflected the lowest observed levels in affected individuals or family-specific boundaries rather than validated pathogenic cutoffs. Functional findings support a staged mechanism involving disturbed transfer RNA processing, structure, stability, or aminoacylation, followed by impaired mitochondrial protein synthesis and respiratory-chain dysfunction. Integrated mechanistic support was limited to a few variants, including m.4295A>G; evidence for most variants remained incomplete or indirect.
    CONCLUSION: Diagnosis requires tissue-informed heteroplasmy assessment integrated with phenotype, maternal family history, and functional evidence. Current treatment is supportive, and proposed reproductive and molecular strategies lack MT-TI-specific clinical-trial evidence.
    Keywords:  Ile; RNA; heteroplasmy; mitochondrial; mitochondrial diseases; oxidative phosphorylation; transfer
    DOI:  https://doi.org/10.1111/ahg.70056
  11. J Vis Exp. 2026 Sep 03.
    Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
    Teresa Kloimboeck, Thomas Ebner, Kateryna Makova, Barbara Arbeithuber.
      Oocytes are densely packed with mitochondria, the energy-producing organelles that contain their own genome, mitochondrial DNA (mtDNA). Each cell contains multiple copies of mtDNA, with copy number varying among tissue types. Oocytes possess the highest mtDNA copy number, containing hundreds of thousands of mtDNA molecules per cell. Because mitochondria are inherited exclusively through the maternal lineage, accurate detection of mtDNA variants is essential for studies of inheritance, aging, and disease. The presence of multiple mtDNA copies allows wild-type and mutant molecules to coexist within the same cell, a condition known as heteroplasmy, in which low-frequency and de novo variants may occur at frequencies below 1%. Conventional next-generation sequencing (NGS) lacks sufficient accuracy to reliably distinguish these rare variants from errors introduced during library preparation and sequencing. Here, we present a protocol for enriching mtDNA from single human oocytes using Exonuclease V to remove linear DNA, followed by duplex sequencing library preparation for highly accurate mtDNA analysis. This workflow enables error-corrected sequencing of individual oocytes, facilitating reliable detection of low-frequency mtDNA variants and analysis of heteroplasmy and de novo mutagenesis. The protocol provides a reproducible approach for investigating mitochondrial genome variation in single oocytes using Illumina-compatible sequencing platforms.
    DOI:  https://doi.org/10.3791/73071
  12. Nat Commun. 2026 08 03. pii: 9338. [Epub ahead of print]17(1):
    Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
    Helin Hocaoglu, Shenlu Qin, Leah Eller, Farhan Abu, Benjamin Ohlstein, Lei Wang, Matthew H Sieber.
      Maternal metabolic stress is a major determinant of progeny health and disease susceptibility, yet the mechanisms linking germline metabolism to lifelong changes in tissue physiology remain poorly defined. Here, we show that maternal metabolic stress alters the cellular composition of the progeny intestinal epithelium through a conserved metabolic pathway. Germline metabolic dysfunction depletes NAD⁺ in mature oocytes, reprogramming progeny redox metabolism and impairing the methionine cycle. This metabolic shift reduces protein levels of the Notch ligand Delta, disrupting intestinal stem cell niche signaling and altering progeny intestinal physiology. Across insect and mammalian models, our findings reveal that maternal metabolic health has conserved effects on progeny metabolism and intestinal function. Together, this work identifies heritable redox-metabolic changes as a mechanistic link between maternal metabolic stress, stem cell regulation, and intestinal disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-76249-1
  13. Front Immunol. 2026 ;17 1898280
    Mitochondria transfer research from cellular mechanisms to immune-inflammatory and translational frontiers: a bibliometric analysis from 2006 to 2026.
    Peiwei Su, Wanyu Luo, Chao Zhu, Xudong Zhufu, Xianyi Zhang, Haoxin Wu, Rui Xu, Haijun Zhao.
       Background: Mitochondria transfer is an emerging mechanism of intercellular communication involved in mitochondrial homeostasis, metabolic remodeling, immune regulation, inflammatory responses, tumor progression, and mitochondrial transplantation-based therapy. However, the global research landscape and immune-inflammatory frontiers remain unclear.
    Methods: Publications on mitochondria transfer published between 1 January 2006 and 8 April 2026, were retrieved from the Web of Science Core Collection and Scopus. After deduplication and manual screening, 851 English-language articles and reviews were analyzed using bibliometrix, CiteSpace, VOSviewer, and Pajek.
    Results: The 851 publications included 566 articles and 285 reviews. They received 38,879 citations and an average of 45.69 citations per publication. Annual output increased markedly after 2018 and peaked in 2025. China and the USA were the leading contributors. Journal, co-citation, and keyword analyses showed that mitochondria transfer research has expanded from mitochondrial biology, stem cell-mediated repair, and cellular metabolism toward immune regulation, inflammation, tumor microenvironment remodeling, biomaterials, and translational medicine. Major knowledge bases and emerging hotspots included tunneling nanotubes, extracellular vesicles, mitochondrial transplantation, mitochondrial quality control, metabolic homeostasis, macrophages, T cells, B cells, immune evasion, macrophage polarization, and cGAS/STING-related mechanisms.
    Conclusion: Mitochondria transfer has developed into an interdisciplinary field connecting cellular mechanisms, immune-inflammatory regulation, disease microenvironment remodeling, and translational therapy. Future studies should clarify its molecular regulation and context-dependent consequences, particularly in immune cells, inflammatory diseases, tumor immune evasion, and mitochondrial transplantation-based interventions.
    Keywords:  immune regulation; inflammation; metabolic homeostasis; mitochondria transfer; mitochondria transplantation; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fimmu.2026.1898280
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