bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–05–04
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
  2. Ramping up mitochondrial DNA replication.
  3. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
  4. Spectrum of clinical neuroimaging in mitochondrial disorders: a neuroanatomical approach.
  5. Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.
  6. Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
  7. Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
  8. Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
  9. Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
  10. Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
  11. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
  12. 4D mitochondrial network assumes distinct and predictive phenotypes through human lung and intestinal epithelial development.
  13. High Content Analysis of Mitochondrial Function in Induced Pluripotent Stem Cell-Derived Neurons.
  14. Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effects.
  15. Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
  16. Mitochondria - the CEO of the cell.
  17. Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.
  18. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  19. The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.
  20. Label-Free Visualization and Segmentation of Endothelial Cell Mitochondria Using Holotomographic Microscopy and U-Net.
  21. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  22. Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.
  23. Uncovering Mitochondrial Defects Induced by Chemicals: A Case Study of Low-Dose Medium-Chain Chlorinated Paraffin Exposure.
  24. Impairment of Muscle Function Causes Pupal Lethality in Flies Expressing the Mitochondrial Alternative Oxidase.
  25. Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review.
  26. Pleiotropic effects of MORC2 derive from its epigenetic signature.
  27. NAD augmentation as a disease-modifying strategy for neurodegeneration.
  28. Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
  29. Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.
  30. Recent advances in mitochondrial transplantation to treat disease.
  31. Nucleic acid sequence determinants of transcriptional pausing by human mitochondrial RNA polymerase (POLRMT).
  32. Precision medicine in the pediatric and neonatal intensive care units through genomics.
  33. Neuronal C/EBPβ Shortens the Lifespan via Inactivating NAMPT.
  34. Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
  35. Progress with stem cell therapy in Parkinson's disease.
  36. Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.
  37. DPP8/9 processing of human AK2 unmasks an IAP binding motif.
  38. Clozapine blunts mitochondrial biogenesis in differentiating adipocytes: The increased ATP demand is met via stimulation of electron transport chain expression and activity in residual mitochondria.
  39. Systematic review of mitochondrial dysfunction and oxidative stress in aging: A focus on neuromuscular junctions.
  40. Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model of severe malnutrition.
  41. Coenzyme Q10 and the Blood-Brain Barrier: An Overview.
  42. The application of Large Language Models to the phenotype-based prioritization of causative genes in rare disease patients.
  43. Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.
  44. The Multifaceted Role of LRRK2 in Parkinson's Disease.
  45. A tissue-specific atlas of protein-protein associations enables prioritization of candidate disease genes.
  46. Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies-A Comprehensive Narrative Review.
  47. Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.
  48. Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.
  49. Altering metabolism programs cell identity via NAD+-dependent deacetylation.
  50. Rapid Whole-Genome Sequencing in Critically Ill Infants and Children with Suspected, Undiagnosed Genetic Diseases: Evolution to a First-Tier Clinical Laboratory Test in the Era of Precision Medicine.
  51. Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
  52. T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
  53. Regional differences in progenitor metabolism shape brain growth during development.
  54. Stem cells as role models for reprogramming and repair.
  55. Regulation of translation elongation and integrated stress response in heat-shocked neurons.
  56. AlphaMissenseR: an integrated framework for investigating missense mutations in human protein-coding genes.
  57. Precision nutrition for cardiometabolic diseases.
  58. Potential and value of rescuing dying neurons.
  59. Bystander editing by adenine base editors impairs vision restoration in a mouse model of Leber congenital amaurosis.
  60. Revealing secrets of human genetic variation with population databases.
  1. Am J Hum Genet. 2025 Apr 23. pii: S0002-9297(25)00144-2. [Epub ahead of print]
    Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
    Solve-RD Consortium
      The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed "phenotype test cohort" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.
    Keywords:  Solve-RD; bioinformatics; mitochondrial DNA; phenotype similarity; reanalysis
    DOI:  https://doi.org/10.1016/j.ajhg.2025.04.003
  2. Nat Rev Drug Discov. 2025 May 02.
    Ramping up mitochondrial DNA replication.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-025-00079-x
  3. Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]
    NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
    Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
    Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
  4. Pediatr Radiol. 2025 May 02.
    Spectrum of clinical neuroimaging in mitochondrial disorders: a neuroanatomical approach.
    Kate Kielty, John Collyer, Krrithvi Dharini Ganesh, Srikala Narayanan, Deepa S Rajan.
      Mitochondrial disorders are a highly heterogeneous group of genetic diseases that impact pathways associated with the structure and function of the mitochondrion. Clinical presentations of mitochondrial disorders include a wide range of onset, progression, and spectrum of neurological symptoms - ranging from episodic, focal neurological deficits to gradual onset of developmental delays, sensorineural hearing loss, visual impairment, or ataxia. This variability provides clinicians with a diagnostic challenge in identifying suspicion of a mitochondrial disorder and prioritizing specific mitochondrial disorders within their differential. While next-generation sequencing of both the nuclear and mitochondrial genomes has aided identification of mitochondrial disorders, testing results are typically not available for weeks to months, and CSF and biochemical studies indicating possible mitochondrial disorder, such as elevated lactate, are nonspecific in differentiating between mitochondrial disorders and other neurogenetic diseases. Neuroimaging can serve as an early tool to help identify specific mitochondrial disorders; however, there are additional variability and overlap between disorders and other non-mitochondrial diseases. This review provides a framework in narrowing the mitochondrial differential by neuroanatomical localization on neuroimaging studies. We will highlight established neuroimaging patterns associated with mitochondrial disorders, review the role of MRS, and discuss the alternative non-mitochondrial etiologies associated with these findings.
    Keywords:  MRI; Metabolic disorders; Mitochondrial disorders; Neuroanatomy; Neurogenetics; Neuroimaging
    DOI:  https://doi.org/10.1007/s00247-025-06252-z
  5. Commun Med (Lond). 2025 Apr 27. 5(1): 141
    Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.
    Simon Ulvenes Kverneng, Kjersti Eline Stige, Haakon Berven, Sepideh Mostafavi, Katarina Lundervold, Michele Brischigliaro, Brage Brakedal, Geir Olve Skeie, Irene Hana Flønes, Lilah Toker, Erika Fernandez-Vizarra, Ragnhild Eide Skogseth, Kristoffer Haugarvoll, Yamila N Torres Cleuren, Christian Dölle, Gonzalo S Nido, Charalampos Tzoulis.
       BACKGROUND: Widespread neuronal mitochondrial complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson's disease (PD). Here, we sought to determine whether a CI-deficient subgroup could be discerned using clinically accessible muscle biopsies. We further hypothesized that the inconsistency of previous findings of mitochondrial respiratory impairment in PD muscle may be due to interindividual variation, with respiratory deficiency only occurring in a subgroup of cases.
    METHODS: Using a cross-sectional design, vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for CI and complex IV (CIV), cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples.
    RESULTS: We show that PD muscle exhibits reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. In contrast, the activities of CII-CIV are not significantly different between the PD and control groups. No quantitative change of CI or CIV is detected, and the observed functional CI deficiency is not associated with mtDNA abnormalities.
    CONCLUSIONS: Our findings support the existence of a PD subpopulation characterized by CI pathology in skeletal muscle and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.
    DOI:  https://doi.org/10.1038/s43856-025-00817-7
  6. Nat Metab. 2025 May 02.
    Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
    Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.
      Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.
    DOI:  https://doi.org/10.1038/s42255-025-01272-3
  7. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141
    Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
    Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.
      Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.
    Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane
    DOI:  https://doi.org/10.1177/25152564251332141
  8. Res Sq. 2025 Apr 09. pii: rs.3.rs-6330979. [Epub ahead of print]
    Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
    David Sherwood, Siddharthan Balachandar Thendral, Sasha Bacot, Katherine Morton, Qiuyi Chi, Isabel Kenny-Ganzert, Joel Meyer.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, metabolic health throughout progeny lifetime, and future generation endurance. High levels of endogenous reactive oxygen species and exogenous toxicants are threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in developed oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here we discover that in C. elegans, the onset of oocyte-to-zygote transition (OZT) developmentally triggers a rapid mitophagy event. We show that mitophagy at OZT (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway, and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Impaired MOZT leads to increased deleterious mtDNA inheritance and decreases embryonic survival. Inherited mtDNA damage accumulates across generations, leading to the extinction of descendent populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity.
    DOI:  https://doi.org/10.21203/rs.3.rs-6330979/v1
  9. Genes Dis. 2025 Jul;12(4): 101437
    Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
    Ye Hong, Ying Song, Wenjun Wang, Jinghui Shi, Xi Chen.
      Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.
    Keywords:  Base editor; CRISPR-Cas9; Mitochondrial DNA; Neurodegenerative diseases; mitoTALENs; mitoZFNs
    DOI:  https://doi.org/10.1016/j.gendis.2024.101437
  10. EMBO Rep. 2025 Apr 29.
    Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
    Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.
      Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.
    Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1
    DOI:  https://doi.org/10.1038/s44319-025-00459-9
  11. Aging Cell. 2025 Apr 25. e70054
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
    Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.
      Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.
    Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria
    DOI:  https://doi.org/10.1111/acel.70054
  12. bioRxiv. 2025 Apr 10. pii: 2025.04.09.648043. [Epub ahead of print]
    4D mitochondrial network assumes distinct and predictive phenotypes through human lung and intestinal epithelial development.
    Gillian McMahon, Dhruv Agarwal, Mehul Arora, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg.
      Mitochondria form a dynamic three-dimensional network within the cell that exhibits a wide range of morphologies and behaviors. Depending on cell state, cell type, and cell fate, a cell's mitochondrial phenotype might range from relatively isolated mitochondrial segments to complex branching networks, and from stationary mitochondria to highly motile structures. While isolated mitochondrial phenotypes have been described for a subset of cell states, types, and fates, an integrated map of how mitochondrial phenotypes change over the full course of tissue development has so far been lacking. Here, we identify the mitochondrial phenotypes that appear throughout the course of lung and intestinal epithelial development from stem cells to differentiated tissue. Using human stem cell-derived intestinal and branching lung organoids that mimic developing human organs as model systems, we extract and analyze key mitochondrial biophysical phenotypes in human development. To achieve this, we employ lattice light-sheet microscopy (LLSM), which enables high-resolution, 4D (x, y, z, time) imaging of mitochondria in organoid tissues with minimal damage to the sample. We image at key developmental time points from stem cell differentiation into mature organoid tissue. For data processing, we utilize the MitoGraph and MitoTNT software packages along with our developed custom computational tools. These tools allow for automated 4D organoid to single cell image processing and quantitative 4D single cell mitochondrial temporal network tracking. This work represents the first 4D high spatiotemporal-resolution quantification of live human organoid tissues at the single-cell level through development. We identified distinct mitochondrial phenotypes unique to each organoid type and found correlations between mitochondrial phenotypes, cellular age, and cell type. Furthermore, we demonstrate that mitochondrial network characteristics can predict both organoid type and cell age. Our findings reveal fundamental aspects of mitochondrial biology that were previously unobservable, offering new insights into cell-type-specific mitochondrial dynamics and enabling new findings in relevant human model systems. We believe that our findings and methods will be essential for advancing 4D cell biology, providing a powerful framework for characterizing organelles in organoid tissues.
    DOI:  https://doi.org/10.1101/2025.04.09.648043
  13. Methods Mol Biol. 2025 ;2924 259-268
    High Content Analysis of Mitochondrial Function in Induced Pluripotent Stem Cell-Derived Neurons.
    Daniel Little, Christin Luft, Olukunbi Mosaku, Robin Ketteler, Michael J Devine, Paul Gissen.
      Mitochondrial dysfunction is linked to many neurological diseases; therefore, the ability to measure mitochondrial function is of great use for researching disease and testing potential therapeutics. Here we describe a high-content assay to simultaneously measure mitochondrial membrane potential, morphology, and cell viability in iPSC-derived neurons. Neurons are seeded into plates suitable for fluorescent microscopy, and stained with the mitochondrial membrane potential-dependent dye TMRM, cytoplasmic dye Calcein-AM, and nuclear stain Hoechst-33,342. Images are acquired in live cells and analyzed using automated image analysis software.
    Keywords:  High content screening; Image analysis; Induced pluripotent stem cells; Mitochondria; Neurons
    DOI:  https://doi.org/10.1007/978-1-0716-4530-7_19
  14. Biomed Pharmacother. 2025 Apr 27. pii: S0753-3322(25)00250-1. [Epub ahead of print]187 118056
    Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effects.
    Hani N Sabbah, Nathan N Alder, Genevieve C Sparagna, James E Bruce, Brian L Stauffer, Luke H Chao, Robert D S Pitceathly, Christoph Maack, David J Marcinek.
      Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide's MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide's ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide's MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.
    Keywords:  Barth syndrome; Cardiolipin; Elamipretide; MOA; Mechanism; Mitochondria
    DOI:  https://doi.org/10.1016/j.biopha.2025.118056
  15. Curr Stem Cell Res Ther. 2025 Apr 25.
    Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
    Jingyi Chen, Zhilang Xie, Huayin Zhou, Yingxin Ou, Wenwen Tan, Aizhen Zhang, Yuying Li, Xingliang Fan.
      Mesenchymal stem cells (MSCs) hold transformative potential in translational medicine due to their versatile differentiation abilities and regenerative properties. Notably, MSCs can transfer mitochondria to unrelated cells through intercellular mitochondrial transfer, offering a groundbreaking approach to halting the progression of mitochondrial diseases and restoring function to cells compromised by mitochondrial dysfunction. Although MSC mitochondrial transfer has demonstrated significant therapeutic promise across a range of diseases, its application in clinical settings remains largely unexplored. This review delves into the novel mechanisms by which MSCs execute mitochondrial transfer, highlighting its profound impact on cellular metabolism, immune modulation, and tissue regeneration. We provide an in-depth analysis of the therapeutic potential of MSC mitochondrial transfer, particularly in treating mitochondrial dysfunction-related diseases and advancing tissue repair strategies. Additionally, we propose innovative considerations for optimizing MSC mitochondrial transfer in clinical trials, emphasizing its potential to reshape the landscape of regenerative medicine and therapeutic interventions.
    Keywords:  Mesenchymal stem cells; immunomodulation; mitochondrial transfer; oxidative stress; therapeutic potential.
    DOI:  https://doi.org/10.2174/011574888X362739250416153254
  16. J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):
    Mitochondria - the CEO of the cell.
    Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.
      As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.
    Keywords:  Mitochondria; Organelle; mtDNA
    DOI:  https://doi.org/10.1242/jcs.263403
  17. medRxiv. 2025 Apr 12. pii: 2025.04.09.25325473. [Epub ahead of print]
    Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.
    Caroline Trumpff, David Shire, Jeremy Michelson, Natalia Bobba-Alves, Temmie Yu, Richard P Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.
      Human blood contains cell-free mitochondrial DNA (cf-mtDNA) that dynamically increases in concentration in response to acute mental stress. Like other neuroendocrine stress markers, we previously found that cf-mtDNA is also detectable in saliva, calling for studies examining saliva cf-mtDNA reactivity to mental stress. In healthy women and men from the MiSBIE (Mitochondrial Stress, Brain Imaging, and Epigenetics) study (n=68, 66% women), a brief socio-evaluative stressor induced a striking 280% or 2.8-fold increase in saliva cf-mtDNA concentration within 10 minutes (g=0.55, p<0.0001). In blood drawn concurrently with saliva sampling, stress increased cf-mtDNA by an average 32% at 60 min in serum (g=0.20), but not in anticoagulated plasma where cf-mtDNA decreased by 19% at 60 min (g=0.25). Examining the influence of mitochondrial health on cf-mtDNA reactivity in participants with rare mitochondrial diseases (MitoD), we report that a subset of MitoD participants exhibit markedly blunted saliva cf-mtDNA stress reactivity, suggesting that bioenergetic defects within mitochondria may influence the magnitude of saliva, and possibly blood cf-mtDNA responses. Our results document robust saliva cf-mtDNA stress reactivity and provide a methodology to examine the psychobiological regulation of cell-free mitochondria in future studies.
    DOI:  https://doi.org/10.1101/2025.04.09.25325473
  18. Nat Commun. 2025 Apr 29. 16(1): 4029
    Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
    DOI:  https://doi.org/10.1038/s41467-025-59427-5
  19. Hum Mol Genet. 2025 Apr 29. pii: ddaf061. [Epub ahead of print]
    The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.
    Claire Almyre, Nolwenn Bounaix, François Godard, Olivier R Baris, Anne-Louise Cayer, Elodie Sardin, Marine Bouhier, Anaïs Hoarau, Laetitia Dard, Jérémy Richard, Vanessa Bergeron, Aurélie Renaud, Nadege Loaëc, Naïg Gueguen, Valérie Desquiret-Dumas, Bénédicte Lelievre, Aurore Inisan, Cristina Panozzo, Genevève Dujardin, Marc Blondel, Agnes Rötig, Véronique Paquis-Flucklinger, Stéphane Azoulay, Nathalie Bonnefoy, Carole H Sellem, Agnès Delahodde, Vincent Procaccio, Déborah Tribouillard-Tanvier.
      The copper ionophore disulfiram (DSF) is commonly used to treat chronic alcoholism and has potential anti-cancer activity. Using a yeast-based screening assay of FDA-approved compounds, DSF was herein identified for its ability to improve oxidative phosphorylation-dependent growth of various yeast models of mitochondrial diseases caused by a wide range of defects in ATP synthase, complexes III and IV, cardiolipin remodeling, maintenance and translation of the mitochondrial genome. This compound also showed beneficial effects in cells derived from patients suffering from Barth or MELAS syndromes, two mitochondrial diseases associated respectively with a lack in cardiolipin remodeling and protein synthesis inside the organelle. We provide evidence that the rescuing activity of DSF results from its ability to transport copper ions across biological membranes. Indeed, other copper ionophores (pyrithione and elesclomol) and supplementation of the growth media with copper ions had also beneficial effects in yeast and human cells with dysfunctional mitochondria. Our data suggest that the copper-dependent rescuing activity in these cells results from a better capacity to assemble cytochrome c oxidase. Altogether, our findings hold promise for the development of new therapeutic strategies for mitochondrial disorders.
    Keywords:  Mitochondrial diseases; copper; disulfiram; drug repositioning; oxidative phosphorylation
    DOI:  https://doi.org/10.1093/hmg/ddaf061
  20. Chem Biomed Imaging. 2025 Apr 28. 3(4): 225-231
    Label-Free Visualization and Segmentation of Endothelial Cell Mitochondria Using Holotomographic Microscopy and U-Net.
    Raul Michael, Tallah Modirzadeh, Tahir Bachar Issa, Patrick Jurney.
      Understanding the physiological processes underlying cardiovascular disease (CVD) requires examination of endothelial cell (EC) mitochondrial networks, because mitochondrial function and adenosine triphosphate production are crucial in EC metabolism, and consequently influence CVD progression. Although current biochemical assays and immunofluorescence microscopy can reveal how mitochondrial function influences cellular metabolism, they cannot achieve live observation and tracking changes in mitochondrial networks through fusion and fission events. Holotomographic microscopy (HTM) has emerged as a promising technique for real-time, label-free visualization of ECs and their organelles, such as mitochondria. This nondestructive, noninterfering live cell imaging method offers unprecedented opportunities to observe mitochondrial network dynamics. However, because existing image processing tools based on immunofluorescence microscopy techniques are incompatible with HTM images, a machine-learning model is required. Here, we developed a model using a U-net learner with a Resnet18 encoder to identify four classes within HTM images: mitochondrial networks, cell borders, ECs, and background. This method accurately identifies mitochondrial structures and positions. With high accuracy and similarity metrics, the output image successfully provides visualization of mitochondrial networks within HTM images of ECs. This approach enables the study of mitochondrial networks and their effects, and holds promise in advancing understanding of CVD mechanisms.
    DOI:  https://doi.org/10.1021/cbmi.4c00100
  21. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  22. Exerc Sport Sci Rev. 2025 May 01.
    Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.
    Maya Semel, Cole Lukasiewicz, Russell T Hepple.
       ABSTRACT: Our Perspective for Progress highlights sex differences in skeletal muscle mitochondrial function that evolve with aging, with an influence of denervation emerging in advanced age. Gaps include knowledge about mitochondrial alterations in microdomains of muscle fibers, plasticity of the mitochondrial reticulum to acute muscle contractions, and advanced age of both sexes.
    Keywords:  Mitochondria; aging; denervation; heterogeneity; skeletal muscle
    DOI:  https://doi.org/10.1249/JES.0000000000000364
  23. Environ Sci Technol. 2025 Apr 28.
    Uncovering Mitochondrial Defects Induced by Chemicals: A Case Study of Low-Dose Medium-Chain Chlorinated Paraffin Exposure.
    Ningbo Geng, Shuangshuang Chen, Yangyang Bian, Chengcheng Shi, Chenhao Huang, Lin Cheng, Yun Luo, Ying Yu, Yuan Gao, Li Wang, Haijun Zhang, Yufeng Gong, Jiping Chen.
      Given the susceptibility of mitochondria to environmental pollutants, mitochondrial defects are critical end points for chemical safety evaluation. In this study, we present a comprehensive strategy for assessing mitochondrial toxicity, exemplified through a case study on medium-chain chlorinated paraffins (MCCPs, CxH2x+2-yCly with 14-17 carbon atoms), one of the most abundant organic pollutants in the human body. Our results demonstrate that MCCP exposure at levels commonly found in humans significantly reduces cellular ATP content by impairing mitochondrial respiration rather than glycolysis. Using an optimized mitochondrial metabolomics approach combined with dose-resolved proteomics, we elucidated the molecular mechanisms underlying MCCP-induced mitochondrial defects, including inhibition of the electron transport chain, mitochondrial membrane damage, accumulation of reactive oxygen species, and disruptions in nucleotide metabolism. Notably, over 80% of the MCCP-regulated mitochondrial proteins exhibited EC50 values below the human internal levels of MCCPs, highlighting a significant threat to human health. This proposed strategy for mitochondrial toxicity assessment is expected to facilitate future research in mitochondrial toxicology.
    Keywords:  MCCPs; Seahorse respirometry; TCA; mitochondrial metabolomics; oxidative phosphorylation; proteomics-based dose−response curve
    DOI:  https://doi.org/10.1021/acs.est.4c09460
  24. Biomolecules. 2025 Apr 11. pii: 570. [Epub ahead of print]15(4):
    Impairment of Muscle Function Causes Pupal Lethality in Flies Expressing the Mitochondrial Alternative Oxidase.
    Carlos A Couto-Lima, Sina Saari, Geovana S Garcia, Gabriel H Rocha, Johanna Ten Hoeve, Eric Dufour, Marcos T Oliveira.
      The mitochondrial alternative oxidase (AOX) from the tunicate Ciona intestinalis has been explored as a potential therapeutic enzyme for human mitochondrial diseases, yet its systemic effects remain poorly understood. Here, we investigate the metabolic and physiological consequences of AOX expression during the development of Drosophila cultured under dietary stress. We show that the combination of strong, ubiquitous AOX expression and a low-nutrient condition leads to pupal lethality and severe defects in larval musculature, characterized by actin aggregation and muscle shortening. These structural abnormalities correlate with a decrease in larval biomass and motility. Interestingly, the muscle defects and the motility impairments vary in severity among individuals, predicting survival rates at the pupal stage. AOX expression in specific tissues (muscle, nervous system or fat body) does not individually recapitulate the lethal phenotype observed with ubiquitous expressions of the enzyme, indicating a complex metabolic imbalance. Metabolomic analysis revealed that the low-nutrient diet and AOX expression have opposite effects on most metabolites analyzed, especially in the levels of amino acids. Notably, supplementation of the low-nutrient diet with the essential amino acids methionine and/or tryptophan partially rescues pupal viability, body size, muscle morphology, and locomotion, whereas supplementation with proline and/or glutamate does not, highlighting a specific perturbation in amino acid metabolism rather than general bioenergetic depletion. These findings demonstrate that AOX expression disrupts metabolic homeostasis, with developmental and physiological consequences that must be considered when evaluating AOX for therapeutic applications.
    Keywords:  amino acid metabolism; mitochondria; musculature; nutrient deprivation; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/biom15040570
  25. Hum Mutat. 2025 ;2025 9326326
    Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review.
    Jun Kido, Keishin Sugawara, Sotiria Tavoulari, Georgios Makris, Véronique Rüfenacht, Kimitoshi Nakamura, Edmund R S Kunji, Johannes Häberle.
      Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in SLC25A13. The disease presents with age-dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult-onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to "adolescent and adult citrin deficiency," AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post-NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G>A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (< -2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain SLC25A13 genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post-NICCD cases and 49% (20/41) of AACD patients.
    Keywords:  SLC25 mitochondrial carrier family; citrin deficiency; mitochondrial aspartate/glutamate carrier; mitochondrial disease; urea cycle disorders
    DOI:  https://doi.org/10.1155/humu/9326326
  26. Brain. 2025 Apr 30. pii: awaf159. [Epub ahead of print]
    Pleiotropic effects of MORC2 derive from its epigenetic signature.
    Fatemeh Peymani, Tomohiro Ebihara, Dmitrii Smirnov, Robert Kopajtich, Masahiro Ando, Enrico Bertini, Rosalba Carrozzo, Daria Diodato, Felix Distelmaier, Fang Fang, Daniele Ghezzi, Maja Hempel, Katarzyna Iwanicka-Pronicka, Thomas Klopstock, Sarah L Stenton, Costanza Lamperti, Zhimei Liu, Aysylu Murtazina, Yuji Okamoto, Yasushi Okazaki, Dorota Piekutowska-Abramczuk, Agnés Rötig, Oxana Ryzhkova, Christian Schlein, Olga Shagina, Hiroshi Takashima, Polina G Tsygankova, Michael Zech, Thomas Meitinger, Masaru Shimura, Kei Murayama, Holger Prokisch.
      Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes -ERCC8, NDUFAF2, and FKTN- at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.
    Keywords:  CMT; Leigh syndrome; MORC2; episignature; multi-omics; pleiotropy
    DOI:  https://doi.org/10.1093/brain/awaf159
  27. Trends Endocrinol Metab. 2025 Apr 25. pii: S1043-2760(25)00070-0. [Epub ahead of print]
    NAD augmentation as a disease-modifying strategy for neurodegeneration.
    Christian Dölle, Charalampos Tzoulis.
      Neurodegenerative diseases (NDDs) pose a significant and rapidly growing global health challenge, but there are no effective therapies to delay or halt progression. In recent years augmentation of nicotinamide adenine dinucleotide (NAD) has emerged as a promising disease-modifying strategy that targets multiple key disease pathways across multiple NDDs, such as mitochondrial dysfunction, energy deficits, proteostasis, and neuroinflammation. Several early clinical trials of NAD augmentation have been completed, and many more are currently underway, reflecting the growing optimism and urgency within the field. We discuss the rationale and evolving therapeutic landscape of NAD augmentation. We argue that, to fully realize its therapeutic potential, it is essential to determine the specific contexts in which NAD supplementation is most effective and to address crucial knowledge gaps.
    Keywords:  Parkinson's disease; neurodegenerative disease; therapeutic
    DOI:  https://doi.org/10.1016/j.tem.2025.03.013
  28. Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]
    Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
    Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.
      Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.
    Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
  29. Antioxidants (Basel). 2025 Mar 28. pii: 401. [Epub ahead of print]14(4):
    Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.
    Giuseppe Petito, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Gilda Cobellis, Antonia Lanni, Flora Guerra, Cecilia Bucci, Rosalba Senese, Roberta Romano.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of upper and lower motor neurons in the brain, brainstem and spinal cord. About 10% of familial ALS cases are linked to pathogenetic substitution in TARDBP, the gene encoding the TDP-43 protein. A novel rare causative variant in TARDBP (p.G376D) was recently reported in ALS patients. It leads to TDP-43 cytoplasmic mislocalization, increased oxidative stress and reduced cell viability. However, functional studies on the effects of this molecular defect have not yet been carried out. Mitochondria are highly dynamic organelles, and their deregulation has emerged as a key factor in many diseases, among which is ALS. Therefore, this study aimed at determining the impact of this causative variant on mitochondria. In cellular models expressing TDP-43G376D and in fibroblasts derived from patients carrying this molecular defect, we observed alterations of mitochondrial functionality. We demonstrated increased localization of the mutated protein to mitochondria and a reduced abundance of subunits of complex I and complex II of the mitochondrial respiratory chain, associated with a decrease in mitochondrial membrane potential, in cellular respiration and in cytochrome C oxidase (COX) activity. Moreover, ALS cells showed increased mitochondrial fragmentation and reduced abundance of antioxidant enzymes causing increased oxidative stress. These results expand our knowledge about the molecular mechanisms underlying ALS pathogenesis associated with TDP-43 p.G376D and could help to identify new therapeutic strategies to counteract this disease.
    Keywords:  TARDBP; TDP-43; amyotrophic lateral sclerosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/antiox14040401
  30. Biomater Transl. 2025 ;6(1): 4-23
    Recent advances in mitochondrial transplantation to treat disease.
    Xiangling Li, Yanjun Guan, Chaochao Li, Haofeng Cheng, Jun Bai, Jinjuan Zhao, Yu Wang, Jiang Peng.
      Mitochondrial transplantation (MT), an innovative regenerative technique widely used to treat diseases caused by mitochondrial dysfunction, shows great promise for clinical application. This procedure can increase the number of mitochondria and improve the function of damaged mitochondria, resulting in increased adenosine triphosphate levels, decreased reactive oxygen species production, improved Ca2+ buffering capacity, modulated inflammatory response, and reduced apoptosis to protect cells, thus promoting tissue repair. In this review, we describe research advances in MT over the last five years, focusing on its application in treating various diseases, including ischaemic injuries (of the kidney, heart, lung, and liver), neurodegenerative disorders, spinal cord injury, sepsis, diabetes mellitus, stroke, and ultraviolet radiation injuries, as well as in procedures such as organ transplantation, focusing on instances where MT demonstrated good efficacy. We also cover the application of engineered mitochondria and mitochondrial combination therapies and present the latest advances in improving MT efficiency, as well as the current clinical applications and shortcomings of MT, aiming to provide a theoretical foundation for enhanced MT utilisation in the future.
    Keywords:  cardiovascular diseases; ischaemia/reperfusion injury; mitochondrial dysfunction; mitochondrial transplantation; neurodegenerative diseases
    DOI:  https://doi.org/10.12336/biomatertransl.2025.01.002
  31. bioRxiv. 2025 Apr 26. pii: 2025.04.25.650729. [Epub ahead of print]
    Nucleic acid sequence determinants of transcriptional pausing by human mitochondrial RNA polymerase (POLRMT).
    An H Hsieh, Tatiana V Mishanina.
      Transcription by RNA polymerase (RNAP) lies at the heart of gene expression in all organisms. The speed with which RNAPs produce the RNA is tuned in part by the signals in the transcribed nucleic-acid sequences, which temporarily arrange RNAPs into a paused conformation unable to extend the RNA. In turn, the altered transcription kinetics determines the three-dimensional shape into which RNA ultimately folds, dictates the chromatin state, and promotes or inhibits co-transcriptional events. While pause sequence determinants have been characterized for multi-subunit RNAPs in bacteria and the eukaryotic nuclei, this information is lacking for the single-subunit RNAP of human mitochondria, POLRMT. Here, we developed a robust nucleic-acid scaffold system to reconstitute POLRMT transcription in vitro and identified multiple transcriptional pause sites on the human mitochondrial genomic sequence (mtDNA). Using one of the pause sequences as a representative, we performed a suite of mutational studies to pinpoint the nucleic-acid elements that enhance, weaken, or completely abolish POLRMT pausing. Finally, a search of the human mtDNA for the pause motif revealed multiple predicted pause sites, with potential roles in mitochondrial co-transcriptional processes.
    DOI:  https://doi.org/10.1101/2025.04.25.650729
  32. Curr Opin Pediatr. 2025 Apr 14.
    Precision medicine in the pediatric and neonatal intensive care units through genomics.
    Phan Q Duy, Benjamin Dylik, Engin Deniz.
       PURPOSE OF REVIEW: Genome-wide sequencing technologies have revolutionized the understanding of human disorders and advanced precision medicine, especially for pediatric disorders. Here, we discuss the utility of genomic technologies in advancing the care of children admitted to the pediatric and neonatal intensive care units.
    RECENT FINDINGS: Rapid molecular diagnosis permitted by genomic medicine has yielded clinically actionable findings that influence decision-making and facilitate timely therapeutic interventions. Identifying a genetic association provides a causal anchor to understanding disease biology at the single nucleotide resolution, revealing hidden biological heterogeneity that may be obscured by traditional imaging, laboratory, and pathological workup. The importance of a genetic diagnosis is further highlighted by the promise of gene therapy to correct the underlying genetic perturbation, as evidenced by the recent emergence of FDA-approved gene therapies for childhood genetic conditions.
    SUMMARY: We predict that whole-genome sequencing, in conjunction with other omic technologies, will become critical diagnostic adjuncts in the clinical workup of critically ill children.
    Keywords:  molecular diagnosis; multiomics; next-generation sequencing; precision medicine; whole-exome sequencing; whole-genome sequencing
    DOI:  https://doi.org/10.1097/MOP.0000000000001471
  33. Adv Sci (Weinh). 2025 Apr 30. e2414871
    Neuronal C/EBPβ Shortens the Lifespan via Inactivating NAMPT.
    Bowei Li, Zhongyun Xie, Mengmeng Wang, Shuke Nie, Zhengjiang Qian, Xin Meng, Xia Liu, Seong Su Kang, Keqiang Ye.
      The brain plays a central role in aging and longevity in diverse model organisms. Morphological and functional alteration in the aging brain elicits age-associated neuronal dysfunctions. However, the primary mechanism deteriorating the brain functions to regulate the aging process remains incompletely understood. Here, it is shown that neuronal CCAAT/enhancer binding protein β (C/EBPβ) escalation during aging dictates the frailty and lifespan via inactivating nicotinamide phosphoribosyltransferase (NAMPT). Upregulated C/EBPβ drives neuronal senescence and neuronal loss, associated with NAMPT fragmentation by active asparagine endopeptidase (AEP), leading to nicotinamide adenine dinucleotide (NAD+) depletion. Knockout of AEP or expression of AEP-resistant NAMPT N136A mutant significantly elongates the lifespan of neuronal-specific Thy 1-C/EBPβ transgenic mice. Overexpression of the C. elegans C/EBPβ ortholog cebp-2 in neurons shortens lifespan and decreases NAD+ levels, which are restored by feeding nicotinamide mononucleotide (NMN) or AEP inhibitor #11a. Feeding NMN or #11a substantially ameliorates the cognitive and motor impairments of Thy 1-C/EBPβ mice and increases the life expectancy. Notably, #11a demonstrates a better therapeutic effect than NMN in improving aging phenotype in Thy 1-C/EBPβ transgenic mice, which show accelerated aging features. Hence, blockade of AEP via therapeutic intervention may provide an unprecedented strategy for fighting aging and various age-associated diseases.
    Keywords:  CCAAT/enhancer binding protein β (C/EBPβ); asparagine endopeptidase (AEP); brain aging; nicotinamide adenine dinucleotide (NAD+); nicotinamide phosphoribosyltransferase (NAMPT)
    DOI:  https://doi.org/10.1002/advs.202414871
  34. Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]
    Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
    Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.
      Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.
    Keywords:  CCN1; cell death; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
  35. Nat Med. 2025 Apr 30.
    Progress with stem cell therapy in Parkinson's disease.
    Karen O'Leary.
      
    Keywords:  Cell therapies; Clinical trials; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41591-025-00029-5
  36. Alzheimers Dement. 2025 Apr;21(4): e70198
    Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.
    Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Alexandra I Soto-Beasley, Jens O Watzlawik, Jing Zhao, Rebecca R Valentino, Patrick W Johnson, Launia J White, Zachary S Quicksall, Joseph S Reddy, Jose Bras, Rita Guerreiro, Na Zhao, Guojun Bu, Dennis W Dickson, Owen A Ross, Wolfdieter Springer.
       INTRODUCTION: Phosphorylated ubiquitin (p-S65-Ub) is generated during PINK1-PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.
    METHODS: To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples.
    RESULTS: We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.
    DISCUSSION: Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.
    HIGHLIGHTS: p-S65-Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p-S65-Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology-dependent and pathology-independent mechanisms. ZMIZ1 was linked to reduced p-S65-Ub and neuropathology indicative of protection.
    Keywords:  GWAS; PINK1; PRKN; Parkin; Parkinson's disease; ZMIZ1; autophagy; mitochondria; phosphorylated ubiquitin; ubiquitin
    DOI:  https://doi.org/10.1002/alz.70198
  37. EMBO Rep. 2025 May 01.
    DPP8/9 processing of human AK2 unmasks an IAP binding motif.
    Kim J Lapacz, Konstantin Weiss, Franziska Mueller, Yuxing Xue, Simon Poepsel, Matthias Weith, Tanja Bange, Jan Riemer.
      Adenylate kinase 2 (AK2) is localized in the intermembrane space of mitochondria, where it ensures efficient adenine nucleotide exchange between cytosol and mitochondria. For mitochondrial import, AK2 relies on the MIA40 disulphide relay system. Its cytosolic stability is subject to regulation through N-terminal processing by the dipeptidyl peptidases DPP8 and DPP9, which sensitize AK2 for proteasomal degradation. Here, we find that cytosolic AK2 degradation is mediated by Inhibitors of Apoptosis (IAPs), a class of E3 ligases that interacts with target proteins by binding to IAP-binding motifs (IBM). We have identified an IBM at the very end of AK2's novel N-terminus, which becomes exposed due to processing by DPP8/9. N-terminal acetylation mediated by the N-acetyltransferase NatA prevents this AK2-IAP interaction, therefore stabilizing AK2 in the cytosol. Performing a genome-wide in silico screen, we could identify 129 potential substrates in which an IBM becomes potentially unmasked by DPP8/9 processing. For one of these potential substrates, EIF2A, we demonstrate its targeting to IAPs after IBM exposure by DPP8/9 indicating that DPP8/9-mediated unmasking of IBMs is a general phenomenon.
    Keywords:  AK2; DPP9; IAP‐binding Motif; Inhibitor of Apoptosis (IAP) Proteins; N-terminal Acetylation
    DOI:  https://doi.org/10.1038/s44319-025-00455-z
  38. Biochim Biophys Acta Mol Cell Res. 2025 Apr 23. pii: S0167-4889(25)00072-2. [Epub ahead of print]1872(6): 119967
    Clozapine blunts mitochondrial biogenesis in differentiating adipocytes: The increased ATP demand is met via stimulation of electron transport chain expression and activity in residual mitochondria.
    Mara Fiorani, Gloria Buffi, Nazanin Bagherlou, Barbara Canonico, Rita De Matteis, Andrea Guidarelli, Mariele Montanari, Michela Battistelli, Stefano Papa, Lucia Coppo, Liana Cerioni, Andrea Spina, Orazio Cantoni.
      Clozapine (CLZ), a second-generation antipsychotic, is associated with an elevated risk of metabolic syndrome, the underlying mechanism of which remains poorly understood. We recently showed that CLZ inhibits lipid accumulation and CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ expression in early differentiating SW872 liposarcoma cells. Additionally, while not affecting viability, CLZ disrupts the cellular redox state of these cells by inhibiting NADPH oxidase-dependent ROS formation, thereby leading to nuclear factor (erythroid-derived2)-like 2 downregulation, reduced antioxidant defence and increased mitochondrial ROS emission. We confirmed and extended these results by showing that, under the same conditions, CLZ reduces the size of the lipid droplets, inhibits the otherwise increased expression of transcription factors regulating mitochondrial biogenesis, as peroxisome proliferator-activated receptor γ coactivator 1-α, and prevents the increase in mitochondrial DNA and mass. Consistently, decreased expression of mitochondrial proteins as thioredoxin 2, 2-oxoglutarate/malate carrier, and translocase of outer mitochondrial membrane 20 was also observed. However, the expression of various components of the electron transport chain was unexpectedly increased, and this event was accompanied by enhanced mitochondrial dehydrogenase activity, coupled oxygen consumption, mitochondrial membrane potential, ATP synthesis and ROS production. Moreover, residual mitochondria appeared remarkably enlarged and functional, with dense and organized cristae and uniform electron density. Thus, early adipocytes differentiated with or without CLZ meet the increased ATP demand by switching from glycolysis to oxidative phosphorylation, respectively via enhanced mitochondrial biogenesis, and increased activity of residual mitochondria.
    Keywords:  Adipocyte differentiation; Clozapine; Mitochondrial biogenesis; Mitochondrial hyperactivity
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119967
  39. Neural Regen Res. 2025 Apr 29.
    Systematic review of mitochondrial dysfunction and oxidative stress in aging: A focus on neuromuscular junctions.
    Senlin Chai, Ning Zhang, Can Cui, Zhengyuan Bao, Qianjin Wang, Wujian Lin, Ronald Man Yeung Wong, Sheung Wai Law, Rebecca Schönmehl, Christoph Brochhausen, Wing Hoi Cheung.
       ABSTRACT: Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases. The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia. However, the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood. A defined systematic search of the PubMed, Web of Science and Embase databases (last accessed on October 30, 2024) was conducted with search terms including 'mitochondria', 'aging' and 'NMJ'. Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging. Twentyseven studies were included in this systematic review. This systematic review provides a summary of morphological, functional and biological changes in neuromuscular junction, mitochondrial morphology, biosynthesis, respiratory chain function, and mitophagy during aging. We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging. Aging is characterized by significant reductions in mitochondrial fusion/fission cycles, biosynthesis, and mitochondrial quality control, which may lead to neuromuscular junction dysfunction, denervation and poor physical performance. Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities, ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function. Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways, including the mitochondrial respiratory chain, energy deficiency, oxidative stress, and inflammation. Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation, resulting in muscle atrophy and a decrease in strength during aging. Physical therapy, pharmacotherapy, and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function. Therefore, mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.
    Keywords:  aging; mitochondrial dysfunction; neuromuscular junction; oxidative stress; sarcopenia; systematic review
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01338
  40. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 29. pii: S0925-4439(25)00194-2. [Epub ahead of print]1871(6): 167849
    Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model of severe malnutrition.
    José M Horcas-Nieto, W Alfredo Rios-Ocampo, Miriam Langelaar-Makkinje, Rinse de Boer, Albert Gerding, Serhii Chornyi, Ingrid A Martini, Justina C Wolters, Ronald J A Wanders, Hans R Waterham, Ida J Van der Klei, Robert H J Bandsma, Johan W Jonker, Barbara M Bakker.
       INTRODUCTION: Acute and chronic exposure of cells to low amino acid conditions have been shown to lead to a reduction in hepatic peroxisomal and mitochondrial content. There is limited understanding of the underlying mechanisms behind this loss, but data suggests degradation through autophagy. Both organelles play a key role in fatty acid metabolism, which may explain why dysfunction in either one of them might lead to hepatic steatosis.
    METHODS: Using a previously established murine hepatic organoid model of severe malnutrition, we characterized the effects of prolonged amino-acid restriction on peroxisomal and mitochondrial protein levels and on autophagic flux. To do so, we developed concatemers of 13C-labelled peptide standards for quantification of over 50 different peroxisomal proteins. To assess the autophagic flux, we transduced hepatic organoids with a GFP-LC3-RFP-LC3ΔG probe. Finally, the effect of PPAR-α activation on peroxisomal loss was determined with various agonists.
    RESULTS: Prolonged (96 h) amino-acid restriction led to a more severe loss of peroxisomes than a 48 h restriction, and with a substantial induction of autophagic flux. This was accompanied by accumulation of intracellular triglycerides, loss of mitochondrial and peroxisomal proteins, and loss of peroxisomal functionality. While PPAR-α agonists WY-14643 and linoleic acid (LA) had no effect, docosahexaenoic acid (DHA) supplementation partly prevented peroxisomal and mitochondrial loss under amino-acid restricted conditions and partly inhibited autophagy.
    DISCUSSION: The potential of DHA to prevent loss of peroxisomes and mitochondrial functions in low protein diets and severe malnutrition warrants further causal and translational testing in preclinical models and clinical trials, including its use as nutritional supplement.
    Keywords:  Autophagy; Malnutrition; Organoids; Peroxisomes; Polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167849
  41. J Clin Med. 2025 Apr 16. pii: 2748. [Epub ahead of print]14(8):
    Coenzyme Q10 and the Blood-Brain Barrier: An Overview.
    David Mantle, Iain Hargreaves.
      Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Given the importance of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, and the deficiency of CoQ10 reported in such neurological disorders, there is a rationale for investigating the potential therapeutic role of supplementary CoQ10. However, while there is evidence for the efficacy of CoQ10 supplementation in animal models of the above disorders, randomised controlled clinical trials supplementing CoQ10 in PD, AD, or ALS have had disappointing outcomes. This in turn may be a reflection of the current uncertainty as to whether CoQ10 can access the blood-brain barrier in human subjects. In an attempt to further elucidate the disparity in outcomes of such preclinical and clinical studies, in this article we have reviewed evidence from the peer-reviewed literature to establish the ability of CoQ10 to access the brain via the BBB.
    Keywords:  blood CSF barrier; blood–brain barrier; coenzyme Q10; intranasal drug delivery; mitochondrial dysfunction; neurological disorders
    DOI:  https://doi.org/10.3390/jcm14082748
  42. Sci Rep. 2025 Apr 29. 15(1): 15093
    The application of Large Language Models to the phenotype-based prioritization of causative genes in rare disease patients.
    Şenay Kafkas, Marwa Abdelhakim, Azza Althagafi, Sumyyah Toonsi, Malak Alghamdi, Paul N Schofield, Robert Hoehndorf.
      Computational methods for identifying gene-disease associations can use both genomic and phenotypic information to prioritize genes and variants that may be associated with genetic diseases. Phenotype-based methods commonly rely on comparing phenotypes observed in a patient with databases of genotype-to-phenotype associations using measures of semantic similarity. They are constrained by the quality and completeness of these resources as well as the quality and completeness of patient phenotype annotation. Genotype-to-phenotype associations used by these methods are largely derived from the literature and coded using phenotype ontologies. Large Language Models (LLMs) have been trained on large amounts of text and data and have shown their potential to answer complex questions across multiple domains. Here, we evaluate the effectiveness of LLMs in prioritizing disease-associated genes compared to existing bioinformatics methods. We show that LLMs can prioritize disease-associated genes as well, or better than, dedicated bioinformatics methods relying on pre-defined phenotype similarity, when gene sets range from 5 to 100 candidates. We apply our approach to a cohort of undiagnosed patients with rare diseases and show that LLMs can be used to provide diagnostic support that helps in identifying plausible candidate genes. Our results show that LLMs may offer an alternative to traditional bioinformatics methods to prioritize disease-associated genes based on disease phenotypes. They may, therefore, potentially enhance diagnostic accuracy and simplify the process for rare genetic diseases.
    Keywords:  Diagnosis support; Gene prioritization; Large language models; Phenotypes; Rare diseases
    DOI:  https://doi.org/10.1038/s41598-025-99539-y
  43. Antioxid Redox Signal. 2025 Apr 26.
    Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.
    Miguel González-Hernández, Laura Gallardo-Andalucía, Pablo Hernansanz-Agustín.
      Background: Inflammation is one of the most important pathways in innate immunity and its relationship with redox biology is becoming increasingly clear in the last decades. However, the specific redox modes and pathways by which inflammation is produced are not yet well defined. Significance: In this review, we provide a general explanation of the reactive oxygen species (ROS) production and quenching modes occurring in mammalian mitochondria, as well as a summary of the most recent advances in mitochondrial redox biology and bioenergetics regarding sodium (Na+) homeostasis. In addition, we provide a collection of examples in which several inflammatory pathways have been associated with specific modes of either mitochondrial ROS production or quenching. Innovation: The role of Na+ in mitochondrial biology is being developed. Since its discovery as a second messenger, the research of its role in the immune system has emerged. Now, the role of Na+ in mitochondrial bioenergetics has recently been identified, which owns unprecedented applications. The potential implication of Na+ in inflammatory mechanisms grows as its role does not only cover ROS production and respiration but also the control through the management of mitochondrial membrane potential. Future directions: Na+ is becoming relevant for mitochondrial biology. Thus, processes regarding mitochondrial bioenergetics, redox state, or metabolism may probably need to include the study of Na+ in their road map. Some of these pathways are involved in inflammation and more are possibly to come. This review is expected to serve as a bridge between both fields. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  ROS; antioxidant system; bioenergetics; inflammation; mitochondria; sodium
    DOI:  https://doi.org/10.1089/ars.2024.0737
  44. Brain Sci. 2025 Apr 17. pii: 407. [Epub ahead of print]15(4):
    The Multifaceted Role of LRRK2 in Parkinson's Disease.
    Dong Hwan Ho, Sun Jung Han, Ilhong Son.
      Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein kinase intricately involved in the pathogeneses of various neurodegenerative diseases, particularly Parkinson's disease (PD). LRRK2 plays a pivotal role in mitochondrial function and cellular senescence by regulating key processes such as autophagy, oxidative stress, and protein aggregation. LRRK2 is also associated with ciliogenesis in regulating neuronal development. In addition, LRRK2 has been implicated as a putative mediator in neuroinflammation via promoting the reactivation of microglia and influencing cytokine production, a factor that may have therapeutic implications. Furthermore, mutations in LRRK2 have been found to impact the production of neurotrophic factors in astrocytes, the star-shaped glial cells of the central nervous system, thereby affecting neuronal health and contributing to the pathology of neurodegenerative diseases like PD. The multifaceted roles of LRRK2 in cellular senescence, interaction with LRS, neuroinflammation, the maintenance of mitochondria, and astrocyte function highlight its significance as a therapeutic target for neurodegenerative disorders.
    Keywords:  Parkinson’s disease; cellular senescence; ciliogenesis; leucine-rich repeat kinase 2; mitochondrial homeostasis; neuroinflammation; neurotrophic factor; translation
    DOI:  https://doi.org/10.3390/brainsci15040407
  45. Nat Biotechnol. 2025 May 02.
    A tissue-specific atlas of protein-protein associations enables prioritization of candidate disease genes.
    Diederik S Laman Trip, Marc van Oostrum, Danish Memon, Fabian Frommelt, Delora Baptista, Kalpana Panneerselvam, Glyn Bradley, Luana Licata, Henning Hermjakob, Sandra Orchard, Gosia Trynka, Ellen M McDonagh, Andrea Fossati, Ruedi Aebersold, Matthias Gstaiger, Bernd Wollscheid, Pedro Beltrao.
      Despite progress in mapping protein-protein interactions, their tissue specificity is understudied. Here, given that protein coabundance is predictive of functional association, we compiled and analyzed protein abundance data of 7,811 proteomic samples from 11 human tissues to produce an atlas of tissue-specific protein associations. We find that this method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while cell-type-specific cellular structures, such as synaptic components, are found to represent a substantial driver of differences between tissues. Over 25% of associations are tissue specific, of which <7% are because of differences in gene expression. We validate protein associations for the brain through cofractionation experiments in synaptosomes, curation of brain-derived pulldown data and AlphaFold2 modeling. We also construct a network of brain interactions for schizophrenia-related genes, indicating that our approach can functionally prioritize candidate disease genes in loci linked to brain disorders.
    DOI:  https://doi.org/10.1038/s41587-025-02659-z
  46. Genes (Basel). 2025 Apr 18. pii: 465. [Epub ahead of print]16(4):
    Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies-A Comprehensive Narrative Review.
    Consolato M Sergi.
      Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. There are several organs that may be affected, but striking is the cardiological involvement. Cardiovascular disease, which may be the trigger starting the diagnostic procedure in a proband, may include a range of diseases from a severely dilated heart to a hypertrophic heart in the spectrum of anomalies encountered. Left ventricular non-compaction of the heart is also occasionally encountered. This cardiac event may reveal the prognosis of the affected patients. In this narrative review, we highlight the gene's characteristics, the reactome, the cardiological features of the cardiovascular disease observed in patients affected with BTHS, emphasize the most current studies on BTHS cardiomyopathy, and delineate the biological underlying mechanisms supporting the proposal of new therapeutic options.
    Keywords:  BTHS; Barth syndrome; TAFAZZIN; TAZ; cardiac surgery; cardiovascular disease; left ventricular non-compaction; metabolic disease; outcome; prognosis
    DOI:  https://doi.org/10.3390/genes16040465
  47. Front Physiol. 2025 ;16 1554222
    Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.
    Yuqing Li, Wanjun Zhao, Qi Yang.
      Exercise and physical activity confer health advantages, in part, by enhancing skeletal muscle mitochondrial respiratory function. The objective of this study is to analyze the impacts of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the dynamics and functionality of the mitochondrial network within skeletal muscle. 20 young male participants were assigned to either HIIT or MICT group. Initial assessments of exercise-related indicators were conducted, followed by skeletal muscle biopsies from the vastus lateralis before, 1 day after, and 6 weeks post-experiment. We utilized multi-dimensional myofiber imaging to analyze mitochondrial morphology and arrangement, and assessed citrate synthase activity, complex I activity, and dynamics-related mRNA. Both training modalities increased VO2max, Wmax, citrate synthase and complex I activities, mitochondrial content, and volume density, though the changes differed between the two groups. 6 weeks training induced remodeling of the mitochondrial network within skeletal muscle. Before training, the network appeared sparse and punctate. After MICT, it adopted a grid-like structure with partially robust longitudinal connections. In contrast, HIIT resulted in a less obvious grid structure but showed a stronger longitudinally oriented network. Training also increased mRNA expression of mitochondrial fusion proteins and decreased fission protein expression, with these effects being more pronounced in HIIT. Similarly, peroxisome proliferator-activated receptor γ coactivator 1-alpha mRNA expression showed a comparable trend, though the changes differed between 1 day and 6 weeks of training. In conclusion, HIIT and MICT induce distinct mitochondrial adaptation in skeletal muscle, reflected in different network remodeling and molecular pathways. These findings may be due to HIIT's more pronounced effect on mitochondrial dynamics or respiratory function, but the study has only conducted preliminary observational experiments and further evidence is required for confirmation.
    Keywords:  high-intensity interval training; mitochondrial dynamics; mitochondrial network remodeling; moderate-intensity interval training; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2025.1554222
  48. J Clin Med. 2025 Apr 08. pii: 2537. [Epub ahead of print]14(8):
    Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.
    Michael Otakhor Erhunmwunse, Pushpa Raj Joshi.
      Introduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the 'common' 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
    Keywords:  CPEO; common deletion (CD); mitochondrial DNA; ptosis
    DOI:  https://doi.org/10.3390/jcm14082537
  49. EMBO J. 2025 Apr 25.
    Altering metabolism programs cell identity via NAD+-dependent deacetylation.
    Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.
      Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
    Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins
    DOI:  https://doi.org/10.1038/s44318-025-00417-0
  50. Children (Basel). 2025 Mar 28. pii: 429. [Epub ahead of print]12(4):
    Rapid Whole-Genome Sequencing in Critically Ill Infants and Children with Suspected, Undiagnosed Genetic Diseases: Evolution to a First-Tier Clinical Laboratory Test in the Era of Precision Medicine.
    Rina Kansal.
      The completion of the Human Genome Project in 2003 has led to significant advances in patient care in medicine, particularly in diagnosing and managing genetic diseases and cancer. In the realm of genetic diseases, approximately 15% of critically ill infants born in the U.S.A. are diagnosed with genetic disorders, which comprise a significant cause of mortality in neonatal and pediatric intensive care units. The introduction of rapid whole-genome sequencing (rWGS) as a first-tier test in critically ill children with suspected, undiagnosed genetic diseases is a breakthrough in the diagnosis and subsequent clinical management of such infants and older children in intensive care units. Rapid genome sequencing is currently being used clinically in the USA, the UK, the Netherlands, Sweden, and Australia, among other countries. This review is intended for students and clinical practitioners, including non-experts in genetics, for whom it provides a historical background and a chronological review of the relevant published literature for the progression of pediatric diagnostic genomic sequencing leading to the development of pediatric rWGS in critically ill infants and older children with suspected but undiagnosed genetic diseases. Factors that will help to develop rWGS as a clinical test in critically ill infants and the limitations are briefly discussed, including an evaluation of the clinical utility and accessibility of genetic testing, education for parents and providers, cost-effectiveness, ethical challenges, consent issues, secondary findings, data privacy concerns, false-positive and false-negative results, challenges in variant interpretation, costs and reimbursement, the limited availability of genetic counselors, and the development of evidence-based guidelines, which would all need to be addressed to facilitate the implementation of pediatric genomic sequencing in an effective widespread manner in the era of precision medicine.
    Keywords:  chromosomal microarray; ethics; exome sequencing; genome sequencing; intensive care; neonatology; pediatric genetics; precision medicine; rapid genomic sequencing; secondary findings
    DOI:  https://doi.org/10.3390/children12040429
  51. Biomolecules. 2025 Apr 14. pii: 580. [Epub ahead of print]15(4):
    Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
    Varshini V Suresh, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy.
      Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.
    Keywords:  GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/biom15040580
  52. Nat Commun. 2025 May 01. 16(1): 4080
    T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
    Qiuya Shao, Anas Khawaja, Minh Duc Nguyen, Vivek Singh, Jingdian Zhang, Yong Liu, Joel Nordin, Monika Adori, C Axel Innis, Xaquin Castro Dopico, Joanna Rorbach.
      Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.
    DOI:  https://doi.org/10.1038/s41467-025-59388-9
  53. Cell. 2025 Apr 25. pii: S0092-8674(25)00405-2. [Epub ahead of print]
    Regional differences in progenitor metabolism shape brain growth during development.
    Natalia Baumann, Robin J Wagener, Awais Javed, Eleonora Conti, Philipp Abe, Andrea Lopes, Roberto Sansevrino, Adrien Lavalley, Elia Magrinelli, Timea Szalai, Daniel Fuciec, Clothilde Ferreira, Sabine Fièvre, Andreane Fouassier, Davide D'Amico, Oliver Harschnitz, Denis Jabaudon.
      Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.
    Keywords:  brain development; metabolism; mitochondria dynamics; progenitor diversity
    DOI:  https://doi.org/10.1016/j.cell.2025.04.003
  54. Science. 2025 May;388(6746): eadp2959
    Stem cells as role models for reprogramming and repair.
    Magdalena Götz, Maria-Elena Torres-Padilla.
      Stem cells are a promising source for cellular therapies across many diseases and tissues. Their inherent ability to differentiate into other cell types has been the focus of investigation over decades. This ability is currently being exploited for therapies using strategies to repair or replace damaged tissues and cells or to alleviate immune rejection. Exploring stem cell function has enabled direct reprogramming approaches, for example, through the production of induced pluripotent stem cells and the generation of tissue-specific stem cells. Understanding stem cell function has emerged as an important strategy for repopulating stem cell pools or generating differentiated cells for therapy. Here, we review general principles of mammalian stem cell biology and cellular reprogramming approaches and their use for current and future therapeutic purposes.
    DOI:  https://doi.org/10.1126/science.adp2959
  55. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00410-3. [Epub ahead of print]44(5): 115639
    Regulation of translation elongation and integrated stress response in heat-shocked neurons.
    Caitlin M Seluzicki, Milad Razavi-Mohseni, Fulya Türker, Priyal Patel, Boyang Hua, Michael A Beer, Loyal Goff, Seth S Margolis.
      Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.
    Keywords:  CP: Molecular biology; CP: Neuroscience; ISR; eEF2; eIF2α; elongation; heat shock; integrated stress response; neurons; translation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115639
  56. Bioinform Adv. 2025 ;5(1): vbaf093
    AlphaMissenseR: an integrated framework for investigating missense mutations in human protein-coding genes.
    Tram N Nguyen, Tyrone Lee, Nitesh Turaga, Robert Gentleman, Ludwig Geistlinger, Martin Morgan.
       Summary: AlphaMissense is an AI model from Google DeepMind that predicts the pathogenicity of every possible missense mutation in the human proteome. We present AlphaMissenseR, an R/Bioconductor package that facilitates performant and reproducible access to these predictions and that provides functionality for analysis, visualization, validation, and benchmarking. AlphaMissenseR integrates with Bioconductor facilities for genomic region analysis, and provides multi-level visualization and interactive exploration of variant pathogenicity in a genome browser and on 3D protein structures. In addition, AlphaMissenseR integrates with major clinical and experimental variant databases for contrasting predicted and clinically derived pathogenicity scores, and for systematic benchmarking of existing and new variant effect prediction methods across a large collection of deep mutational scanning assays.
    Availability and implementation: AlphaMissense data resources are distributed under the CC-BY 4.0 license and the AlphaMissenseR package is available from Bioconductor (https://bioconductor.org/packages/AlphaMissenseR) under the Artistic 2.0 license.
    DOI:  https://doi.org/10.1093/bioadv/vbaf093
  57. Nat Med. 2025 Apr 30.
    Precision nutrition for cardiometabolic diseases.
    Marta Guasch-Ferré, Clemens Wittenbecher, Marie Palmnäs, Orly Ben-Yacov, Ellen E Blaak, Christina C Dahm, Tove Fall, Berit L Heitmann, Tine R Licht, Marie Löf, Ruth Loos, Chirag J Patel, Carmelo Quarta, Leanne M Redman, Eran Segal, Nicola Segata, Michael Snyder, Qi Sun, Deirdre K Tobias, Frank B Hu, Paul W Franks, Rikard Landberg, Jennifer L Sargent, Jordi Merino.
      Precision nutrition is a vibrant and rapidly evolving field of scientific research and innovation with the potential to deliver health, societal and economic benefits by improving healthcare delivery and policies. Advances in deep phenotyping technologies, digital tools and artificial intelligence have made possible early proof-of-concept research that expands the understanding of within- and between-person variability in responses to diet. These studies illustrate the promise of precision nutrition to complement the traditional 'one size fits all' dietary guidelines, which, while considering broad life-stage and disease-specific nutritional requirements, often lack the granularity to account fully for individual variations in nutritional needs and dietary responses. Despite these developments, however, considerable challenges remain before precision nutrition can be implemented on a broader scale. This Review examines the current state of precision nutrition research, with a focus on its application to reducing the incidence and burden of cardiometabolic diseases. We critically examine the evidence base, explore the potential benefits and discuss the challenges and opportunities ahead.
    DOI:  https://doi.org/10.1038/s41591-025-03669-9
  58. Neural Regen Res. 2025 Apr 29.
    Potential and value of rescuing dying neurons.
    Wenting You, Tos T J M Berendschot, Birke J Benedikter, Carroll A B Webers, Chris P M Reutelingsperger, Theo G M F Gorgels.
       ABSTRACT: Unwarranted death of neurons is a major cause of neurodegenerative diseases. Since mature neurons are postmitotic and do not replicate, their death usually constitutes an irreversible step in pathology. A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive, i.e. protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying. Regarding the latter, recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated. In many situations, the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage, recover, and survive. In this review, we explore the factors, which determine the fate of neurons engaged in the cell death process. A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.
    Keywords:  apoptosis; dying neurons; neuronal recovery; neurorescue; reversible cell death process
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01134
  59. Mol Ther Methods Clin Dev. 2025 Jun 12. 33(2): 101461
    Bystander editing by adenine base editors impairs vision restoration in a mouse model of Leber congenital amaurosis.
    Seok-Hoon Lee, Jun Wu, Dongjoon Im, Gue-Ho Hwang, You Kyeong Jeong, Hui Jiang, Seok Jae Lee, Dong Hyun Jo, William A Goddard, Jeong Hun Kim, Sangsu Bae.
      Base editors (BEs) have emerged as a powerful tool for gene correction with high activity. However, bystander base editing, a byproduct of BEs, presents challenges for precise editing. Here, we investigated the effects of bystander edits on phenotypic restoration in the context of Leber congenital amaurosis (LCA), a hereditary retinal disorder, as a therapeutic model. We observed that in retinal degeneration 12 (rd12) of LCA model mice, the highest editing activity version of an adenine base editors (ABEs), ABE8e, generated substantial bystander editing, resulting in missense mutations despite RPE65 expression, preventing restoration of visual function. Through AlphaFold-based mutational scanning and molecular dynamics simulations, we identified that the ABE8e-driven L43P mutation disrupts RPE65 structure and function. Our findings underscore the need for more stringent requirements in developing precise BEs for future clinical applications.
    Keywords:  AlphaFold; CRISPR; Leber congenital amaurosis; RPE65; adenine base editor; molecular dynamics simulation; undesired bystander editing
    DOI:  https://doi.org/10.1016/j.omtm.2025.101461
  60. Nat Rev Genet. 2025 May 02.
    Revealing secrets of human genetic variation with population databases.
    Nicole J Lake.
      
    DOI:  https://doi.org/10.1038/s41576-025-00848-9
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