bims-polgdi Biomed News
on POLG disease
Issue of 2026–04–05
fifty-two papers selected by
Luca Bolliger, lxBio
  1. Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
  2. MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
  3. Why selection for mitochondrial quality drives the evolution of sexes.
  4. Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
  5. Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
  6. Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.
  7. Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
  8. NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
  9. Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
  10. Mitochondrial genomes on a string of pearls.
  11. Mitochondrial DNA alterations in mothers and offspring following in utero exposure to ionizing radiation.
  12. Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling.
  13. Within-individual changes in mitochondrial DNA copy number across the life course and links to individual performance.
  14. TUFM: a central regulator in mitochondrial quality control and beyond.
  15. Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
  16. Microscopy in mitochondrial research - a comprehensive review.
  17. MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
  18. Rare coding and noncoding variants map 1,342 diseases and biomarkers in 490,549 whole genomes.
  19. Mitochondrial signals in the bloodstream: Peripheral signature of mitochondrial dysfunction in mental health. A systematic review.
  20. The Potential of Digital Twins for Pediatric Rare Diseases.
  21. Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
  22. High-content microscopy quantification of mitochondrial membrane potential.
  23. From confusion to diagnosis: a rare case of melas syndrome in a patient with familial consanguinity, recurrent stroke-like episodes, and concurrent FSGS.
  24. The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
  25. Mitochondria and the epigenome: maternal co-inheritance and crosstalk from oocyte to embryo.
  26. An Open-Source Code to Analyze Mitochondrial Intracellular Distribution from Fluorescence Microscopy Images.
  27. Navigating the methodological, ethical, and operational challenges of Trials within Cohorts (TwiCs): insights from a French pediatric research-based cohort.
  28. Bioinformatics and AI/ML approaches using multi-omics data to accelerate diagnosis and delivery of precision care for patients with rare diseases.
  29. Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.
  30. Mitochondrial dysfunction in chemical anemia: can nursing led exercise programs improve red blood cell production?
  31. Facilitated DNA damage repair as an emerging therapeutic strategy for inflammatory and fibrotic diseases.
  32. Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.
  33. Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
  34. Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.
  35. Optimizing regional rare disease management systems within China's policy framework: practical insights from the shantou experience.
  36. Ethical and Regulatory Considerations for Developing Gene Therapies Involving Genome Editing.
  37. Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
  38. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  39. Intercompartmental communication in senescence.
  40. Extracellular Vesicles as Key SASP Carriers Driving Cellular Senescence, Inflammaging, and Therapeutic Opportunities in Aging and Age-Related Diseases.
  41. Mitochondrial transplantation ameliorates experimental autoimmune encephalomyelitis by modulating the Th17/Treg balance and restoring metabolic homeostasis.
  42. Genetic analysis of neurodegenerative diseases.
  43. Mitochondria power immunity against cancer.
  44. Targeting the Gut-Liver Mitochondria Axis in MASLD: Mechanisms and Therapeutic Perspectives.
  45. Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
  46. Targeting muscle, mitochondria, and microbiome: nutritional and exercise strategies across wasting diseases and conditions.
  47. Examination of shared gut microbiome signatures in aging and Parkinson's disease.
  48. The Bidirectional Regulatory Role of Neuroimmune Interaction in Neurodevelopment and Neurodegenerative Diseases.
  49. Mitonuclear dynamics in unisexual vertebrates.
  50. Reprogramming the mitochondrial-circadian energy code with incretins.
  51. Exploring the Intersection of Rare Diseases and Mental Health Within the Diagnostic Odyssey: A Narrative Review and Thematic Synthesis.
  52. Adeno-Associated Virus Gene Delivery to Hard-to-Transduce Tissues: Biological Barriers, Engineering Strategies, and Clinical Challenges.
  1. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250075. [Epub ahead of print]381(1947):
    Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
    Iain G Johnston.
      Mitochondrial DNA (mtDNA) encodes essential bioenergetic and metabolic machinery across eukaryotes, but it is susceptible to mutational damage. The high copy number, physical location and inheritance patterns of mtDNA mean that specialist approaches to mitigate such damage are needed. A common theme across many species is segregation or 'sorting out' of different mtDNA types-generating variance in mutant frequencies within and between generations, so that multiscale selection can act to remove deleterious mutations. Eukaryotes with different physiologies and ecologies use different strategies for this segregation. This article attempts to review and-with the aid of some bioinformatics and new modelling results-synthesize the ways that this segregation is achieved across different eukaryotic organisms. In parallel, the importance of segregation in human disease, longevity, agriculture and for biology on a rapidly changing planet is discussed. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  bottleneck; cross-eukaryote; evolution; mitochondria; mtDNA
    DOI:  https://doi.org/10.1098/rstb.2025.0075
  2. Nat Struct Mol Biol. 2026 Apr 01.
    MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
    Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.
      Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41594-026-01779-7
  3. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250076. [Epub ahead of print]381(1947):
    Why selection for mitochondrial quality drives the evolution of sexes.
    Nick Lane, Andrew Pomiankowski.
      The evolution of sexes is closely tied to uniparental inheritance (UPI) of mitochondrial DNA (mtDNA), where only females transmit mtDNA. Unlike nuclear DNA, mtDNA is highly polyploid and never evolved to be part of meiotic sex. Modelling shows that UPI increases mtDNA mutational variance, enhancing selection for high-quality mtDNA and promoting the emergence of sexes from mating types in unicellular eukaryotes. Paternal control of mitochondrial transfer favours some degree of mtDNA leakage, whereas maternal control favours strict UPI, leading to sexual conflict driving turnover in transmission mechanisms. In multicellular organisms, mitotic segregation of mtDNA increases variance in gametes, again facilitating selection. Surprisingly, germline evolution seems to reflect mtDNA mutation rates: plants and sessile metazoans have low rates and produce gametes from somatic cells, while bilaterians and ctenophores with higher rates sequester germlines with restricted cell division. High mtDNA ploidy in oocytes allows early embryonic cell division without replication, reducing mutational variance across tissues and enhancing somatic fitness. Germline mtDNA quality is maintained by mitotic over-proliferation of germ cells and the selective transfer of mtDNA into primordial oocytes linked with massive apoptotic germ-cell atresia. Overall, selection for mtDNA quality elucidates the evolution of sexes and the architecture of the female germline. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  Balbiani body; germline; mitochondria; mitochondrial mutation; mtDNA; oogenesis; sexes; uniparental inheritance
    DOI:  https://doi.org/10.1098/rstb.2025.0076
  4. Autophagy. 2026 Mar 31. 1-3
    Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
    Polyxeni Papadea, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
    Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations
    DOI:  https://doi.org/10.1080/15548627.2026.2650772
  5. Trends Mol Med. 2026 Apr 02. pii: S1471-4914(26)00061-4. [Epub ahead of print]
    Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
    Junlin Wei, Fang Wang.
      Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
    Keywords:  diabetic peripheral neuropathy; mitochondrial transfer; neuroprotection; satellite glial cells; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.molmed.2026.03.004
  6. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250079. [Epub ahead of print]381(1947):
    Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.
    Jade R Kannangara, Hansong Ma, Damian K Dowling.
      Mitochondrial DNA (mtDNA) variation is increasingly recognized for its role in shaping evolutionary changes at the species and population levels. Yet, its evolutionary relevance within individuals remains less explored. Eukaryotic cells typically carry multiple copies of mtDNA. When these copies differ in sequence, heteroplasmy arises-a form of intra-organismal genetic diversity with potentially profound biological implications. To elucidate the evolutionary significance of heteroplasmy in animals, we first review how natural selection shapes adaptive mtDNA dynamics at broader biological levels, via cases of mito-nuclear coadaptation, environmental-mediated and sex-specific selection and balancing selection. We then explore whether analogous selective pressures may operate at the intra-individual level. Heteroplasmy introduces the potential for multi-level selection-from the genome to the organism-potentially yielding synergistic or antagonistic evolutionary outcomes. This framework encompasses both the selfish transmission of certain mtDNA variants and emerging evidence for adaptive shifts in heteroplasmy levels under environmental stress. These findings are supported by theoretical models suggesting that paternal mtDNA transmission-historically viewed as a stochastic anomaly-may confer adaptive benefits under specific ecological and evolutionary contexts by introducing intra-individual mtDNA diversity. Collectively, these insights suggest that heteroplasmy may act as an underappreciated reservoir of adaptive potential, enhancing the evolutionary capacity of organisms in a changing world. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  adaptation; adaptive; environmental change; evolution; heteroplasmy; mito-nuclear; mitochondria; mtDNA; selfish; selfish drive
    DOI:  https://doi.org/10.1098/rstb.2025.0079
  7. bioRxiv. 2026 Mar 25. pii: 2026.03.20.711686. [Epub ahead of print]
    Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
    Lucía Fernández-Del-Río, Andrea Eastes, David Rincón Fernández Pacheco, Nikole Scillitani, Jasmine Garza, Matthew Dugan, Matheus Pinto de Oliveira, Pradnya Kadam, Iman Gauhar, Karel Erion, Kathleen Rodgers, Kevin Gaffney, Amy Wang, Marc Liesa, Cristiane Benincá, Orian Shaul Shirihai.
      Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.03.20.711686
  8. Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714
    NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
    George B Stefano.
      Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.
    Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.31083/FBL49714
  9. Brain Commun. 2026 ;8(2): fcag095
    Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
    Alessandra Torraco, Charlotte L Alston, Giulia Barcia, Daniela Verrigni, Teresa Rizza, Michela Di Nottia, Anastasia Altobelli, Diego Martinelli, Daria Diodato, Stephanie Efthymiou, Melis Kose, Yamna Kriouile, Albert Z Lim, Silvia Morlino, Barbara Siri, Nebal Waill Saadi, Antonio Novelli, Henry Houlden, Carlo Dionisi-Vici, Robert McFarland, Agnès Rötig, Enrico Bertini, Robert W Taylor, Rosalba Carrozzo.
      NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)-ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function. Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient's mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies. Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability. To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics-including age of symptom onset, phenotypic variability, and patient outcomes-aiming to improve prognostic information and facilitate genetic counselling in clinical practice.
    Keywords:  Assembly factors; Leigh syndrome; Mitochondrial disease; NADH–ubiquinone oxidoreductase; Respiratory chain complexes
    DOI:  https://doi.org/10.1093/braincomms/fcag095
  10. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  11. Free Radic Biol Med. 2026 Mar 27. pii: S0891-5849(26)00256-X. [Epub ahead of print]250 168-173
    Mitochondrial DNA alterations in mothers and offspring following in utero exposure to ionizing radiation.
    Ryosuke Seino, Haruka Kubo, Atsuko Ikeda, Hisanori Fukunaga.
      Ionizing radiation can perturb mitochondrial homeostasis and genomic stability, yet its developmental consequences remain insufficiently understood. We investigated how in utero X-ray exposure may affect mitochondrial DNA (mtDNA) regulation and developmental parameters in a mouse model. Pregnant C57BL/6N mice were exposed to 0 (sham-irradiated), 0.05, 0.2, 0.5 and 2 Gy X-rays at gestational day 8, corresponding to the onset of organogenesis. In maternal peripheral blood, mtDNA copy number (mtDNAcn) increased at 2 Gy, while the intact mtDNA ratio, defined as the degree of mtDNA homoplasy estimated by long-fragment PCR, decreased at ≥ 0.5 Gy. Pregnancy resulted in live offspring at GD8 X-ray doses of 0.5 Gy or lower. Offspring sex ratios and body weights did not differ between control and irradiated groups. Notably, offspring examined at two weeks of age exhibited significantly elevated mtDNAcn at ≥ 0.2 Gy, whereas intact mtDNA ratios were unchanged. These results demonstrate that in utero X-ray exposure is associated with dose-dependent alterations in mtDNA regulation in both mothers and their offspring, with distinct sensitivities observed between maternal and offspring responses. These findings highlight mitochondrial responses to radiation exposure during early development and suggest that prenatal irradiation may influence mtDNA regulation, with potential implications for mitochondrial function later in life.
    Keywords:  Copy number variation; Heteroplasmy; In utero exposure; Mitochondrial DNA; Radiation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.065
  12. Int Immunopharmacol. 2026 Mar 30. pii: S1567-5769(26)00427-3. [Epub ahead of print]178 116582
    Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling.
    Junhui Yao, Mengjie Shi, Siyan Chen, Huan Zhang, Yiming Lin, Chunyan Hua, Sheng Gao.
      Cytidine monophosphate kinase 2 (CMPK2) is a pivotal mitochondrial enzyme that plays a multifaceted role in cellular nucleotide metabolism, immune regulation, and disease pathogenesis. This review comprehensively examines the structural characteristics, enzymatic functions, and regulatory mechanisms of CMPK2, emphasizing its significance in maintaining mitochondrial DNA (mtDNA) integrity and energy metabolism. We explore how CMPK2 links mitochondrial stress to inflammation through its involvement in key immune signaling pathways, including the NLRP3 inflammasome and cGAS-STING pathway, thereby modulating innate immune responses. Notably, CMPK2 is upregulated during viral infections, such as SARS-CoV-2 and Zika virus, where it restricts virus replication and enhance antiviral defenses. Furthermore, we discuss the implications of CMPK2 dysregulation in various non-communicable diseases, including systemic lupus erythematosus and neuroblastoma, highlighting its potential as a diagnostic biomarker and candidate therapeutic target. By integrating recent advances in our understanding of CMPK2's roles across infectious and non-infectious diseases, this review establishes CMPK2 as a pivotal node connecting mitochondrial metabolism, immune responses, and disease mechanisms. Our findings underscore the need for further research to elucidate CMPK2's complex functions and to explore its therapeutic potential in clinical applications, ultimately contributing to improved disease management strategies.
    Keywords:  Antiviral defense; CMPK2; Immunity; Inflammation; Mitochondrial metabolism; Therapeutic target
    DOI:  https://doi.org/10.1016/j.intimp.2026.116582
  13. Biol Lett. 2026 Apr 01. pii: 20250521. [Epub ahead of print]22(4):
    Within-individual changes in mitochondrial DNA copy number across the life course and links to individual performance.
    Pablo Salmón, Miguel Hernandez-Gonzalez, Winnie Boner, Edward R Ivimey-Cook, Pat Monaghan.
      Ageing is characterized by complex biological processes reflected in cellular and molecular changes. Mitochondria, which are crucial for energy production and cellular homeostasis, are particularly vulnerable to age-related deterioration. The number of copies of mitochondrial DNA (mtDNAcn) varies across and within tissues in response to energetic activity and mtDNA integrity, and is related to health and physical performance. Age-related changes in mtDNAcn can be difficult to study due to differential survival of phenotypes into older ages, but studies of changes in mtDNAcn within individuals are very limited. In this study, we investigated changes in red blood cell mtDNAcn across the life course within individual zebra finches (Taeniopygia guttata), a well-established avian model, from the nestling stage into old age. Our findings revealed a pronounced decline in relative mtDNAcn during post-natal development, followed by comparative stability throughout adulthood. This pattern was remarkably consistent among individuals. We found no significant relationship between variation in mtDNAcn and growth during the nestling period. However, based on measurements of disturbed take-off speed in late adulthood, we found that individuals with higher physical performance at that stage had higher relative mtDNAcn, suggesting a link between variation in individual bioenergetics and biological state.
    Keywords:  ageing; birds; flight performance; life history; mitochondria; within-individual
    DOI:  https://doi.org/10.1098/rsbl.2025.0521
  14. Cell Death Discov. 2026 Mar 28.
    TUFM: a central regulator in mitochondrial quality control and beyond.
    Xuanyi Li, Liangjie Dong, Tian Xiao, Jiayi Chen, Hang Ye, Siyi Zhu, Fulin Chen, Yuan Yu.
      Tu translation elongation factor, mitochondrial (TUFM) is a highly conserved, nuclear-encoded GTPase that is indispensable for mitochondrial protein synthesis. Beyond this canonical function, TUFM has emerged as a central regulator of mitochondrial quality control (MQC), orchestrating mitochondrial biogenesis, dynamics, and mitophagy through a location-dictates-function paradigm. Its subcellular localization and activity are precisely regulated by post-translational modifications, including phosphorylation, lactylation, ubiquitination, and acetylation, which collectively dictate its functional outputs in cellular homeostasis and stress responses. TUFM also serves as a critical interface in host-pathogen interactions, where viruses often hijack its pro-mitophagic function to evade mitochondrial antiviral signaling. Functioning as a cellular fate switch, the TUFM-MQC axis determines context-dependent pathological outcomes: its hyperactivation promotes cell growth and fuels oncogenesis, whereas its deficiency exacerbates cell death and contributes to neurodegeneration, inflammatory damage, and metabolic dysfunction. This review synthesizes current mechanistic insights into TUFM as a central MQC coordinator and delineates how its functional imbalance redirects cellular trajectories toward survival or death. Deciphering the regulatory logic and spatiotemporal dynamics of this pivotal hub offers promising avenues for developing targeted strategies to restore cellular homeostasis across a spectrum of diseases.
    DOI:  https://doi.org/10.1038/s41420-026-03075-1
  15. FEBS Lett. 2026 Mar 30.
    Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
    Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton.
      Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.
    Keywords:  mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter
    DOI:  https://doi.org/10.1002/1873-3468.70335
  16. J Cell Sci. 2026 Mar 15. pii: jcs263933. [Epub ahead of print]139(6):
    Microscopy in mitochondrial research - a comprehensive review.
    Prasanna Katti, Prasanna Venkhatesh, C Nivedya, Andrea Marshall, Amber Crabtree, Zahra Elly Soltani, Olga Korolkova, Vineeta Sharma, Suraj Thapliyal, Karthik Naik, Kit Neikirk, Rodolpho Ornitz Oliveira Souza, Sepiso K Masenga, Nelson Wandira, Magdalene Ameka, Okwute M Ochayi, Christian A Combs, Lucy Collinson, Nalan Liv, Antentor Hinton.
      Mitochondria are highly dynamic, double-membrane organelles that play integral roles beyond energy production. Mitochondria adapt their morphology to meet diverse cellular demands, and highly plastic mitochondrial networks interact and communicate with various cellular components to maintain cellular health. Advances in both light and electron microscopy (EM) have greatly enhanced our understanding of mitochondrial structure and function. However, the small diameter of mitochondrial tubules, often near the diffraction limit of light, poses challenges for visualizing submitochondrial structures and protein distributions with conventional microscopy. Recently, super-resolution microscopy has offered unprecedented insights into mitochondrial dynamics, interactions and architecture. In this Review, we discuss how imaging techniques have advanced our understanding of mitochondrial biology. We critically assess the contributions of two-dimensional EM to elucidating the native architecture of cristae and respiratory chain complexes. Additionally, we explore how three-dimensional EM and super-resolution methods have reshaped our comprehension of mitochondrial network dynamics, heterogeneity and interactions with other cellular components. Finally, we discuss the strengths and limitations of various approaches, considering their potential to overcome current challenges and open new avenues in mitochondrial research, and illuminate how advanced microscopy continues to drive discoveries in mitochondrial biology with implications for metabolic diseases and aging.
    Keywords:  CLEM; Confocal; EM; Mitochondria; Super-resolution microscopy; Volume EM
    DOI:  https://doi.org/10.1242/jcs.263933
  17. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250078. [Epub ahead of print]381(1947):
    MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
    Francis Robitaille, Amy Campbell, Aziz Ben Hadj, Sarah Cornet, Ludovic Nadeau-Lachance, Thierry Niaison, Thierry Choquette, Liam Nyffeler, Xavier Roucou, Annie Angers, Sophie Breton.
      Mitochondrial alternative open reading frames (ORFs) substantially broaden the functional scope traditionally attributed to mitochondrial DNA, encoding peptides and proteins that participate in diverse cellular processes. These newly identified ORFs are embedded within annotated sequences, both coding and non-coding, and reveal layers of overlapping genetic information. We report the discovery of MTALTCO1, a 259 amino-acid protein, the longest mitochondrial alternative protein identified to date, encoded by an ORF located within the human cytochrome oxidase 1 gene, in the +3 reading frame. We confirm the expression and mitochondrial origin of MTALTCO1 through multiple independent lines of evidence, including a custom-designed antibody, mass spectrometry-derived peptides, sequence analysis and inhibitors of mitochondrial expression. Despite encoding AGR codons as arginine, contrary to the prevailing view that these function invariably as stop codons in the vertebrate mitochondrial genetic code, MTALTCO1 shows strong evidence of mitochondrial translation, challenging established models of mitochondrial codon usage and gene expression. Co-immunoprecipitations and pulldown assays delineate MTALTCO1's interaction landscape across major cellular pathways. Finally, we present the first in-depth analysis of conservation for a mitochondrial alternative ORF overlapping a reference protein-coding gene and discuss the results in light of MTALTCO1's suggested role in protein scaffolding. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  alternative proteins; conservation; intrinsically disordered proteins; mitochondria; mitochondrial-derived peptides; mitrochondrial translation; overlapping open reading frame; overprinting; protein function; scaffold proteins
    DOI:  https://doi.org/10.1098/rstb.2025.0078
  18. medRxiv. 2026 Mar 26. pii: 2026.03.24.26349148. [Epub ahead of print]
    Rare coding and noncoding variants map 1,342 diseases and biomarkers in 490,549 whole genomes.
    Yuxin Yuan, Yuanyuan Guan, Yannuo Feng, Tony Chen, Yingzi Zhang, Baoqun Chang, Shijie Fan, Chang Lu, Wenyuan Li, Xiaoyu Li, Xihao Li, Xihong Lin, Zilin Li.
      Rare genetic variants are increasingly recognized as important contributors to human trait architecture, with noncoding variants accounting for a substantial portion of the heritability. These variants tend to be less polygenic and more biologically specific than common variants, remaining understudied across large biobanks. Here we analyzed whole genome sequencing (WGS) data from up to 490,549 UK Biobank participants to assess the effects of rare coding and noncoding variants across 1,342 phenotypes, including 944 diseases, 76 clinical biomarkers, and 322 metabolomics traits. We developed and applied STAARpipelinePheWAS , a scalable framework for WGS phenome-wide rare variant association analysis, identifying 49,121 genome-wide significant gene-trait pairs. Our study presents a comprehensive map of noncoding rare variant associations in both disease and biomarker domains. Many associations were undetected in prior exome- or array-based studies and were enriched in drug targets and biologically coherent pathways. All results are publicly accessible through an interactive portal ( https://www.staarphewas.org/ ), offering a foundational resource for rare variant discovery, functional interpretation, and translational genomics.
    DOI:  https://doi.org/10.64898/2026.03.24.26349148
  19. Neurosci Biobehav Rev. 2026 Mar 30. pii: S0149-7634(26)00127-2. [Epub ahead of print]186 106670
    Mitochondrial signals in the bloodstream: Peripheral signature of mitochondrial dysfunction in mental health. A systematic review.
    Inés Lucía Fernández-Pech, María Fernández-Guillén, Cristina Morente-Montilla, Benedicto Crespo-Facorro, Celia Martín-Cuevas.
      Psychiatric disorders are characterized by marked clinical heterogeneity, overlapping symptom dimensions, and the persistent lack of objective biomarkers. Liquid biopsy has emerged as a promising, non-invasive strategy to identify peripheral molecular signatures that may inform diagnosis and treatment monitoring. Given the central involvement of mitochondrial dysfunction in psychiatric pathophysiology, circulating cell-free mitochondrial DNA (ccf-mtDNA) has attracted increasing interest as a candidate biomarker. Following PRISMA 2020 guidelines, this systematic review synthesized evidence on ccf-mtDNA alterations in bipolar disorder (BD), depressive disorders (DD), and schizophrenia (SCZ). Findings in BD were heterogeneous: several studies reported elevated ccf-mtDNA, particularly in unmedicated individuals and those with cognitive deficits, whereas others observed no differences or even decreased levels compared with healthy controls (HC). In DD, evidence more consistently indicated increased ccf-mtDNA, especially in unmedicated or late-life depression, where higher levels correlated with symptom severity, frailty, and inflammatory indices. These data support ccf-mtDNA as a peripheral marker of mitochondrial and inflammatory dysregulation in DD. Conversely, most studies in SCZ reported no significant differences relative to HC; however, elevated ccf-mtDNA levels observed in cognitively impaired subgroups and in patients exhibiting alterations in brain bioenergetics point to underlying clinical and biological heterogeneity. Collectively, current evidence implicates ccf-mtDNA as a putative biomarker of mitochondrial dysfunction in psychiatry, with greater translational potential in DD and BD. Nonetheless, methodological heterogeneity, small sample sizes, and cross-sectional designs underscore the need for standardized, longitudinal investigations to establish its diagnostic and prognostic validity.
    Keywords:  bipolar disorder; circulating cell-free mitochondrial DNA (ccf-mtDNA); cognition; depressive disorder; liquid biopsy; neuroinflammation; schizophrenia
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106670
  20. CPT Pharmacometrics Syst Pharmacol. 2026 Apr;15(4): e70234
    The Potential of Digital Twins for Pediatric Rare Diseases.
    Rahuman S Malik-Sheriff, Anurag Limdi, Evangelia Petsalaki, Henning Hermjakob, Ellen M McDonagh.
      Rare diseases affect over 300 million people globally, with approximately 75% manifesting in childhood. Their diagnosis is often delayed and approved treatments are lacking for most of the conditions. Pediatric rare diseases research is further complicated by ethical constraints and developmental diversity across childhood. Digital Twins, virtual representations of patients built from mechanistic and AI/ML models, offer a promising solution by enabling hypothesis testing, precision diagnostics, personalized therapies, and in silico trials for pediatric rare diseases. This article discusses the potential of DT applications in advancing precision medicine for pediatric rare diseases, alongside associated regulatory perspectives, modeling strategies, uncertainty analysis, as well as data, ethical and legal challenges.
    DOI:  https://doi.org/10.1002/psp4.70234
  21. Aging Cell. 2026 Apr;25(4): e70462
    Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
    Yiting Lei, Meng Yang, Xiaoyun Jiang, Yujie Zhang, Yuzhi Chen, Weiheng Xie, Qihui Dai, Weihong Qin, Xiuqin Deng, Xiaojun Zhang, Zhongjun Zhou, Gonghua Huang, Xinguang Liu.
      Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.
    Keywords:  Pck1; TCA cycle; aging; cGAS/STING signaling; cellular senescence; white adipose tissue
    DOI:  https://doi.org/10.1111/acel.70462
  22. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00100-1. [Epub ahead of print]204 141-153
    High-content microscopy quantification of mitochondrial membrane potential.
    Camilla Bean, Federica Dal Bello, Caterina Vianello, Luca Persano, Elena Rampazzo, Tomáš Knedlík, Emad Norouzi Esfahani, Saradha Ramesh, Alessio Gianelle, Marta Giacomello.
      In nearly all pathophysiological processes, mitochondrial membrane potential serves as a crucial indicator of mitochondrial function and activity. However, there remains a need for high-content imaging techniques that incorporate multiparametric measurements for comprehensive mitochondrial assessment. This paper introduces a novel unbiased approach for quantifying mitochondrial membrane potential in vitro, applicable to both two-dimensional and three-dimensional experimental systems. Furthermore, the incorporation of automated image analysis with machine learning algorithms enabled precise identification and segregation of distinct cell types within complex co-culture systems, allowing for targeted evaluation of individual subpopulations. Here, we provide a protocol for large-scale profiling of mitochondrial activity across various experimental contexts.
    Keywords:  Automated image analysis; Co-culture; High-content microscopy; Machine learning; Mitochondrial membrane potential; NSCs; Single muscle fibers; Spheroids; TMRM
    DOI:  https://doi.org/10.1016/bs.mcb.2025.03.019
  23. BMC Neurol. 2026 Apr 02.
    From confusion to diagnosis: a rare case of melas syndrome in a patient with familial consanguinity, recurrent stroke-like episodes, and concurrent FSGS.
    Majd Mohsen, Salsabeel Juma, Dana Saleh, Tala Saleh, Aya Amayra, Jawad Atrash.
      
    Keywords:  Case report; MELAS syndrome; Mitochondrial disease; Stroke-like
    DOI:  https://doi.org/10.1186/s12883-026-04853-1
  24. Sci Adv. 2026 Apr 03. 12(14): eaea4279
    The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
    Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Eric Hwang, Claire S Chung, Jaye L Weinert, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.
      Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
    DOI:  https://doi.org/10.1126/sciadv.aea4279
  25. Cell Commun Signal. 2026 Mar 30.
    Mitochondria and the epigenome: maternal co-inheritance and crosstalk from oocyte to embryo.
    Song-Hee Lee, Xiang-Shun Cui.
      
    Keywords:  DNA methylation; Embryo; Epigenetic regulation; Inheritance; Mitochondria; Oocyte
    DOI:  https://doi.org/10.1186/s12964-026-02844-w
  26. Biosci Rep. 2026 Mar 30. pii: BSR20260140. [Epub ahead of print]
    An Open-Source Code to Analyze Mitochondrial Intracellular Distribution from Fluorescence Microscopy Images.
    Giovanna C Cavalcante, Alicia J Kowaltowski.
      Mitochondria have a plethora of roles in cells, many of which are related to dynamic changes in their size, shape, and intracellular location. Mitochondrial morphology is commonly assessed by microscopy with targeted fluorescent probes. However, tools to easily estimate mitochondrial localization within a cell are still lacking. A code was designed to estimate per-cell mitochondrial radial localization (perinuclear or peripheral) from fluorescence microscopy files in a variety of formats and using different mitochondrial markers (https://github.com/cavalcantegc/mito_localization.git). Three case studies with different cell types and stainings demonstrate that mitochondrial localization can be easily extracted and plotted with this code.
    Keywords:  Immunofluorescence; MitoTracker; Mitochondria; Mitochondrial localization; Mitochondrial morphology
    DOI:  https://doi.org/10.1042/BSR20260140
  27. J Clin Epidemiol. 2026 Mar 31. pii: S0895-4356(26)00135-6. [Epub ahead of print] 112260
    Navigating the methodological, ethical, and operational challenges of Trials within Cohorts (TwiCs): insights from a French pediatric research-based cohort.
    Claire Bahans, Claire Dossier, Olivier Dunand, Cyrielle Parmentier, Bruno Ranchin, Gwenaelle Roussey, Stéphanie Tellier, Charlotte Samaille, Isabelle Vrillon, Céline Cluzan, Olivia Boyer, Vincent Guigonis.
      Trials within Cohorts (TwiCs) provide a pragmatic framework to improve recruitment and external validity by embedding randomized controlled trials within longitudinal observational cohorts. In pediatrics, and particularly in rare diseases, this design is especially attractive but remains difficult to implement in routine practice due to intertwined methodological, ethical, and operational complexities. Building on the development of a national pediatric platform for idiopathic nephrotic syndrome in France, this commentary highlights key challenges and proposes practical strategies to address them. We focus on three domains: (i) informed consent, with particular attention to the ethical and regulatory challenges raised by staged information and deferred consent approaches; (ii) data quality, including the long-term requirements for high-quality, interoperable, and research-ready clinical data ; and (iii) sustainability, covering governance and funding models needed to maintain a cohort-based trial infrastructure beyond short-term, project-driven grants. We argue that scalable pediatric TwiCs would benefit from secure and family-centered e-consent solutions, robust real-world data infrastructures aligned with interoperability standards, and hybrid funding strategies. Overall, this commentary offers practical strategies to help teams overcome key ethical, methodological, and operational challenges to implementing pediatric TwiCs. PLAIN LANGUAGE SUMMARY: Trials within Cohorts (TwiCs) represent an innovative approach to clinical research where randomized trials are embedded directly into existing groups of patients, known as cohorts. By using this framework, researchers can ensure that their findings more accurately reflect real-world medical practice. This design is particularly valuable in fields like pediatrics and the study of rare diseases, where the limited number of available patients often makes traditional trial recruitment exceptionally difficult. Despite their potential, implementing TwiCs involves practical complexities that require careful management. One primary challenge involves the information and consent process, as researchers must find ways to properly inform patients and families while complying with strict national ethical and regulatory frameworks. Additionally, ensuring the accuracy and seamless sharing of long-term medical data remains a significant technical struggle, as routine clinical data require substantial curation to be "research-ready". There is also the persistent issue of financial sustainability, as traditional funding models often prioritize individual short-term projects rather than the long-term maintenance required to keep a research infrastructure functional over many years. Drawing from experience with a national platform for children with kidney disease in France, several strategic solutions can help overcome these difficulties. Utilizing digital tools such as electronic consent can streamline the enrollment process, improve the delivery of information, and make it more accessible for families to participate. Furthermore, investing in robust and interoperable data systems ensures that high-quality information is consistently available for analysis. Finally, a shift in funding strategy is essential, moving away from temporary grants toward sustained support that recognizes cohorts as vital research infrastructures. By adopting these improvements, TwiCs can become a powerful and efficient tool for evaluating how medical treatments perform in everyday clinical settings.
    Keywords:  Informed consent; Pediatrics; Pragmatic trials; Real-world evidence; Research infrastructure; Trials within Cohorts (TwiCs)
    DOI:  https://doi.org/10.1016/j.jclinepi.2026.112260
  28. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00099-8. [Epub ahead of print]204 109-139
    Bioinformatics and AI/ML approaches using multi-omics data to accelerate diagnosis and delivery of precision care for patients with rare diseases.
    Kritika Singh, Sarah Usman, Saman Zeeshan, Naveena Yanamala, Mark Nichols, Vikram Bhise, Sabahat Bokhari, Partho P Sengupta, Zeeshan Ahmed.
      Rare diseases, characterized by their low prevalence, cumulatively affect millions of people around the world and place significant burden on the healthcare system. With limited clinical expertise and infrastructure in this field, patients encounter barriers in obtaining an accurate diagnosis and accessing treatment. Rare diseases are commonly attributable to genetic alterations; thus, we can optimize modern genetic technologies to pinpoint pertinent genes and molecular pathways involved in disease phenotypes. In this article, we discuss rare diseases in context of multi-omics, an integrative approach combining data from various sources, including genomics, transcriptomics, and epigenomics. Advancements in multi-omics have facilitated the collection of more high-dimensional data, particularly useful for rare diseases comprising limited sample sizes. Artificial intelligence (AI) and machine learning (ML) are powerful tools for extracting disease-relevant patterns from complex datasets and unraveling causative markers underlying disease. Together, these tools are invaluable for incorporating precision medicine in rare diseases through guiding therapeutic strategies aimed at modifying the structure and functionality of specific genes to address the root cause of disease. Specifically, we curate a list of twenty-three rare diseases, prioritized by the medical community based on unmet medical needs and prevalence. To illustrate the current landscape of precision medicine for these diseases, we summarize advancements in genomic sequencing and computational methods for their diagnosis, and utilization of gene-editing technologies for personalized treatment. Overall, the various bioinformatic strategies discussed in this paper help formulate an end-to-end workflow of the integration of gene testing, multi-omics, and AI/ML to guide effective rare disease management.
    Keywords:  Artificial intelligence; Bioinformatics; Machine learning; Precision medicine; Rare diseases
    DOI:  https://doi.org/10.1016/bs.mcb.2025.03.018
  29. Eur J Hum Genet. 2026 Mar 31.
    Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.
    Eva S van Zanten, Elizabeth A Loehrer, Joyce B J van Meurs, Roberto Narcisi, Joost H Gribnau, Raymond A Poot, Hieab H H Adams.
      Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally, iPSCs have been used to model monogenic diseases, where highly penetrant variants produce robust cellular phenotypes detectable in few cell lines. Recent advances in scalability and standardisation now enable systematic comparisons across many donors. This development is particularly relevant for complex diseases, which are driven by numerous genetic variants with small individual effects and therefore require population-scale designs to resolve genotype-phenotype relationships. However, several limitations of iPSC technology continue to challenge the reliability and reproducibility of such studies, constraining their translational relevance. Here, we review the challenges and opportunities of using iPSCs to model complex diseases, structured around three key themes: detecting subtle effects, modelling environmental context, and expanding genetic diversity.
    Keywords:  Complex diseases; Disease modelling; Functional genomics; Genetic variation; Induced pluripotent stem cells
    DOI:  https://doi.org/10.1038/s41431-026-02071-4
  30. Hematology. 2026 Dec 31. 31(1): 2650062
    Mitochondrial dysfunction in chemical anemia: can nursing led exercise programs improve red blood cell production?
    Minqiang Yin, Heng Li, Zhuqing Zhu, Hang Shi.
       INTRODUCTION: Chemical anemia, a common consequence of chemotherapy and environmental toxins, is conventionally attributed to bone marrow suppression. This traditional view may oversimplify the underlying pathology, potentially overlooking critical cellular mechanisms that could serve as novel therapeutic targets.
    OBJECTIVES: This review aims to (1) propose a paradigm shift in understanding chemical anemia by reframing it as a disorder of mitochondrial dysfunction within erythroid precursors and (2) evaluate the potential of structured exercise as a multi-targeted countermeasure to restore erythropoiesis by addressing this mitochondrial root cause.
    METHODS: We synthesized evidence from cellular, molecular, and clinical studies to trace the pathway from chemical exposure to erythroid failure. This review integrates data on mitochondrial integrity, oxidative stress, mtDNA damage, heme synthesis, and cell death pathways (ferroptosis/apoptosis). Subsequently, we analyzed the impact of exercise on key molecular regulators (PGC-1α, AMPK) and mitochondrial quality control to assess its therapeutic potential.
    RESULTS: The synthesis reveals that chemical agents disrupt erythroid maturation primarily by compromising mitochondrial function. This leads to an energetic crisis, stalled heme synthesis, and the activation of ferroptotic and apoptotic pathways, resulting in ineffective erythropoiesis independent of general marrow suppression. Structured exercise is identified as a powerful physiological intervention that activates PGC-1α and AMPK, promoting mitochondrial biogenesis, enhancing mitophagy, and reducing oxidative stress, thereby directly counteracting the proposed pathogenic mechanism.
    DISCUSSION: By acting as a 'exercise mimetic,' physical activity offers a multi-targeted approach to restore mitochondrial health in erythroid precursors. Nurse-led exercise programs are uniquely positioned to translate this biological rationale into practice. By integrating aerobic and resistance training with patient safety monitoring and technology, nurses can operationalize exercise as a pragmatic, patient-centered, mitochondrial-supportive therapy.
    CONCLUSION: Reframing chemical anemia as a mitochondrial disorder highlights critical therapeutic vulnerabilities. Structured exercise, delivered through nurse-led programs, represents a promising complementary approach that targets the root cause of ineffective erythropoiesis, offering the potential to improve red blood cell production and reduce reliance on traditional interventions like transfusions and pharmacotherapy.
    Keywords:  Mitochondrial dysfunction; PGC-1α; chemical-induced anemia; exercise prescription; hematopoesis; ineffective erythropoiesis; nurse-led intervention; physical activity
    DOI:  https://doi.org/10.1080/16078454.2026.2650062
  31. RSC Chem Biol. 2026 Mar 23.
    Facilitated DNA damage repair as an emerging therapeutic strategy for inflammatory and fibrotic diseases.
    Maurice Michel, Nayere Taebnia, Volker M Lauschke.
      DNA damage arising from metabolic stress, oxidative injury, and impaired genome maintenance emerges as a common driver for chronic inflammatory and fibrotic diseases across multiple organs. While rapid and effective DNA damage repair is essential for the response to acute injury, sustained activation of these pathways promotes cellular senescence, sterile inflammation and fibroblast activation, ultimately driving fibrogenesis and pathological tissue remodelling. In recent years, DNA repair processes, particularly base excision repair in both the nucleus and mitochondria, receive increasing attention as modulators of inflammatory and fibrotic outcomes. Here, we review the molecular mechanisms by which unresolved nuclear and mitochondrial DNA lesions translate into chronic inflammation and fibrosis across skin, liver, lung and cardiovascular tissues. We discuss the roles of chromatin context, NAD+ availability, repair intermediates and mitochondrial genome instability in shaping DNA damage responses and highlight emerging chemical biology strategies to facilitate DNA repair, including organocatalytic switches of DNA glycosylases, DNA polymerase γ (POLG) activators or small molecules targeting the inflammasome or cGAS-STING pathway. Based on the available evidence from animal models and organotypic human in vitro cultures, we propose that facilitated DNA repair may represent a promising therapeutic strategy for chronic inflammatory and fibrotic diseases. This perspective positions genome maintenance pathways as upstream intervention points for chronic inflammatory and fibrotic diseases.
    DOI:  https://doi.org/10.1039/d5cb00327j
  32. Exp Neurol. 2026 Mar 31. pii: S0014-4886(26)00115-9. [Epub ahead of print] 115752
    Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.
    Shuhong Wang, Lili Shi, Yin Tian, Jin Wu, Fujian Guo, Anyong Yu.
      Traumatic brain injury (TBI) initiates a complex secondary injury cascade, within which the bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation forms a self-amplifying vicious cycle, termed the "mitochondria-inflammation axis." This axis is increasingly recognized as a core mechanism driving progressive neural damage. Following TBI, impaired mitochondria not only cause bioenergetic failure but also release copious damage-associated molecular patterns (mtDNA, etc.) and reactive oxygen species (ROS), which potently activate innate immune platforms such as the NLRP3 inflammasome and NF-κB signaling. Conversely, the ensuing inflammatory milieu further aggravates mitochondrial damage through oxidative stress and disruption of quality control, creating a feed-forward loop. This review systematically synthesizes recent advances in understanding this axis, highlighting novel concepts like immunometabolic reprogramming of microglia and intercellular mitochondrial transfer. Furthermore, we critically evaluate emerging therapeutic strategies aimed at breaking this cycle, including mitochondria-targeted antioxidants, precise immunomodulators, and pioneering mitochondrial transplantation. By integrating evidence from multi-omics studies and diverse models, this review provides a unified conceptual framework for understanding TBI pathophysiology and illuminates promising avenues for future translational research.
    Keywords:  Immunometabolism; Mitochondria-inflammation axis; Mitochondrial dysfunction; Neuroinflammation; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115752
  33. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123
    Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
    Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.
      Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
    Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia
    DOI:  https://doi.org/10.1073/pnas.2508286123
  34. Free Radic Biol Med. 2026 Mar 26. pii: S0891-5849(26)00250-9. [Epub ahead of print]
    Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.
    Daniela Cortés-Díaz, Claudia Jara, Ítalo Fuentes, Jesús Llanquinao, Matías Lira, Micaela Ricca, Sebastián Valenzuela, Carolina A Oliva, Cheril Tapia-Rojas.
      Lonp1 is the main mitochondrial matrix protease responsible for maintaining mitochondrial proteostasis through the degradation of damaged or misfolded proteins. Although impaired Lonp1 expression or activity has been linked to mitochondrial dysfunction and oxidative stress in peripheral tissues and non-neuronal cells, its role in the brain, and particularly in hippocampal function, remains unexplored. Here, we provide the first in vivo evidence that Lonp1 activity is a critical regulator of mitochondrial redox homeostasis, synaptic integrity, and learning in the hippocampus. We administered the Lonp1 inhibitor Sesamin intranasally to 4-month-old adult Senescent-Acelerated Mouse Prone 8 (SAMP8) mice for 6 weeks. Subsequently, we conducted cognitive tests to assess hippocampal-dependent learning and memory. We also examined Lonp1 proteolytic activity using the FITC-Casein assay, performed Golgi staining to evaluate dendritic spines, and used fluorescent and luminescent probes to investigate mitochondrial function. Interestingly, we selectively impaired Lonp1 function at an early stage of age-related brain vulnerability. Lonp1 inhibition led to the accumulation of mitochondrial Lonp1 substrates and a marked reduction in mitochondrial bioenergetic capacity, as reflected by decreased ATP production and a robust increase in mitochondrial reactive oxygen species (ROS). These redox alterations were accompanied by selective synaptic remodeling, characterized by a reduction in thin dendritic spines without changes in total spine density, and by impaired hippocampus-dependent learning, while memory retention remained preserved. Thus, our findings identify Lonp1 as a previously unrecognized regulator of mitochondrial redox balance and synaptic structure in the hippocampus. Importantly, Lonp1 inhibition recapitulates key features of brain aging, linking defective mitochondrial proteostasis to ROS-driven synaptic vulnerability and cognitive dysfunction. This study establishes Lonp1-dependent mitochondrial quality control as a central node connecting redox dysregulation to synaptic failure and highlights Lonp1 as a novel target for strategies aimed at preserving mitochondrial and cognitive function during aging.
    Keywords:  Lonp1; Mitochondrial dysfunction; SAMP8 mice; hippocampal-dependent learning
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.059
  35. Orphanet J Rare Dis. 2026 Apr 01.
    Optimizing regional rare disease management systems within China's policy framework: practical insights from the shantou experience.
    Beiyan Wu, Yali Wang, Chao Liu, Qilin Wang, Mengchun Gong, Yongsong Chen.
      
    Keywords:  Medical insurance access; Rare disease drug supervision; Rare disease treatment; Shantou experience
    DOI:  https://doi.org/10.1186/s13023-026-04340-3
  36. Hum Gene Ther. 2026 Mar 28. 10430342261430765
    Ethical and Regulatory Considerations for Developing Gene Therapies Involving Genome Editing.
    Pishoy Gouda, Lauren Cohen, Keith Berelowitz, Juli Bollinger, Julianne Bruno, Jeffrey Cehelsky, R Alta Charo, Jamie Harrop, Jeffrey Kahn, Amy L McGuire, Pearl O'Rourke, Naimish Patel, Eugene Patin, Tammy L Reece, Alan Regenberg, Ricardo Rocha, Hannah Webster, Kevin Weinfurt, Jeremy Sugarman, Adrian F Hernandez.
      Developing gene therapies involving gene editing is a rapidly evolving field with large potential implications for improving health for both rare and common diseases. Ensuring that these technologies are developed safely, efficiently, and fairly is essential. To better understand the ethical considerations and regulatory requirements and challenges with gene therapies involving gene editing that may advance precision health. Through a multistakeholder workshop and subsequent engagements, multiple ethical and regulatory barriers to developing and implementing gene therapies involving gene editing were identified. Eight major themes emerged that warrant careful consideration, including (1) objectives (treatment, risk reduction, and enhancement) for the intervention; (2) competing interests of safety, equity, and desire for research efficiencies; (3) unique aspects of gene editing related to rare and ultrarare genetic conditions; (4) considerations in the pediatric population; (5) regulatory requirements and ethics oversight; (6) challenges with long-term follow-up and data sharing; and (7) communication. To promote the safe, efficient development of gene therapies involving gene editing that will reach their full potential, all stakeholders will have to undertake an unprecedented degree of collaboration. However, this will be essential to ensure that these interventions are effective, ethically sound, and patient-centered.
    Keywords:  ethics; gene therapy; regulatory
    DOI:  https://doi.org/10.1177/10430342261430765
  37. Biochem Pharmacol. 2026 Mar 29. pii: S0006-2952(26)00268-6. [Epub ahead of print] 117935
    Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
    Jimna Mohamed Ameer, Sneha Mary Alexander, K Navya, Rajesh A Shenoi, Goutam Chandra.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the midbrain substantia nigra, resulting in debilitating motor and non-motor symptoms. No disease modifying therapy is currently available for PD patients. Mounting evidence implicates impaired mitochondrial quality control (MQC) as a central driver of PD pathogenesis. MQC maintains mitochondrial integrity and function through coordinated mechanisms such as mitochondrial biogenesis, dynamics, mitophagy, the ubiquitin-proteasome system, and the formation of mitochondria-derived vesicles (MDVs). MDVs are small vesicular structures that selectively sequester and transport damaged mitochondrial components to lysosomes for degradation, representing a rapid and localized quality control pathway distinct from mitophagy. Beyond their degradative role, MDVs also participate in inter-organelle signalling and intercellular communication, suggesting a broader influence on neuronal homeostasis. Disruption of MDV biogenesis, trafficking, or clearance has been emerging as a key contributor of mitochondrial dysfunction and neurodegeneration in PD. This review synthesizes current understanding of MDV biology, its integration within the MQC network, role in PD pathogenesis and explores how targeting MDV pathways may offer novel diagnostic and therapeutic strategies to modify disease progression in PD.
    Keywords:  Endolysosome; Mitochondrial dynamics; Mitophagy; SNARE proteins; Transport vesicles; Ubiquitin-protein ligases
    DOI:  https://doi.org/10.1016/j.bcp.2026.117935
  38. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  39. FEBS Open Bio. 2026 Mar 30.
    Intercompartmental communication in senescence.
    Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.
      Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.
    Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence
    DOI:  https://doi.org/10.1002/2211-5463.70236
  40. Aging Dis. 2026 Mar 25.
    Extracellular Vesicles as Key SASP Carriers Driving Cellular Senescence, Inflammaging, and Therapeutic Opportunities in Aging and Age-Related Diseases.
    Syeda Warisha Aamir, Jen-Wei Huang, Abdul Qadeer, Khalid J Alzahrani, Khalaf F Alsharif, Fuad M Alzahrani, Sumbal Zaheen, Abdulwahab Abuderman, Chien-Chin Chen, Shahid Hussain.
      The progressive decline in physiological processes with aging is a complex biological process that increases susceptibility to age-related diseases. Cellular senescence is a primary contributor to this process, a state of sustained cell cycle arrest accompanied by a distinctive secretory profile known as the Senescence-Associated Secretory Phenotype (SASP). In recent years, extracellular vesicles (EVs), including exosomes and microvesicles (MVs), have emerged as key mediators of intercellular communication by carrying bioactive molecules, such as proteins, lipids, and nucleic acids. In this review, we describe how EVs are important SASP vectors that transmit senescent signals to nearby cells, driving immunosenescence, persistent inflammation (inflammaging), and other aging characteristics, such as stem cell exhaustion and genomic instability. Furthermore, we highlight the dual function of EVs as both pathogenic drivers of aging-related dysfunctions and promising therapeutic agents. In addition, we emphasize their potential as diagnostic biomarkers for age-related diseases, including cardiovascular disease, osteoporosis, and Alzheimer's disease. Finally, we explore the emerging therapeutic uses of EVs, particularly those derived from mesenchymal stem cells (MSCs), to promote tissue repair, reduce aging phenotypes, and serve as engineered drug-delivery systems. This study highlights the critical role of EVs in aging mechanisms and establishes them as potent diagnostic and therapeutic tools for anti-aging.
    DOI:  https://doi.org/10.14336/AD.2026.0134
  41. Front Immunol. 2026 ;17 1698136
    Mitochondrial transplantation ameliorates experimental autoimmune encephalomyelitis by modulating the Th17/Treg balance and restoring metabolic homeostasis.
    A Ram Lee, Suh Won Yang, Seon-Yeong Lee, Su Been Jeon, Hye Yeon Kang, Jeong Won Choi, Jin Hyung Park, Ju Hyeon Park, Su Bin Son, Yunju Jeong, Jung Hwan Lee, Woojun Kim, Mi-La Cho.
       Introduction: Mitochondrial dysfunction has been increasingly implicated in the pathogenesis of multiple sclerosis (MS), contributing to oxidative stress, immune dysregulation, and neurodegeneration. Current therapies primarily target inflammation but do not adequately address mitochondrial impairment or progressive tissue damage. This study aimed to evaluate the therapeutic potential of mitochondrial transplantation in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by investigating its effects on immune modulation, mitochondrial function, and tissue integrity.
    Methods: EAE was induced in mice using myelin oligodendrocyte glycoprotein. Isolated mitochondria were administered intravenously, and clinical progression, spinal cord histology, immune cell populations, mitochondrial activity, fibrosis, and gut microbiota composition were assessed. Additionally, human peripheral blood mononuclear cells (PBMCs) from MS patients were co-cultured with mitochondria to examine ATP production, reactive oxygen species levels, and T cell differentiation.
    Results: Mitochondrial transplantation significantly reduced EAE severity, spinal cord inflammation, demyelination, and fibrosis. Treated mice showed increased regulatory T (Treg) cells, reduced T helper 17 (Th17) cells, improved mitochondrial biogenesis, and decreased oxidative stress. Gut microbiome analysis revealed beneficial compositional changes. In human PBMCs, mitochondrial transfer enhanced ATP synthesis, suppressed mitochondrial ROS, and promoted Treg differentiation while inhibiting pro-inflammatory cytokines.
    Discussion: Our findings suggest that mitochondrial transplantation restores mitochondrial function, rebalances immune responses, and mitigates neuroinflammation and fibrosis in EAE. This approach offers a novel therapeutic strategy for MS by addressing both metabolic and immunological drivers of disease progression.
    Keywords:  T cell; experimental autoimmune encephalomyelitis (EAE); mitochondria; multiple sclerosis; spinal cord
    DOI:  https://doi.org/10.3389/fimmu.2026.1698136
  42. J Clin Invest. 2026 Apr 01. pii: e199840. [Epub ahead of print]136(7):
    Genetic analysis of neurodegenerative diseases.
    Maurizio Grassano, Alice B Schindler, Bryan J Traynor, Sonja W Scholz.
      Recent advances in genomic technologies have greatly enhanced our understanding of neurodegeneration. Techniques like whole-genome sequencing, long-read sequencing, and large-scale population studies have expanded the range of identified genetic risk factors, uncovering new disease mechanisms and biological pathways that could serve as therapeutic targets. However, translating these genetic insights into clinical practice remains difficult because of challenges in interpreting variants and the limited functional validation of new discoveries. This Review highlights the key genomic technologies advancing diagnosis and research in neurodegeneration. We focus on improvements in variant classification, detection of structural variants and repeat expansions, and combining transcriptomic, proteomic, and functional data to better determine variant pathogenicity. The ongoing integration of genomics, molecular neurobiology, and data science offers great potential for more accurate, biologically informed diagnosis and treatment of neurodegenerative disorders.
    DOI:  https://doi.org/10.1172/JCI199840
  43. Science. 2026 Apr 02. 392(6793): 24-25
    Mitochondria power immunity against cancer.
    Irene S Molina, Malay Haldar.
      A subset of dendritic cells relies on mitochondrial fitness to trigger antitumor responses in mice.
    DOI:  https://doi.org/10.1126/science.aeg4325
  44. Curr Med Sci. 2026 Apr 02.
    Targeting the Gut-Liver Mitochondria Axis in MASLD: Mechanisms and Therapeutic Perspectives.
    Yu-Hang Wang, Xue-Song He, Li Lin, Lu-Lu Ning, Ya Zhao, Meng-Xiao Zhang, Le Chen, Min Chen.
      The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing continuously, posing a substantial threat to public health. This study examines the critical role of imbalanced interactions within the gut‒liver-mitochondrial axis in MASLD pathogenesis. Dysregulation of mitochondrial homeostasis, including metabolic disturbances, impaired quality control, and disrupted interorganelle interactions, significantly contributes to MASLD progression. Through the gut‒liver axis, the gut microbiota establishes a bidirectional regulatory network with mitochondria. Dysbiosis disrupts mitochondrial homeostasis via multiple pathways, while mitochondrial dysfunction aggravates imbalances in the gut microbiota, creating a vicious cycle. Therefore, in this study, the molecular basis of mitochondrial abnormalities was investigated, and the mechanisms of reciprocal regulation were clarified. Additionally, targeted intervention strategies, including the modulation of mitochondrial homeostasis and the regulation of the gut microbiota, are explored to provide novel therapeutic perspectives for MASLD.
    Keywords:  Gut microbiota; Gut-liver mitochondria axis; Metabolic dysfunction-associated steatotic liver disease (MASLD); Mitochondrial homeostasis; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s11596-026-00190-z
  45. medRxiv. 2026 Mar 25. pii: 2026.03.23.26348537. [Epub ahead of print]
    Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
    Lauren Petri, Sun Ah Lee, David Shire, Samantha Leonard, Alexander Behnke, Jody Greaney, Lacy Alexander, David M Almeida, Martin Picard, Caroline Trumpff.
      The present study analyzes the impact of naturalistic stress and emotions on saliva cell-free mitochondrial DNA (cf-mtDNA) in daily life across two independent cohorts with different temporal resolutions. Study 1 examined the interaction between daily stress and major depressive disorder (MDD) on cf-mtDNA in young adults (n= 18, 8 MDD, 10 controls) across four days. For individuals with MDD, stress exposure was associated with a 68% reduction in cf-mtDNA. A higher number or greater severity of stressors also reduced cf-mtDNA by 24 to 27%. Study 2 extended this framework by implementing a finer temporal resolution, measuring saliva and affective states every hour, up to 20 times per day for 2 days (n = 25). Negative emotions, including stress and frustration, were associated with reductions in cf-mtDNA of 15%, whereas positive emotions, such as happiness and calm, predicted increases of up to 28%. The strength and direction of the effects were person- and context-dependent. These findings suggest that cf-mtDNA does not exhibit a uniform stress response in daily life. Instead, it reflects dynamic signaling shaped by timing, emotional context, and diagnostic status. This work demonstrates that interpreting cf-mtDNA as a stress biomarker in real-world settings requires modeling timing and heterogeneity of effects.
    Highlights: Saliva cf-mtDNA dynamically tracks with psychosocial experience in real-world contexts.Daily stress was associated with marked cf-mtDNA reductions in MDD, revealing stress-contingent vulnerability.Higher stressor load was associated with dose-dependent suppression of cf-mtDNA.At the hourly level, negative emotions predicted lower cf-mtDNA, whereas positive emotions predicted higher levels.cf-mtDNA showed greater sensitivity to psychosocial experience than cf-nDNA, supporting the notion that mitochondrial DNA release is regulated beyond passive cell death.
    DOI:  https://doi.org/10.64898/2026.03.23.26348537
  46. Curr Opin Clin Nutr Metab Care. 2026 May 01. 29(3): 211-213
    Targeting muscle, mitochondria, and microbiome: nutritional and exercise strategies across wasting diseases and conditions.
    Mariëlle P K J Engelen, Barbara S van der Meij.
      
    DOI:  https://doi.org/10.1097/MCO.0000000000001220
  47. Front Aging Neurosci. 2026 ;18 1745455
    Examination of shared gut microbiome signatures in aging and Parkinson's disease.
    Teddy Jia Wei Tng, Sarivin Vanan, Eng-King Tan, Li Zeng, Wilson Wen Bin Goh, Sunny Hei Wong, Kah-Leong Lim.
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder that is characterized clinically by a constellation of motoric deficits including resting tremors, bradykinesia, and rigidity. In recent years, there has been increasing interest in the gut-brain axis with several studies examining the relationship between gut microbiome and PD. Although association studies have reported multidimensional microbiome changes in PD, these observed changes may be confounded by various factors, especially age. Notably, existing literature on gut microbiome tends to consider aging and PD separately. This review thus examines the gut microbiome factors associated with both aging and PD. Our comprehensive analysis of the available literature reveals significant overlaps in gut microbes that are associated with aging and PD. For example, the bacterial genera Akkermansia, and Alistipes have shown increased abundance in both conditions, while Faecalibacterium and Blautia conversely show decreased abundance. Our findings were temporally consistent with more recent studies. These shared gut microbiome signatures were identified in patients across the clinical spectrum of PD symptom severity, and may influence aging and disease pathogenesis via depletion of butyrate, a beneficial anti-inflammatory microbial metabolite, since major producers of butyrate (such as Faecalibacterium and Blautia) were constantly decreased with age (across both Asian and Western populations). Given these observations, we wish to highlight the need to consider age-related factors in understanding microbiome changes in PD; the intersection of which could reveal gut microbes and their corresponding microbial metabolites such as butyrate as potential therapeutic targets for PD.
    Keywords:  Parkinson’s disease; aging; bacterial metabolites; butyrate; gut microbiome
    DOI:  https://doi.org/10.3389/fnagi.2026.1745455
  48. Yale J Biol Med. 2026 Mar;99(1): 233-242
    The Bidirectional Regulatory Role of Neuroimmune Interaction in Neurodevelopment and Neurodegenerative Diseases.
    Junjie Liu, Yangke Wang, Yifan Long, Guangxue Guo, Dong Liu.
      Neurological disorders pose a major public health challenge worldwide, with neuroimmune interaction emerging as a core regulatory mechanism underlying their pathogenesis. This review highlights the progression from static association to dynamic mechanisms between neuroimmune interaction and neurological diseases, filling the research gap in immune function changes during development and aging. We propose a triple regulatory logic framework, including multicellular crosstalk network, context-dependent signaling pathway switching, and host microenvironmental state, which clarifies the bidirectional regulatory patterns of neuroimmune interaction in physiological neurodevelopment and pathological neurodegeneration. Specifically, the neuroimmune system maintains central nervous system (CNS) homeostasis through four core processes during development, while its dysfunction drives chronic neuroinflammation and neurodegeneration via cascading pathological mechanisms. We further discuss clinical translation bottlenecks and targeted intervention strategies based on this framework, providing a theoretical basis for constructing a stage-specific neuroimmune interaction and regulation theory. This review offers new insights into the pathogenesis of neurological diseases and potential therapeutic targets for clinical practice.
    Keywords:  Clinical translation; Neurodegeneration; Neurodevelopment; Neuroimmune Interaction; Staged intervention
    DOI:  https://doi.org/10.59249/XKOG6244
  49. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250081. [Epub ahead of print]381(1947):
    Mitonuclear dynamics in unisexual vertebrates.
    Randy L Klabacka, Geoffrey E Hill, Damian K Dowling, Joel Sharbrough, Robert D Denton, Joshua M Hall, Justin C Havird.
      Sex and mitochondria are inextricably linked in the eukaryotic tree of life, a confounding situation given the uniparental inheritance of mitochondria and the biparental inheritance that sexual reproduction entails. Unisexual vertebrate lineages, which arise via hybridization and asexually pass on their genetic material to clonal descendants, provide a unique opportunity to study mitochondrial evolution without potentially confounding effects of sex. Hybridity and clonality set unisexual vertebrates apart from other vertebrates and establish a distinct genetic environment that shapes their evolution, especially dynamics between mitochondrial and nuclear genomes. Here, we provide a perspective on the mitonuclear genomic interactions experienced by unisexual vertebrates and the implications of these interactions on mitochondrial function and integration into organismal performance and fitness. Building upon the hypothesis that sexual reproduction arose to maintain coadaptation between co-functioning nuclear and mitochondrial genes, we propose that unisexual vertebrates may be confined to predominantly 'young' lineages because mitonuclear incompatibilities-arising from either hybridity or clonality-increase the probability of extinction over time (the Mitonuclear Erosion Hypothesis). We provide a multidisciplinary collection of strategies to disentangle the effects of clonality and hybridity and quantify the relative degree to which these characteristics contribute to differences in mitochondrial function, organismal performance and fitness. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  asexual reproduction; mitochondrial function; mitonuclear incompatibility; unisexual; vertebrates
    DOI:  https://doi.org/10.1098/rstb.2025.0081
  50. Trends Endocrinol Metab. 2026 Mar 31. pii: S1043-2760(26)00046-9. [Epub ahead of print]
    Reprogramming the mitochondrial-circadian energy code with incretins.
    Enzo Nisoli, Maurizio Ragni, Chiara Ruocco, Alessandra Valerio.
      Mitochondrial dysfunction, circadian disruption, and the accumulation of senescent cells converge to impair metabolic flexibility, a unifying phenotype of obesity and aging. We frame obesity as a nutrient-driven and aging as a time-driven expression of a disrupted mitochondrial-circadian energy code, with shared outputs: impaired substrate switching and flattened energy rhythms. This opinion argues that restoring code integrity, indexed clinically by gains in metabolic flexibility, should guide therapy. Beyond appetite and glycemia, GLP-1 (glucagon-like peptide-1) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) agonists may enhance mitochondrial efficiency, support circadian alignment, and temper prosenescent signaling across target tissues (muscle, liver, adipose, islets, and brain). We outline how node-specific and combination strategies (senolytics/senomorphics, mitophagy/NAD+ support, and chrono-entrainment) could reprogram systemic energy coordination, improve durability of response, and delay age-related metabolic decline.
    Keywords:  GLP-1 receptor agonists; GLP-1/GIP dual agonists; circadian rhythms; metabolic flexibility; mitochondrial dysfunction; senescence
    DOI:  https://doi.org/10.1016/j.tem.2026.02.011
  51. Nurs Open. 2026 Apr;13(4): e70488
    Exploring the Intersection of Rare Diseases and Mental Health Within the Diagnostic Odyssey: A Narrative Review and Thematic Synthesis.
    Eileen Wu, Sophie Isobel, Paul Beckett.
       AIM: To explore what is known about the intersection of mental health and rare diseases.
    DESIGN: Narrative review with peer-reviewed literature from 2009 onwards.
    METHODS: The study searched for literature on these databases in September 2024: CINAHL, Scopus, Pubmed, Medline, Embase, and PsycInfo, as well as citation chaining and supplementary searches on Google Scholar. A combination of MeSH headings, keywords, truncations, and proximity searches with Boolean operators was used.
    RESULTS: Relevant literature highlighted four themes that underpinned the intersection of mental health and rare diseases: (1) hope and hopelessness, (2) identity formation and conflicts, (3) connection and disconnection, and (4) access, advocacy, and a lack of service integration.
    CONCLUSION: The narrative review highlighted the complex intersection and poor integration of mental health and rare diseases, where distress and uncertainty are core aspects of the living experience. Despite challenges, hope and resilience persevere.
    IMPLICATIONS: Better understanding of the connection between mental health and rare diseases allows for holistic patient care. It raises awareness for the need for increased proactive mental health services and highlights shared experiences of a broad community. This allows systemic changes to be more feasible and help improve patient outcomes.
    IMPACT: This narrative review deepens knowledge of the complex connections between mental health and rare diseases through a lived experience lens, opening pathways for further research into the unique but shared struggles of the community. Emphasising the need for holistic disease management of physical and psychosocial impacts, nurses and healthcare workers alike are then better equipped to provide tailored care.
    PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution to this paper as the review utilised existing studies and research in the academic field.
    Keywords:  health services; lived experience; mental health; psychological; rare diseases; resilience
    DOI:  https://doi.org/10.1002/nop2.70488
  52. Hum Gene Ther. 2026 Apr 03. 10430342261432669
    Adeno-Associated Virus Gene Delivery to Hard-to-Transduce Tissues: Biological Barriers, Engineering Strategies, and Clinical Challenges.
    Xiaoyu Nan, Jiawen Sun, Yunuo Jiao, Wangan Li, Yujuan Chen, Yurong Liu, Bo Xu, Li Yu, Wenyan Guo, Yang Wu.
      Adeno-associated virus (AAV) is widely regarded as a leading vector for gene therapy, underscored by clinical successes such as Luxturna and Zolgensma. However, efficient gene delivery to hard-to-transduce tissues-including the retina, deep skeletal muscle, and the central nervous system-remains a significant challenge, limited by structural barriers, preexisting immunity, and dose-dependent toxicities. This review systematically outlines recent advances in overcoming these delivery bottlenecks. We delve into four key strategic areas: (i) capsid engineering (e.g., rational design, directed evolution, and computational approaches) to enhance tropism and evade immune detection; (ii) innovative delivery routes (local, systemic, and physical/chemical methods) to improve vector bioavailability; (iii) modulation of intracellular trafficking to boost nuclear delivery; and (iv) immunomodulatory strategies to mitigate both innate and adaptive immune responses. We further highlight translational progress in neuromuscular and retinal diseases and discuss persistent challenges. Looking forward, we envision that the convergence of next-generation capsids, smart vector systems, and integrated delivery platforms will be critical to expand the therapeutic landscape of AAVs from rare monogenic disorders to broader clinical applications.
    Keywords:  adeno-associated virus; delivery strategies; gene therapy; hard-to-transduce tissues; vector engineering
    DOI:  https://doi.org/10.1177/10430342261432669
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