bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–10–12
sixty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
  2. First approved drug for mitochondrial disease raises hopes for more.
  3. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  4. Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
  5. PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
  6. Proteasome regulation of petite-negativity in fission yeast.
  7. Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency.
  8. Visual Recovery in Leber's Hereditary Optic Neuropathy Plus: A Case Report and Literature Insight.
  9. Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
  10. Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases.
  11. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  12. Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
  13. Activity-dependent citrate dynamics in neurons.
  14. Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
  15. Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
  16. Approaches to Humanization of Mitochondrial Proteins in Saccharomyces cerevisiae on the Example of Replacing the Yeast Mitochondrial Translation Termination Factor MRF1 with Its Human Homologues.
  17. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  18. Genetics of Mitochondrial Aminoacyl-tRNA Synthetases Associated with Sensorineural Hearing Loss.
  19. The Case of a 25-Year-Old Woman With Isolated Head Tremor.
  20. The biophysical mechanism of mitochondrial pearling.
  21. Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
  22. Sudden bilateral vision loss in a child with LYRM7-related leukoencephalopathy.
  23. Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
  24. Skeletal Muscle PGC-1α Remodels Mitochondrial Phospholipidome but Does Not Alter Energy Efficiency for ATP Synthesis.
  25. Modulation of cellular and mitochondrial dysfunction by TRPV4 during early stages of Vincristine-induced neurotoxicity in cultured neuronal model.
  26. A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.
  27. Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.
  28. Quantitative CRACI reveals transcriptome-wide distribution of RNA dihydrouridine at base resolution.
  29. Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.
  30. Ultra-fast variant effect prediction using biophysical transcription factor binding models.
  31. Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.
  32. Myocardial disarray drives metabolic inefficiency in human cardiomyocytes.
  33. A ternary-code DNA methylome atlas of mouse tissues.
  34. Mapping the evolution of mitochondrial complex I through structural variation.
  35. A Novel HERC2 Variant in Two Siblings with Autosomal Recessive Intellectual Developmental Disorder-38 and Cardiomyopathy.
  36. Mesenchymal stromal cell-mediated mitochondrial transfer unveils new frontiers in disease therapy.
  37. Will AI ever win its own Nobel? Some predict a prize-worthy science discovery soon.
  38. Safe Use of Metformin in Mitochondrial Diabetes in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes: Insights From a Patient With m.3243A>G Mutation.
  39. Public funding for mitochondrial donation: An Australian public deliberation.
  40. Developing Treatments for Rare Diseases on a Shoestring.
  41. ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish.
  42. Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study.
  43. ASPL couples the assembly of stress granules with their VCP-mediated disassembly.
  44. Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
  45. DNA methylation and machine learning: challenges and perspective toward enhanced clinical diagnostics.
  46. PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.
  47. Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
  48. Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
  49. Onion-Mitochondria Inhibit Lipopolysaccharide-Induced Acute Lung Injury by Shaping Lung Macrophage Mitochondrial Function.
  50. Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.
  51. Experimental Evidence Against Taurine Deficiency as a Driver of Aging in Humans.
  52. Senescence-coupled differentiation selectively eliminates cancer-prone stem cells.
  53. P-Rex1 limits glucose clearance and suppresses hepatocyte glucose uptake and mitochondrial metabolism independently of its Rac-GEF activity.
  54. Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
  55. Mondo: Integrating Disease Terminology Across Communities.
  56. Thermochemical heterolytic hydrogenation catalysis proceeds through polarization-driven hydride transfer.
  57. RRP12 Variants Are Associated With Autosomal Recessive Brain Calcifications.
  58. Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism.
  59. Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.
  60. A Novel Compound Heterozygous CYP27A1 Variant in Cerebrotendinous Xanthomatosis: A Case Report from a Non-Consanguineous Family.
  61. Primary systemic carnitine deficiency: Phenotypic variability, diagnostic challenges, and long-term outcomes.
  62. Clinical use of polygenic risk scores: current status, barriers and future directions.
  1. Cell Death Dis. 2025 Oct 06. 16(1): 693
    The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
    Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna.
      The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.
    DOI:  https://doi.org/10.1038/s41419-025-08030-z
  2. Science. 2025 Oct 09. 390(6769): 114-115
    First approved drug for mitochondrial disease raises hopes for more.
    Mitch Leslie.
      Researchers are testing multiple treatments for the rare genetic conditions.
    DOI:  https://doi.org/10.1126/science.aec9018
  3. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  4. Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00390-0. [Epub ahead of print]37(10): 1927-1928
    Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
    Joanne F Garbincius, John W Elrod.
      The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.1 propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.005
  5. J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]
    PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
    Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.
      Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.
    Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5
    DOI:  https://doi.org/10.1242/jcs.263903
  6. BMC Biol. 2025 Oct 09. 23(1): 302
    Proteasome regulation of petite-negativity in fission yeast.
    Katie Lin Amberg, Lyrica Hao, Susanne Cranz-Mileva, Mikel Zaratiegui.
       BACKGROUND: Mitochondria carry out essential functions in eukaryotic cells. The mitochondrial genome encodes factors critical to support oxidative phosphorylation and mitochondrial protein import necessary for these functions. However, organisms like budding yeast can readily lose their mitochondrial genome, yielding respiration-deficient petite mutants. The fission yeast Schizosaccharomyces pombe is petite-negative, but some nuclear mutations enable the loss of its mitochondrial genome.
    RESULTS: Here, we characterize the classical petite-positive mutation ptp1-1 as a loss of function allele of the proteasome 19S regulatory subunit component mts4/rpn1, involved in the ubiquitin-dependent degradation pathway. By comparison with another petite-enabling mutation in the g-subunit of the F1-ATPase, we show that ptp1-1 does not rescue mitochondrial membrane potential. Instead, the mutation results in increased levels of mitochondrial and cytoplasmic chaperones and an altered oxidative stress response.
    CONCLUSIONS: ptp1-1 is a partial loss of function mutation of the proteasome that enables growth of cells devoid of mitochondrial DNA through a mechanism that is independent of mitochondrial membrane potential rescue and associated with proteasome-dependent regulation of mitochondrial protein import precursors and the oxidative stress response.
    Keywords:  Fission yeast; Mitochondria; MtDNA; Petite; Proteasome; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1186/s12915-025-02409-2
  7. Brain Commun. 2025 ;7(5): fcaf369
    Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency.
    Francesca Magrinelli, Lucie S Taylor, Sahar Sedighzadeh, Dalila Moualek, Mariasavina Severino, Daniel N Grba, Charlotte L Alston, Michael Champion, Ali Reza Tavasoli, Karine Lascelles, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Sahand Tehrani Fateh, Mohammad Kordi-Tamandani, Ali Khajeh, Saeedeh Yaghoubi, Natalia Dominik, Meisam Babaei, Mohsen Javadzadeh, Jamileh Rezazadeh Varaghchi, Mohammad Miryounesi, Ehsan Ghayoor Karimiani, Meriem Tazir, Lamia Ali Pacha, Kailash P Bhatia, Robert W Taylor, Henry Houlden, Reza Maroofian.
      Biallelic NDUFA9 variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of NDUFA9-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of NDUFA9-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic NDUFA9 variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new NDUFA9 variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic NDUFA9 variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.
    Keywords:  Leigh syndrome; lactic acidosis; mutational hotspot; seizures; spasticity
    DOI:  https://doi.org/10.1093/braincomms/fcaf369
  8. Case Rep Ophthalmol. 2025 Jan-Dec;16(1):16(1): 686-692
    Visual Recovery in Leber's Hereditary Optic Neuropathy Plus: A Case Report and Literature Insight.
    Radhika Paranjpe, Himani Yadav, Preethi Abraham, Kalibo Jakhalu.
       Introduction: Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder that primarily affects young men, leading to subacute, painless, bilateral loss of central vision. It is caused by point mutations in mitochondrial DNA, especially those involving the MT-ND1, MT-ND4, and MT-ND6 genes, which disrupt complex I function in the mitochondrial respiratory chain.
    Case Presentation: We describe an 18-year-old male cricket player who presented with a 6-month history of gradually worsening, painless visual loss in both eyes. His best corrected visual acuity was 6/60 in the right eye and 3/60 in the left eye. Color vision was reduced in the left eye but improved when tested with a red filter, raising suspicion of optic nerve pathology. Fundus examination revealed subtle hyperemic optic discs, and visual field testing identified central and paracentral scotomas. MRI of the orbits showed bilateral T2 hyperintensities in the intraorbital portions of the optic nerves. Genetic testing confirmed a homoplasmic MT:14484C>T mutation in the MT-ND6 gene. The patient also reported systemic symptoms including palpitations and excessive sweating. Cardiac evaluation revealed mitral valve prolapse, sinus tachycardia, and elevated blood pressure. These findings led to a diagnosis of Leber's hereditary optic neuropathy plus (LHON plus). He was started on coenzyme Q10 and oral nutritional supplements. Remarkably, over the course of a year, he regained full visual acuity with only residual optic disc pallor.
    Conclusion: This case underscores the importance of considering LHON plus in young patients with bilateral optic neuropathy and systemic features, particularly when the MT:14484C>T mutation is present, as early mitochondrial support can lead to favorable outcomes.
    Keywords:  Leber’s hereditary optic neuritis; Mitochondrial mutation; Optic neuritis
    DOI:  https://doi.org/10.1159/000547946
  9. Nat Commun. 2025 Oct 10. 16(1): 9053
    Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
    Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.
      Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.
    DOI:  https://doi.org/10.1038/s41467-025-64147-x
  10. Neuromolecular Med. 2025 Oct 11. 27(1): 69
    Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases.
    Mateus Laranjeira, Jorge M A Oliveira, Filippo M Santorelli, Maria Marchese, Célia Nogueira.
      Mitochondrial diseases (MDs) are heterogeneous multisystemic disorders often caused by genetic defects in either nuclear or mitochondrial DNA. Although next-generation sequencing technologies have dramatically expanded the number of variants associated with these diseases, many remain variants of unknown significance (VUS). This review explores the utility of zebrafish (Danio rerio) as a vertebrate model system for studying mitochondrial dysfunction, with a focused analysis on the application of morpholino oligonucleotides (MOs) to functionally characterize and interpret VUS. MO-induced knockdown produces a transient suppression of target genes during zebrafish early development, recapitulating key MD phenotypes. Furthermore, rescue experiments involving co-injection of MO and either wild-type or mutant mRNA have proven useful to functionally assess the pathogenicity of specific variants. Specifically, while wild-type mRNA rescues the morphant phenotype, failure of mutant mRNA to do so confirms the variant's pathogenic effect. This approach has successfully linked previously uncharacterized genes to MD and helped reclassify ambiguous variants. The use of MO-based strategies in zebrafish remains a valuable tool for variant interpretation and functional validation, bridging the gap between genomic data and clinical action, and ultimately reducing the diagnostic odyssey. Overall, this review places MO knockdown and rescue assays in zebrafish as a robust and versatile platform to address functional genomics in MD research.
    Keywords:  Mitochondrial diseases; Morpholino oligonucleotides; Rescue experiments; Variants of unknown significance; Zebrafish
    DOI:  https://doi.org/10.1007/s12017-025-08890-w
  11. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
  12. iScience. 2025 Sep 19. 28(9): 113449
    Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
    Marica Meroni, Erika Paolini, Miriam Longo, Michele Battistin, Daniele Dondossola, Michela Ripolone, Laura Napoli, Ettore Mosca, Stefania Corti, Paola Dongiovanni.
      Hepatic mitochondrial maladaptation features the transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to Steatohepatitis (MASH) up to fibrosis/cirrhosis. However, it is still unexplored whether mitochondrial alterations also affect adipose tissue, muscle and heart during disease progression. C57Bl/6 mice were fed an AMLN diet to recapitulate the human MASLD spectrum. In the liver, TEM depicted a progressive morphologic dysfunction of mitochondria, which appeared swollen in MASH, with disorganized cristae/matrix loss in MASH-fibrosis. The mitophagy pathway was reduced in MASH-fibrosis, thus explaining the accumulation of damaged mitochondria, whereas mitochondrial complexes activities alongside OXPHOS protein levels and ATP production were dampened across the disease in liver, adipose, muscle, and cardiac tissues. Finally, the release of cell-free circulating mitochondrial DNA into the bloodstream reflected tissue mitochondrial impairment. In sum, we demonstrated that alterations in mitochondrial morphology, life cycle, and activity feature all disease stages in the liver but also in other tissues engaged in MASLD evolution.
    Keywords:  Biochemistry; Systems biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113449
  13. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2519902122
    Activity-dependent citrate dynamics in neurons.
    Paul C Rosen, Panhui Fu, Beatriz Ferrán, Erica Kim, Daniel J Brooks, Daniel C Lim, Carlos Manlio Díaz-García, Gary Yellen.
      Glycolytic enzymes sense metabolite levels to adapt rapidly to changing energy demands, but measuring the levels of these effectors with spatiotemporal precision in live cells has been challenging. We addressed this question in the context of neuronal depolarization, which activates glycolysis, focusing on the glycolysis inhibitor citrate. We engineered a pair of quantitative fluorescent biosensors for citrate that address several limitations (affinity, pH, Mg2+, and temperature) of existing citrate biosensors. Using two-photon fluorescence lifetime imaging, we found that free citrate in the cytosol of neurons in acute mouse brain slices declines two-to-threefold within seconds of neuronal activation and then returns to baseline over a few minutes. The stimulation-dependent citrate transient depends at least in part on the mitochondrial calcium uniporter. These types of live metabolite measurements are essential for achieving a nuanced understanding of the fast control of glycolysis.
    Keywords:  fluorescence lifetime; genetically encoded fluorescent biosensor; glycolytic regulation; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.1073/pnas.2519902122
  14. Metabolism. 2025 Oct 06. pii: S0026-0495(25)00282-3. [Epub ahead of print] 156413
    Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
    Pieter R Norden, Riley J Wedan, Samuel E J Preston, Morgan Canfield, Naomi Graber, Jacob Z Longenecker, Olivia A Pentecost, Elizabeth McLaughlin, Madeleine L Hart, Sara M Nowinski.
      4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4'PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
    Keywords:  Electron transport chain; Fatty acid synthesis; Metabolism; Mitochondria; Phosphopantetheine; Reductive carboxylation; Respiration
    DOI:  https://doi.org/10.1016/j.metabol.2025.156413
  15. Clin Genet. 2025 Oct 11.
    Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
    Jun Wang, Minhan Song, Zhimei Liu, Chaolong Xu, Ying Zou, Xin Duan, Yang Liu, Weihua Zhang, Jiuwei Li, Fang Fang.
      This study investigated clinical and genetic characteristics of Chinese pediatric patients with single large-scale mitochondrial DNA deletions (SLSMD). We analyzed 28 patients (July 2004-March 2025) using long-range PCR and next-generation sequencing. Spearman correlation and ANOVA assessed genotype-phenotype relationships. Patients (mean age 5.52 ± 3.96 years) exhibited multi-organ involvement (5.43 ± 1.87 organs). Common initial presentations included ocular (29%), neurologic, and endocrine dysfunction. Only 14.3% had the classic 4977 bp deletion, and 23 novel deletions were identified in 25 patients. Larger deletions correlated with more deleted MRC complexes (r = 0.516, p = 0.0123) and more deleted tRNAs (r = 0.534, p = 0.0103). Kearns-Sayre syndrome (KSS) patients had later onset (p = 0.0337), larger deletions (p = 0.0263), and greater tRNA/MRC complex (p = 0.0263, p = 0.0319) involvement than non-KSS patients. SLSMD in Chinese children primarily causes KSS, Pearson syndrome (PS), and progressive ophthalmoplegia with multi-organ involvement. Genotype-phenotype correlations exist, particularly between deletion size, onset age, and disease severity. KSS patients show distinct genetic and clinical profiles, suggesting slower progression. This study expands the known SLSMD spectrum and underscores mitochondrial testing in pediatric multi-organ disorders.
    Keywords:  KSS; mitochondrial diseases; mtDNA; single large deletions
    DOI:  https://doi.org/10.1111/cge.70089
  16. Biochemistry (Mosc). 2025 Sep;90(9): 1240-1251
    Approaches to Humanization of Mitochondrial Proteins in Saccharomyces cerevisiae on the Example of Replacing the Yeast Mitochondrial Translation Termination Factor MRF1 with Its Human Homologues.
    Rinat A Khannanov, Ivan V Chicherin, Mariya V Baleva, Sergey A Levitskii, Ruslan A Vasilev, Ulyana E Piunova, Piotr Kamenski.
      Mitochondrial translation is a highly specialized process of synthesizing mitochondrially encoded proteins, mainly the components of the oxidative phosphorylation system. It involves four key stages: initiation, elongation, termination, and recycling of mitochondrial ribosomes. Each of these stages is regulated by a specific set of translation factors, most of which are encoded by the nuclear genome and imported into mitochondria. The termination of mitochondrial translation in yeast (Saccharomyces cerevisiae) is carried out by the MRF1 release factor. This nuclear-encoded factor is crucial for ensuring accurate protein synthesis within the organelle, as it recognizes stop codons and facilitates the release of completed polypeptide chains from the ribosome. In addition to this main function, MRF1 participates in maintaining mitochondrial genome stability. The aim of this study was to investigate the capacity of human homologues, hMTRF1, hMTRF1A, and mitoribosome rescue factors hMTRFR and hMRPL58, to compensate for the absence of the yeast mitochondrial translation termination factor MRF1 in S. cerevisiae cells. The results obtained suggest that human orthologues of MRF1, such as hMTRF1 and hMTRF1A, can contribute to maintaining the integrity of the yeast mitochondrial genome. However, they do not fully replace the function of MRF1, as they do not restore normal respiration of the mutant yeast strains.
    Keywords:  baker’s yeast; humanization; mitochondria; mitochondrial DNA; protein biosynthesis; termination; translation
    DOI:  https://doi.org/10.1134/S0006297925601418
  17. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  18. Mol Syndromol. 2025 Oct;16(5): 449-460
    Genetics of Mitochondrial Aminoacyl-tRNA Synthetases Associated with Sensorineural Hearing Loss.
    Baicheng Xu, Jing Chai, Panpan Bian, Yufen Guo.
       Background: Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic and mitochondrial proteins. The mt-ARS genes encode the mitochondrial aminoacyl-tRNA synthetase (mt-ARSs), and variants in mt-ARS genes affect mitochondrial protein synthesis. This can impair the translation of mitochondrial proteins, adversely affecting oxidative phosphorylation and leading to related diseases. To date, 19 mt-ARS genes have been identified and found to be strongly associated with the development of mitochondrial disorders. Hearing loss (HL) is one of the most common chronic conditions in children and a leading cause of communication disorders. Genetic studies of sensorineural HL are critical to diagnosing and treating sensorineural HL. The relationship between mt-ARS genes and sensorineural HL is gradually surfacing as cases of HL phenotypes caused by variants in the mammalian mt-ARS genes continue to be reported. Seven mt-ARS genes have been reported to contribute to various hereditary sensorineural HL.
    Summary: This article reviews studies on mitochondrial aminoacyl-tRNA synthetase, mt-ARS genes, and variants associated with HL phenotypes. Investigating their genetic characteristics provides deeper insights into the pathophysiology and molecular mechanisms of sensorineural hearing loss.
    Key Messages: Disease phenotypes resulting from variants in mt-ARS genes exhibit significant clinical heterogeneity. The varying degrees of sensorineural HL phenotypes caused by mt-ARS gene variants warrant the attention of otologists and researchers. At least seven of the currently reported mt-ARS genes are associated with sensorineural HL. However, the molecular mechanisms by which these genes contribute to HL remain incompletely understood. Further studies of the mt-ARS genes still await additional case reports, as well as related model animal studies and combined functional studies.
    Keywords:  Aminoacyl-tRNA synthetase; Genetic studies; Mitochondria; Mt-ARS gene; Sensorineural hearing loss
    DOI:  https://doi.org/10.1159/000542981
  19. Ann Clin Transl Neurol. 2025 Oct 09.
    The Case of a 25-Year-Old Woman With Isolated Head Tremor.
    Ying Zhao, Zhihong Xu, Xingyu Zhuang, Yuying Zhao, Chuanzhu Yan, Kunqian Ji.
      This study reported a 25-year-old woman with isolated head tremors as the main manifestation, along with type 1 diabetes, bilateral hearing loss, and leukoencephalopathy, who was diagnosed with mitochondrial disease due to a single large mtDNA deletion (m.8647-16082del).
    Keywords:  isolated head tremors; mitochondrial disease; mtDNA deletion; muscle biopsy
    DOI:  https://doi.org/10.1002/acn3.70221
  20. Mol Biol Cell. 2025 Oct 08. mbcE25060302
    The biophysical mechanism of mitochondrial pearling.
    Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.
      Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.
    DOI:  https://doi.org/10.1091/mbc.E25-06-0302
  21. Nat Commun. 2025 Oct 10. 16(1): 9022
    Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
    Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.
      Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.
    DOI:  https://doi.org/10.1038/s41467-025-64072-z
  22. J AAPOS. 2025 Oct 02. pii: S1091-8531(25)00556-7. [Epub ahead of print] 104658
    Sudden bilateral vision loss in a child with LYRM7-related leukoencephalopathy.
    Lubhavni Dewan, Vyshnavika Mupparapu, Ramesh Kekunnaya, Goura Chattanavar.
      A 4-year-old boy presented with poor vision following an episode of febrile illness with abdominal distension, seizures, and respiratory distress with metabolic acidosis. He had bilateral partial optic atrophy. Neuroimaging revealed bilateral symmetric post-contrast enhancement of the optic nerves, diffuse white matter T2-hyperintensities, and a lactate peak on magnetic resonance spectroscopy. Serology for aquaporin-4 and myelin-oligodendrocyte antibodies were negative. Whole exome sequencing showed a homozygous pathogenic variant in the LYRM7 gene (c.2T>C) known to cause mitochondrial complex III deficiency. Following initiation of mitochondrial cocktail therapy, his visual behavior improved.
    DOI:  https://doi.org/10.1016/j.jaapos.2025.104658
  23. Front Neuroendocrinol. 2025 Oct 03. pii: S0091-3022(25)00043-3. [Epub ahead of print] 101217
    Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
    George B Stefano, Pascal Büttiker, Simon Weissenberger, Jiri Raboch, Martin Anders.
      While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.
    Keywords:  Alzheimer’s disease; Glucagon-like Peptide 1; Mitochondria; Neurodegenerative disease; Oxidative phosphorylation; Parkinson’s disease; Semaglutide
    DOI:  https://doi.org/10.1016/j.yfrne.2025.101217
  24. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70090
    Skeletal Muscle PGC-1α Remodels Mitochondrial Phospholipidome but Does Not Alter Energy Efficiency for ATP Synthesis.
    Takuya Karasawa, Ran Hee Choi, Cesar A Meza, Shinya Watanabe, J Alan Maschek, Linda S Nikolova, James E Cox, Katsuhiko Funai.
       BACKGROUND: The coupling of oxygen consumption to ATP synthesis via oxidative phosphorylation (OXPHOS) is central for cellular energy homeostasis. Some studies suggest exercise training increases the efficiency of ATP synthesis, but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes in mitochondrial lipids might influence OXPHOS efficiency (ATP produced per O2 consumed, referred to as P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations, including mitochondria. We hypothesized that increased PGC-1α activity might remodel mitochondrial membrane lipids and promote energy efficiency.
    METHODS: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by Western blotting. High-resolution respirometry and fluorometry analyses were performed to characterize mitochondrial bioenergetics (ATP production, O2 consumption and P/O) for permeabilized fibres and isolated mitochondria. Respiratory supercomplexes were assessed by blue native PAGE.
    RESULTS: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE; +25%, p < 0.0001), cardiolipin (CL; +184%, p < 0.0001) and lysophospholipids (+34%-94%, all p < 0.01), while decreasing the concentrations of phosphatidylcholine (PC; -4%, p = 0.0020), phosphatidylinositol (PI; -17%, p < 0.0001) and phosphatidic acid (PA; -35%, p < 0.0001). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes (two- to fourfold, p < 0.0001), the rate of O2 consumption (1.5-fold, p = 0.0030), or the respiratory supercomplexes (~1.5-fold, p < 0.01), P/O values were unaffected by PGC-1α overexpression in permeabilized fibres or isolated mitochondria.
    CONCLUSIONS: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL, but neither PGC-1α nor the mitochondrial membrane lipid remodelling induced in MCK-PGC-1α mice is sufficient to increase the efficiency of mitochondrial ATP synthesis. These findings indicate that PGC-1α-dependent mechanisms or changes in mitochondrial membrane lipids may be insufficient to alter P/O. While muscles from MCK-PGC-1α mice are known not to completely phenocopy adaptations with exercise training, our findings also highlight that there is a need to examine whether exercise training indeed improves P/O in mouse skeletal muscle.
    Keywords:  exercise; mitochondria; phospholipids; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70090
  25. Neuropharmacology. 2025 Oct 08. pii: S0028-3908(25)00416-2. [Epub ahead of print] 110708
    Modulation of cellular and mitochondrial dysfunction by TRPV4 during early stages of Vincristine-induced neurotoxicity in cultured neuronal model.
    Nilesh Kumar Das, Sushama Mohanta, Tanishaa Aswin, Subham Mishra, Tusar Kanta Acharya, Y T Chang, Chandan Goswami.
      Intracellular and mitochondrial Ca2+ play pivotal role in chemotherapeutics-induced toxicity. Here, we show that TRPV4, a thermosensitive ion channel implicated in pain, modulates mitochondrial Ca2+, ROS and temperature during chemotherapeutic stress. TRPV4 is present in the mitochondria and it regulates mitochondrial Ca2+, ATP, ROS and temperature. In this work, using specific probes and F11 cell (DRG-neuron-derived line) stably-expressing TRPV4 as a model system, we measured live cell cytosolic Ca2+ and mitochondrial Ca2+-levels, membrane potential (ΔΨm), cardiolipin levels and temperature in response to Vincristine-treatment and/or TRPV4 modulation. Live-cell Ca2+-imaging from more than 200 cells and ∼40,000 mitochondrial particles were analysed. Vincristine-treatment increases both basal cytosolic and mitochondrial Ca2+-levels. TRPV4 modulation alters the basal mitochondrial Ca2+-levels in Vincristine-stressed condition. The ΔΨm is altered in a context-dependent manner. Cytosolic ROS is increased when cells are treated with Vincristine and the same is further increased upon TRPV4 inhibition. Notably, Vincristine-treatment cools-down mitochondria than the control conditions. These findings may be relevant for a better understanding of the molecular basis of neuropathic pain and for developing mitochondria-targeted therapeutics in different pathophysiological conditions.
    Keywords:  CIPN; Vincristine; ion channels; live-cell Ca(2+)-imaging mitochondrial dysfunction; neurodegeneration; pain
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110708
  26. Genomics. 2025 Oct 06. pii: S0888-7543(25)00138-7. [Epub ahead of print] 111122
    A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.
    Zhiling Guan, Patrick Lindsey, Rick Kamps, Hubert J M Smeets.
      Mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) are associated with various pathologies, predominantly in energy-demanding tissues like muscles and brain. Characterizing these SNVs at the single-cell level is crucial for understanding their mechanism and clinical manifestation. Publicly available single-cell RNA sequencing (scRNA-seq) data could be an invaluable resource, but existing pipelines fall short in reliable detection of mtDNA SNVs from scRNA-seq data. Therefore, we developed a novel bioinformatics pipeline, that includes quality control, alignment to the mitochondrial genome, SNV calling, and annotation, and that filters-out sequencing errors. Coverage-dependent thresholds are customizable for detecting heteroplasmic SNVs. Duplicate reads can be retained as the majority were valid biological duplicates. Strand bias errors, exceeding a 1:3 ratio, RNA modification-induced errors, identified by the presence of multiple alternative alleles at the same position, and overrepresented SNVs were removed. Our data demonstrated that this pipeline effectively detects homoplasmic and heteroplasmic mtDNA SNVs in scRNA-Seq data.
    Keywords:  Mitochondrial DNA; SNVs calling; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.ygeno.2025.111122
  27. FEBS Open Bio. 2025 Oct 10.
    Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.
    Viet Bui, Maryline Santerre, Natalia Shcherbik, Bassel E Sawaya.
      Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10-50 nm distances by complex tethering proteins, including the core IP3R-GRP7 5-VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer's disease, disrupted MAM spacing directly affects Aβ production and mitochondrial function, while in Parkinson's disease, α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases.
    Keywords:  ER–mitochondria contact sites; calcium signaling; cellular stress responses; lipid metabolism; mitochondria‐associated membranes; neurodegeneration
    DOI:  https://doi.org/10.1002/2211-5463.70121
  28. Nat Commun. 2025 Oct 06. 16(1): 8863
    Quantitative CRACI reveals transcriptome-wide distribution of RNA dihydrouridine at base resolution.
    Cheng-Wei Ju, Han Li, Bochen Jiang, Xuanhao Zhu, Liang Cui, Zhanghui Han, Junxi Zou, Yunzheng Liu, Shenghai Shen, Hardik Shah, Chang Ye, Yuhao Zhong, Ruiqi Ge, Peng Xia, Yiyi Ji, Shun Liu, Fan Yang, Bei Liu, Yuzhi Xu, Jiangbo Wei, Li-Sheng Zhang, Chuan He.
      Dihydrouridine (D) is an abundant RNA modification, yet its roles in mammals remain poorly understood due to limited detection methods. We even do not have a comprehensive profile of D site location and modification stoichiometry in tRNA. Here, we introduce Chemical Reduction Assisted Cytosine Incorporation sequencing (CRACI), a highly sensitive, quantitative approach for mapping D at single-base resolution. Using CRACI, we generate the transcriptome-wide maps of D in both cytoplasmic and mitochondrial tRNAs from mammals and plants. We uncover D sites in mitochondrial tRNAs and identify DUS2L as the 'writer' protein responsible for human mitochondrial tRNAs. Furthermore, we demonstrate that most D modifications have a limited impact on tRNA stability, except for D20a, which also exhibits cis-regulation of adjacent D20 sites. Application of CRACI to human mRNA reveals that D modifications are present but rare and occur at very low stoichiometry. CRACI thus provides a powerful platform for investigating D biology across species.
    DOI:  https://doi.org/10.1038/s41467-025-63918-w
  29. Research (Wash D C). 2025 ;8 0912
    Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.
    Jianliang Huang, Can Zhang, Cheng Huang, Kun Deng, Yun Xiao, Wei Gao, Minghua Wu, Mingsheng Lei.
      Neurodegenerative diseases represent a major health threat, with dysfunction in energy metabolism and imbalance in glucose-lipid homeostasis constituting key pathogenic factors. As the cell's energy hub, mitochondria are closely associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, the precise mechanism by which mitochondrial energy metabolism affects glucose-lipid homeostasis remains unclear. This review summarizes currents insights into the role of mitochondrial function in energy metabolism and glucose-lipid regulation in neurodegenerative diseases. We examined how mitochondrial dynamics, oxidative phosphorylation, calcium homeostasis, and key signaling pathways-AMP-activated protein kinase/mammalian target of rapamycin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and Sirtuin 1-contribute to neuronal energy balance and metabolic regulation. We further explored the impact of other organelles on mitochondria and how the dynamic switching of mitochondrial morphology and function disrupts the critical glucose-lipid homeostasis. By focusing on mitochondrial dysfunction, metabolic disorders, and their interactions, we introduce the mitochondria-centered multi-organelle-energy metabolic-glucose-lipid homeostasis (MMH) network as a unifying theoretical framework that positions the progressive loss of metabolic flexibility as the fundamental essence of neurodegenerative disorders. The MMH network furnishes a novel lens through which the shared mechanistic underpinnings of neurodegenerative diseases can be deciphered, and thereby enable earlier diagnosis and precision therapeutics.
    DOI:  https://doi.org/10.34133/research.0912
  30. Nucleic Acids Res. 2025 Sep 23. pii: gkaf940. [Epub ahead of print]53(18):
    Ultra-fast variant effect prediction using biophysical transcription factor binding models.
    Rezwan Hosseini, Ali Tugrul Balci, Dennis Kostka, Nathan Clark, Maria Chikina.
      Sequence variation within transcription factor (TF)-binding sites can significantly affect TF-DNA interactions, influencing gene expression and contributing to disease susceptibility or phenotypic traits. Despite recent progress in deep sequence-to-function models that predict functional output from sequence data, these methods perform inadequately on some variant effect prediction tasks, especially with common genetic variants. This limitation underscores the importance of leveraging biophysical models of TF binding to enhance interpretability of variant effect scores and facilitate mechanistic insights. We introduce motifDiff, a novel computational tool designed to quantify variant effects using mono- and dinucleotide position weight matrices. motifDiff offers several key advantages, including scalability to score millions of variants within minutes, implementation of statistically rigorous normalization strategy critical for optimal performance, and support for both dinucleotide and mononucleotide models. We demonstrate motifDiff's efficacy by evaluating it across diverse ground truth datasets that quantify the effects of common variants in vivo, thereby establishing robust benchmarks for the predictive value of variant effect calculations. Finally, we show that our tool provides unique insights when interpreting human accelerated regions. motifDiff is available as a standalone Python application at https://github.com/rezwanhosseini/MotifDiff.
    DOI:  https://doi.org/10.1093/nar/gkaf940
  31. Brain Commun. 2025 ;7(5): fcaf342
    Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.
    Renae J Stefanetti, Sarah J Charman, Jane Newman, Kate Hallsworth, Alasdair P Blain, Yi Shiau Ng, Gráinne S Gorman.
      The m.3243A>G variant in the MT-TL1 gene is the most prevalent pathogenic variant in mitochondrial DNA in adults, associated with a wide clinical spectrum from asymptomatic individuals to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Although pharmacological trials in mitochondrial disorders are increasing, the lack of validated endpoints remains a significant barrier to therapeutic development. This cross-sectional observational study aimed to evaluate patients with and without mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome to identify factors associated with disease burden. Seventeen individuals genetically confirmed to harbour the heteroplasmic m.3243A>G pathogenic variant were enrolled: six who met the consensus-based diagnostic criteria for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (median age: 30.0 (inter-quartile range: 29.3-45.0) years). Ten patients who did not have a previous history of stroke-like episodes were assigned as 'non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes' (age: 37.5 (32.8-48.3) years). Of these patients in the non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes group, seven exhibited variable features of mitochondrial disease, including hearing loss, diabetes mellitus, migraine and gastrointestinal involvement, while the remaining three were asymptomatic. One patient was excluded from analysis due to a confirmed ischaemic stroke unrelated to mitochondrial disease. Assessments included disease severity (Newcastle mitochondrial disease adult scale) and patient-reported outcomes of fatigue (fatigue impact scale), health-related quality of life (Newcastle Mitochondrial-QoL), mental well-being (Warwick-Edinburgh mental wellbeing scale), autonomic symptoms (the composite autonomic symptom) and physical activity (The International Physical Activity Questionnaire). Performance outcomes included timed-up and go, handgrip strength, cardiopulmonary exercise testing and accelerometry. Age- and sex-matched healthy controls were included for comparison of accelerometry data (age: 35.5 (28.8-50.5) years). Despite comparable age and mitochondrial DNA heteroplasmy, patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome had significantly higher disease burden, reduced exercise capacity and lower levels of objectively measured physical activity compared to non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and controls (P < 0.05-0.001). Patient-reported outcomes did not significantly differ between mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome/non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. While non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes patients showed expected alignment between perceived and objective measures, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome patients demonstrated weak, absent, or paradoxical associations. This mismatch may reflect altered symptom perception, cognitive impairment, or disease-related adaptation. These findings underscore the complexity of disease expression in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Regulatory agencies encourage the inclusion of patient-centred endpoints; however, this study highlights the potential limitations of relying solely on patient-reported outcomes. The divergence between subjective and objective assessments supports the need for multi-dimensional outcomes that integrate both patient perspectives and objective measures to enhance the reliability and interpretability of clinical trials in primary mitochondrial disease.
    Keywords:  MELAS syndrome; m.3243A>G; mitochondrial; outcome measures; stroke-like episodes
    DOI:  https://doi.org/10.1093/braincomms/fcaf342
  32. Commun Biol. 2025 Oct 09. 8(1): 1445
    Myocardial disarray drives metabolic inefficiency in human cardiomyocytes.
    Charlène Jouve, Andrea Ruiz-Velasco, Erminia Donnarumma, Rémi Le Borgne, Iman Momken, Céline Pereira, Magali Seguret, Eva Vermersch, Elodie Vimont, Ivan Nemazanyy, Luc Bertrand, Timothy Wai, Jean-Marc Verbavatz, Mathias Mericksay, Jean-Sébastien Hulot.
      Adult cardiomyocytes are embedded within a highly organized myocardial microenvironment that imposes critical geometric cues essential for the alignment and distribution of organelles and the shaping of their unique, rectangular cellular morphology. Despite the association of cardiomyocyte disarray with human heart disease, the functional consequences of this cellular disorganization remain poorly understood. Here, we leveraged micropatterned substrates to promote structural alignment in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contrasting the effects of mechanical alignment on mitochondrial form and function with hiPSC-CMs cultured under standard unconstrained conditions. Cardiomyocytes cultured under unconstrained conditions exhibited misaligned sarcomeres and a perinuclear mitochondrial distribution while micropatterned hiPSC-CMs developed linear myofibrils and reconfigured sarcomere and mitochondrial organization, which increased mitochondrial respiration without augmenting mitochondrial mass. Notably, micropatterned hiPSC-CMs exhibited an increased number of mitochondria-associated membranes, as determined by proximity ligation assays and transmission electron microscopy, suggesting enhanced interactions between the sarcoplasmic reticulum and mitochondria. Together, these findings demonstrate that mitochondrial-sarcoplasmic architecture and geometry are critical spatial features that ensure bioenergetic efficiency of cardiomyocytes. This work underscores the importance of cellular organization in cardiomyocyte metabolism and function, providing insights into the pathophysiology of cardiac diseases marked by cellular disarray.
    DOI:  https://doi.org/10.1038/s42003-025-08842-x
  33. Genome Biol. 2025 Oct 07. 26(1): 343
    A ternary-code DNA methylome atlas of mouse tissues.
    Sol Moe Lee, David C Goldberg, Cameron Cloud, Jared B Parker, Christopher Krapp, Christian E Loo, Elliot Kim, Ivan Zhao, Chengcheng Jin, Rishi Porecha, Marisa S Bartolomei, Rahul M Kohli, Wanding Zhou.
       BACKGROUND: DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion.
    RESULTS: Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8-76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner.
    CONCLUSIONS: Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease.
    Keywords:  Aging; Cell identity; DNA methylation; Epigenetics; Hydroxymethylation; Mouse; Transcription regulation
    DOI:  https://doi.org/10.1186/s13059-025-03808-y
  34. FEBS Lett. 2025 Oct 10.
    Mapping the evolution of mitochondrial complex I through structural variation.
    Dong-Woo Shin, Tingting Chen, James A Letts.
      Respiratory complex I (CI) is a multi-subunit membrane protein complex important for the production of ATP via the oxidative phosphorylation pathway. The structure of CI is roughly conserved across species and is composed of subunits that are either embedded in the membrane or are exposed to the aqueous environment that together form an overall L-shaped 'boot'. The conserved core of CI is generally composed of 14 subunits. Across species, various less conserved 'supernumerary' or 'accessory' subunits have been added. Accessory subunits vary in number across species and can include proteins that are unique to specific lineages. Additionally, there are structural variations in the core subunits between clades. In this Review, we compare seven representative CI structures from divergent eukaryotic lineages to identify what aspects of the CI core subunits are susceptible to variation and classify eukaryotic accessory subunits into those conserved from the last eukaryotic common ancestor (LECA) or those that are lineage specific. Impact statement Understanding the biodiversity and evolution of mitochondrial complex I will reveal patterns that may reflect metabolic niche and can be used to constrain quantitative models of molecular evolution.
    Keywords:  OXPHOS; bioenergetics; cellular respiration; complex I; cryoEM structures; evolution; last eukaryotic common ancestor; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.70181
  35. Mol Syndromol. 2025 Oct;16(5): 469-475
    A Novel HERC2 Variant in Two Siblings with Autosomal Recessive Intellectual Developmental Disorder-38 and Cardiomyopathy.
    Hüseyin Bahadır Şenol, Çağatay Günay, Ayşe İpek Polat, Adem Aydın, Ayşe Semra Hız, Uluç Yiş.
       Background: HERC2 encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of HERC2-related disorders, including an unusual cardiac manifestation.
    Case Presentation: The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the HERC2 gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy.
    Conclusion: These patients underscore the importance of recognizing novel clinical features associated with the HERC2 LoF variants, which can guide disease characterization and patient management.
    Keywords:  Developmental delay; Dysmorphology; HERC2; Mitochondrial impairment; Neuronal migration disorders; Whole-exome sequencing
    DOI:  https://doi.org/10.1159/000543054
  36. Stem Cell Res Ther. 2025 Oct 08. 16(1): 546
    Mesenchymal stromal cell-mediated mitochondrial transfer unveils new frontiers in disease therapy.
    Huan Chen, Xu Chen, Zi-Hao Zhou, Jia-Rong Zheng, Ye Lu, Pei Lin, Yun-Fan Lin, Yu-Cheng Zheng, Bin Xiong, Rong-Wei Xu, Li Cui, Xin-Yuan Zhao.
      Mitochondrial dysfunction is a pivotal factor in the progression of various diseases, making it a critical therapeutic target. Mesenchymal stromal cells (MSCs) have shown promise in mitigating this dysfunction through the transfer of healthy mitochondria to damaged cells. This review comprehensively analyzes the mechanisms of MSC-derived mitochondrial transfer, including tunneling nanotubes (TNTs) and extracellular vesicles, and highlights their therapeutic potential across a spectrum of diseases, such as neurodegenerative disorders, ocular diseases, and inflammatory conditions. Additionally, strategies to enhance mitochondrial transfer efficiency-such as genetic modifications and optimization of MSC sources-are thoroughly explored. Despite these promising findings, challenges remain, including the need for a deeper understanding of transfer mechanisms, ensuring the quality and functionality of transferred mitochondria, and addressing potential immune responses. While MSC-derived mitochondrial transfer holds significant therapeutic potential, careful consideration of its dual nature, especially in specific pathological contexts such as cancer, is essential. With further research and technological advancements, this approach could become a cornerstone in the treatment of diseases characterized by mitochondrial dysfunction.
    Keywords:  Mesenchymal stromal cell; Mitochondrial transfer; Therapeutic efficacy
    DOI:  https://doi.org/10.1186/s13287-025-04675-x
  37. Nature. 2025 Oct;646(8084): 276-278
    Will AI ever win its own Nobel? Some predict a prize-worthy science discovery soon.
    Jenna Ahart.
      
    Keywords:  Machine learning; Scientific community; Technology
    DOI:  https://doi.org/10.1038/d41586-025-03223-0
  38. AACE Endocrinol Diabetes. 2025 Sep-Oct;12(3):12(3): 150-152
    Safe Use of Metformin in Mitochondrial Diabetes in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes: Insights From a Patient With m.3243A>G Mutation.
    Thanisha Santhosh, Prakriti Ramamurthy, Vinaya Simha.
       Background/Objective: Diabetes mellitus is often seen in patients with multisystem mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Although metformin is the cornerstone of type 2 diabetes pharmacotherapy, its use in MELAS is discouraged owing to concerns of worsening lactic acidosis. The objective of this report is to present a case where metformin use in MELAS was both clinically beneficial and safely tolerated.
    Case Report: A 49-year-old man, diagnosed with presumed type 2 diabetes at the age of 34 years, was started on metformin and glipizide resulting in good glucose control. Subsequent recognition of MELAS in other family members and the presence of sensorineural hearing loss prompted genetic testing, which confirmed the m.3243A>G mitochondrial sequence variant. Tapering of metformin to avoid potential lactic acidosis resulted in unacceptable hyperglycemia with fasting glucose in the range of 200 to 250 mg/dL. Metformin was then reintroduced, leading to improved glycemic control without elevation in lactate or unmasking of neurologic symptoms.
    Discussion: Metformin can potentially increase lactic acidosis and neurologic manifestations in patients with mitochondrial disorders as reported previously; however, this is not a universal finding. Metformin can be safely used in select patients with MELAS under appropriate clinical supervision. Withholding metformin in all patients with mitochondrial diabetes is unnecessary and possibly disadvantageous.
    Conclusion: This case highlights the importance of individualized therapeutic decisions in MELAS. Metformin, with appropriate monitoring, may represent a safe and effective treatment option for glycemic control even in mitochondrial diabetes.
    Keywords:  MELAS; lactic acidosis; m3243A>G mutation; metformin; mitochondrial diabetes
    DOI:  https://doi.org/10.1016/j.aed.2025.07.001
  39. BMC Med Ethics. 2025 Oct 08. 26(1): 131
    Public funding for mitochondrial donation: An Australian public deliberation.
    Ainsley J Newson, Jane Williams, Giuliana Fuscaldo, Ashleigh Hill, Ezra Kneebone, Karinne Ludlow, Catherine Mills, Megan Munsie, Sarah Norris, Paul Scuffham, Liz Sutton, David R Thorburn, Chris Degeling.
       BACKGROUND: Mitochondrial donation (MD) is a reproductive technique that aims to allow individuals at-risk of having a child with mitochondrial DNA disease avoid this outcome. Research to inform possible clinical use of MD is underway in Australia and births following the use of this technique have been announced in the United Kingdom. However, how the availability of MD will be funded in the mid- to long-term remains uncertain. One factor impacting funding decisions is public sentiment, yet there is scant evidence globally regarding attitudes toward MD funding. We sought to discern attitudes of informed members of the Australian public to how the provision of MD should be funded.
    METHODS: We held three community juries to gauge public views on how MD should be funded. A community jury involves providing a diverse group of citizens with expert testimony and facilitating deliberation to arrive at a position.
    RESULTS: Forty-two jurors participated across three juries. All juries voted by majority to support public funding for MD. Each jury made slightly different funding choices: one preferred full public funding, another preferred co-payment, while the third was divided among full public funding, co-payment, and no public funding. Reasons in favour of public funding comprised value for money, equity (i.e., the fair and just distribution of MD) and promoting innovation. Reasons against were opportunity cost, that MD wasn't necessary, and ethical objections to MD. Jurors also devised conditions for future funding: external review, capped services, better funding for alternative interventions and means testing.
    CONCLUSIONS: Should the current Australian MD research trial enable clinical provision, assuming that our participants' views are consistent with those of most Australians when informed of the trade-offs, benefits and costs, then it is likely that there will be strong public support for governments to fund access. However, some people may object to this expenditure.
    Keywords:  Bioethics; Citizens’ jury; Deliberative public engagement; Health expenditures; Mitochondrial Replacement Therapy; Public opinion
    DOI:  https://doi.org/10.1186/s12910-025-01284-4
  40. GEN Biotechnol. 2023 Oct;2(5): 353-359
    Developing Treatments for Rare Diseases on a Shoestring.
    Ana C Puhl, Sarah Negri, Maggie A Z Hupcey, Sean Ekins.
      There are thousands of rare genetic diseases lacking an approved treatment, many of which are life-limiting to children. Those caused by a missing protein may represent a target for protein replacement either by enzyme replacement therapy or gene therapy. One of the many challenges working on these types of genetic diseases is the availability of funding, as these diseases typically affect very small numbers of patients. Here we offer a novel case study of our approach to developing a treatment for one such rare disease, which has not required venture capital, angel investment or funding by foundations to date. We have instead pursued NIH small business grants to fund the early preclinical work performed by our academic collaborators and ourselves. Our approach to developing a treatment for a rare disease on a shoestring budget is unlike any of the alternative approaches to funding.
    Keywords:  Funding; Rare diseases; SBIR; Small business grants
    DOI:  https://doi.org/10.1089/genbio.2023.0033
  41. J Transl Med. 2025 Oct 06. 23(1): 1054
    ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish.
    Chunyan Xian, Qing Luo, Weiping Li, Lin Zou, Jinbo Liu.
       BACKGROUND: The ATP synthase F1 subunit α (ATP5F1A) gene encodes a critical structural subunit of mitochondrial complex V. ATP5F1A mutations are linked to mitochondrial complex V deficiency diseases. Although only 14 cases have been reported globally, the genotype-phenotype correlations and underlying molecular mechanisms remain poorly understood.
    OBJECTIVE: To investigate the pathogenic mechanisms of ATP5F1A deficiency through functional analysis of a recurrent missense variant.
    METHOD: A Han Chinese family with developmental delay and motor dysfunction was studied. Whole-exome sequencing and trio analysis identified the causative variant. Pathogenicity was evaluated using bioinformatic predictions and structural modeling. HEK293T cells were transfected with wild-type or mutant-type ATP5F1A plasmids for Western blot and immunofluorescence analysis. Morpholino (MO) oligonucleotides were microinjected into zebrafish embryos for gene knockdown. Motor neuron development was observed in Tg(mnx1:eGFP) zebrafish, with accompanying behavioral assessments. RNA sequencing was conducted to explore the underlying molecular pathways.
    RESULTS: A de novo missense variant (c.1252G > A, p.Gly418Arg) in ATP5F1A was identified and shown to segregate with the disease phenotype. The mutation reduced protein stability and expression. In HEK293T cells, the mutant protein exhibited reduced expression without affecting mitochondrial localization. In zebrafish, atp5fa1 knockdown caused growth retardation, motor dysfunction, and impaired motor neuron axon development. Rescue experiments with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Transcriptomic analysis identified 2,261 differentially expressed genes, enriched in neurotransmission and apelin signaling pathways. qPCR confirmed downregulation of autophagy-related genes (apln, becn1, map1lc3b) in knockdown larvae. Western blot showed that atp5fa1 knockdown increased P62 and decreased Lc3b-II expression in zebrafish models.
    CONCLUSION: This study is the first to report pathogenic ATP5F1A mutations in the Chinese population. Atp5fa1 dysfunction leads to multi-system defects and disease phenotypes in a zebrafish model, possibly mediated through inhibiting autophagy activation mechanisms.
    Keywords:  ATP5F1A; Complex v deficiency; Neurodevelopmental deficits; Zebrafish
    DOI:  https://doi.org/10.1186/s12967-025-07032-x
  42. Nat Med. 2025 Oct 09.
    Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study.
    Sebastian Lunke, Lilian Downie, Jade Caruana, Nathasha Kugenthiran, Paul De Fazio, Sebastian Hollizeck, Sophie E Bouffler, David J Amor, Alison D Archibald, Yvonne Bombard, John Christodoulou, Marc Clausen, Wendy Fagan, Clara Gaff, Ronda F Greaves, Christopher Gyngell, Anaita Kanga-Parabia, Nitzan Lang, Crystle Lee, Fiona Lynch, Anthony Marty, Melanie Marty, Candice McGregor, Jessica Riseley, Simon Sadedin, Katrina Scarff, Michelle da Cunha Torres, Erin Tutty, Ching Vang, Meaghan Wall, Ee Ming Wong, Alison Yeung, Ilias Goranitis, Stephanie Best, Danya F Vears, Zornitza Stark.
      Incorporating genomic sequencing into newborn screening will dramatically increase the number of detectable conditions but evidence is needed to guide policy. The prospective BabyScreen+ cohort study screened 1,000 newborns from the state of Victoria, Australia for variants in 605 genes associated with early-onset, severe, treatable conditions using whole-genome sequencing performed on dried blood spot cards. Sixteen infants (1.6%) were identified as having high-chance results. Of these, only one was detected by standard newborn screening. Average time to genomic newborn result was 13 days. Clinical impact ranged from instituting preventative measures or surveillance to active management, including transplantation. Twenty relatives received a diagnosis following cascade testing. Median parental decisional regret was low (median 0, interquartile range 0-10); >99% of participants thought genomic newborn screening should be available to all parents. Our study demonstrates the feasibility of clinically accredited genomic newborn screening, using a scalable model that is highly acceptable to parents. Future research is needed to address issues of scalability and equity.
    DOI:  https://doi.org/10.1038/s41591-025-03986-z
  43. Sci Adv. 2025 Oct 10. 11(41): eady3735
    ASPL couples the assembly of stress granules with their VCP-mediated disassembly.
    Gautam Pareek, Dongfang Li, Bo Wang, Jinjun Wu, Brian D Freibaum, Joseph L Basalla, Tharun Selvam Mahendran, Anurag Singh, Amanda Nourse, Honghu Quan, Ravi Kalathur, Mitra S Rana, Brian Maxwell, Yong-Dong Wang, James Messing, Yonghui Ni, Stanley Pounds, Rachayata Dharmat, Jingjun Lu, Xiujie Li-Harms, Alexandre F Carisey, Shondra M Pruett-Miller, J Paul Taylor, Priya Banerjee, Hong Joo Kim, Mondira Kundu.
      Stress granules (SGs) are dynamic RNA-protein assemblies that form in response to cellular stress and must be efficiently disassembled to restore normal cell function. Valosin-containing protein (VCP), an enzyme implicated in neurodegenerative diseases, is essential for SG disassembly, but whether and how this process is coordinated with SG assembly remains unclear. Here, we identify the VCP cofactor, Alveolar soft part sarcoma locus (ASPL) as a key regulator linking SG assembly and disassembly. ASPL promotes SG assembly by facilitating biomolecular condensation of Ras guanosine triphosphatase-activating protein-binding protein (G3BP) and stabilizing its interactions with other SG proteins. ASPL also facilitates phosphorylation and activation of VCP by UNC-51-like kinases 1 and 2 (ULK1/2), enabling G3BP extraction and efficient SG disassembly. Pathogenic VCP mutations that disrupt ASPL binding impair SG disassembly, a defect rescued by phosphomimetic mutations or ASPL depletion. Our findings suggest that disruptions in the ASPL-VCP interaction uncouple SG assembly and disassembly, representing a potential mechanism underlying VCP-associated neurodegenerative diseases.
    DOI:  https://doi.org/10.1126/sciadv.ady3735
  44. Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01192-1. [Epub ahead of print]44(10): 116421
    Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
    Lin Li, Yulan Chen, Yuanzhi Wang, Yuhui Dong, Haoran Wang, Ziyi Liu, Xin Ge, Puxiu Shen, Yue Li, Dingpu Liu, Xiangmei Zhou.
      Hexokinases (HKs) are essential enzymes in sugar metabolism, but their mitochondrial release also reflects cellular status in disease. Mycobacterium bovis (M. bovis), the causative agent of bovine and human tuberculosis, infects macrophages and induces mitophagy, yet the role of HKs in this process remains unclear. We find that M. bovis infection induces the release of HK2 from mitochondria, where it dissociates from voltage-dependent anion channel (VDAC). This dissociation promotes VDAC oligomerization, pore formation in the outer mitochondrial membrane, and mitochondrial damage. Damaged mitochondria subsequently undergo mitophagy, which enhances the intracellular survival of M. bovis. Consistent with this mechanism, we show that ESAT6-mediated phagosome membrane rupture is critical for HK2 release and subsequent mitochondrial events. Our study identifies a pathway by which M. bovis manipulates host cell processes to promote survival, providing insights into the host-pathogen interaction and potential avenues for tuberculosis prevention and therapy.
    Keywords:  CP: Microbiology; Mycobacterium bovis; VDAC; autophagy; hexokinase; macrophage; mitochondria; mitophagy; tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116421
  45. Clin Epigenetics. 2025 Oct 10. 17(1): 170
    DNA methylation and machine learning: challenges and perspective toward enhanced clinical diagnostics.
    Erfan Aref-Eshghi, Arash B Abadi, Mohammad-Erfan Farhadieh, Amirreza Hooshmand, Fatemeh Ghasemi, Leila Youssefian, Hassan Vahidnezhad, Taylor Martin Kerrins, Xiaonan Zhao, Mahdi Akbarzadeh, Hakon Hakonarson, Amir Hossein Saeidian.
      DNA methylation is an epigenetic modification that regulates gene expression by adding methyl groups to DNA, affecting cellular function and disease development. Machine learning, a subset of artificial intelligence, analyzes large datasets to identify patterns and make predictions. Over the past two decades, advances in bioinformatics technologies for arrays and sequencing have generated vast amounts of data, leading to the widespread adoption of machine learning methods for analyzing complex biological information for medical problems. This review explores recent advancements in DNA methylation studies that leverage emerging machine learning techniques for more precise, comprehensive, and rapid patient diagnostics based on DNA methylation markers. We present a general workflow for researchers, from clinical research questions to result interpretation and monitoring. Additionally, we showcase successful examples in diagnosing cancer, neurodevelopmental disorders, and multifactorial diseases. Some of these studies have led to the development of diagnostic platforms that have entered the global healthcare market, highlighting the promising future of this field.
    Keywords:  Clinical application; CpG sites; DNA methylation; Epigenetics; Machine learning
    DOI:  https://doi.org/10.1186/s13148-025-01967-0
  46. Cell Death Dis. 2025 Oct 06. 16(1): 700
    PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.
    Shiyi Yin, Yibo Zhai, Run Song, Jiannan Wu, Yongjiang Zhang, Miao Yu, Hongxia Ma, Mengmeng Shen, Xiaoyi Lai, Weina Jin, Yunqi Xu, Junqiang Yan.
      Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP+/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 binding. Disrupting this interface abolished BCL-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD. Schematic summary. In normal neuronal cells, PARL can inhibit the release of apoptotic signals by interacting with Nur77. In the MPP+-induced PD model, PARL expression is reduced inhibits the apoptosis of dopaminergic neurons, and reduces cell viability. Mechanistic schema: Normal state: PARL-Nur77 complex stabilizes mitochondrial membrane integrity, inhibiting BCL-2 ubiquitination. MPP+ injury: PARL downregulation disrupts Nur77 binding, triggering BAX oligomerization and caspase-3 activation. Therapeutic rescue: Nur77 overexpression restores PARL-mediated anti-apoptotic signaling.
    DOI:  https://doi.org/10.1038/s41419-025-08035-8
  47. J Respir Biol Transl Med. 2025 ;2(3):
    Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
    Le Xu, Chunting Tan, Nicole Talaba, Andrew Sou, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.
      Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.
    Keywords:  CDH; Diaphragm; FGF10; LONP1; Lung; Mitochondria; SHH
    DOI:  https://doi.org/10.70322/jrbtm.2025.10008
  48. Front Biosci (Landmark Ed). 2025 Sep 26. 30(9): 44648
    Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
    Alina Chaplygina, Daria Zhdanova.
       BACKGROUND: Mitochondrial dynamics-the balance between fission, fusion, and mitophagy-are essential for maintaining cellular homeostasis and are increasingly implicated in the pathogenesis of Alzheimer's disease (AD).
    METHODS: Here, we investigated the effects of targeted modulation of mitochondrial fission and fusion on mitochondrial morphology and metabolic status in primary hippocampal cultures derived from 5xFAD transgenic mice. Mitochondrial dynamics were modulated using the fission inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), the fusion promoter mitochondrial fusion promoter M1 (MFP M1), and exogenous zinc as a fission activator. We evaluated mitochondrial morphology, lipofuscin accumulation, beta-amyloid (Aβ42) levels, and reactive oxygen species (ROS). The general condition of the cultures was assessed morphologically using neuronal and astrocytic markers.
    RESULTS: Modulating mitochondrial dynamics altered mitochondrial morphology, decreased Aβ42, lipofuscin, and ROS levels, and improved cellular organization. Treatments with MFP and Mdivi-1 promoted mitochondrial hyperfusion without complete network integration and were associated with reduced astrogliosis and increased neuronal density. In contrast, zinc induced dose-dependent mitochondrial fragmentation and astrocytic clasmatodendrosis, with lower concentrations enhancing Aβ clearance and higher concentrations inducing toxicity.
    CONCLUSIONS: Mitochondrial fusion and fission significantly influence lipofuscin and amyloid accumulation in 5xFAD cultures, underscoring their potential as therapeutic targets in neurodegenerative diseases. We propose that mitochondrial morphology acts as a key regulator of both cellular homeostasis and disease pathology.
    Keywords:  Alzheimer’s disease; lipofuscin; mitochondria; mitochondrial dynamic; mitochondrial fission; mitochondrial fusion; primary cell culture
    DOI:  https://doi.org/10.31083/FBL44648
  49. Adv Sci (Weinh). 2025 Oct 06. e06107
    Onion-Mitochondria Inhibit Lipopolysaccharide-Induced Acute Lung Injury by Shaping Lung Macrophage Mitochondrial Function.
    Qingbo Xu, Yun Teng, Yinan Huang, Jingyao Mu, Lucy Teng, Hongjia Qian, Qiming Huang, Minmin Liu, Yi Zou, Lifeng Zhang, Michael L Merchant, Xiang Zhang, Jun Yan, Huang-Ge Zhang.
      Mitochondrial dysfunction contributes to various inflammatory-related diseases by triggering the release of inflammatory molecules. Targeting mitochondrial dysfunction is emerging as a promising avenue for treating inflammatory diseases. Here, it is demonstrated that dietary plant-derived mitochondria (P-Mit) are capable of rescuing the lung macrophage mitochondrial (M-Mit) dysfunction in lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI). Specifically, oral administration of dietary onion-derived mitochondria (O-Mit) can travel from the gut to the lungs in ALI mice, where preferentially uptake by lung macrophage mediated by the interaction between O-Mit phosphatic acid (PA) and macrophage complement C3b/C4b receptor 1 Like (CR1L), followed by fusing with murine M-Mit and by reprograming the M-Mit energy metabolism in the lungs of ALI mice. Further evidence suggests that O-Mit enriches methyl 3,4-dihydroxybenzoate (MDHB) inhibits M-Mit NADH dehydrogenase subunit 1 (ND1) gene expression in the epigenetic process, which represses LPS-induced complex I-related oxidative stress activation and excessive mitochondrial fission via modulating dynamin-related protein 1 (DRP1) phosphorylation and cardiolipin peroxidation in M-Mit, eventually rescues the LPS-induced ALI. Given LPS-induced mouse model of ALI is widely used to study human ALI and acute respiratory distress syndrome, this finding provides a clinical potential for the treatment of human ALI via edible P-Mit.
    Keywords:  Cardiolipin peroxidation; Complex I subunits NADH dehydrogenase 1 (ND1); Dynamin‐related protein 1 (DRP1) phosphorylation; Mitochondrial dysfunction; Plant mitochondria‐animal mitochondria cross‐kingdom fusion
    DOI:  https://doi.org/10.1002/advs.202506107
  50. Cell Mol Life Sci. 2025 Oct 07. 82(1): 347
    Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.
    Wei-Chia Tsao, Yi-Chun Huang, Hsin-Ho Sung, Chi-Hung Lin, Hwei-Jan Hsu, Hsiu-Fen Lin, Cheng-Ting Chien.
      The intricate process of dendritic arborization is essential for forming functional neural circuits, and many of the underlying molecular and cellular mechanisms have been uncovered. However, how they are linked to regulate dendritic arborization in neurons remains further exploration. Through genetic screening, we identify the splicing factor Sf3b1 as functioning cell-autonomously in neuronal dendrite growth and maintenance. Our transcriptomic analysis links Sf3b1-regulated alternative splicing to modulation of metabolic pathways, and we assess altered splicing patterns for several mitochondria-related genes. Importantly, Sf3b1 knockdown in neurons results in dramatic mitochondrial fragmentation and specific reductions in mitochondrial counts and ATP levels in dendrites, revealing a pivotal role for Sf3b1 in modulating the energy supply necessary for dendritic arborization. Additionally, a genetic rescue experiment uncovered mitophagy-modulating molecules that effectively restored the mitochondrial health and dendritic arborization of Sf3b1-depeted neurons. Our study establishes a previously unrecognized connection between RNA splicing and mitochondrial demand in differentiating neurons, providing insights into bioenergetic requirements for dendritic growth and maintenance.
    Keywords:  ATP levels; Alternative RNA processing; Metabolic regulation; Mitophagy; Transcriptomic analysis
    DOI:  https://doi.org/10.1007/s00018-025-05860-0
  51. Aging Cell. 2025 Oct;24(10): e70191
    Experimental Evidence Against Taurine Deficiency as a Driver of Aging in Humans.
    Vincent Marcangeli, Marina Cefis, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.
      Taurine deficiency was recently proposed as a driver of aging in various species, including humans. To test this hypothesis, we assessed whether circulating taurine was associated with aging and physical performance in 137 physically inactive and physically active men aged 20-93. No association between circulating taurine levels and age, muscle mass, strength, physical performance, or mitochondrial function was observed, thereby challenging the implication of taurine deficiency as a primary driver of aging in humans.
    Keywords:  aging biomarker; functional capacities; geroscience; mitochondria; mitochondrial function; physical activity; sarcopenia; skeletal muscle; taurine
    DOI:  https://doi.org/10.1111/acel.70191
  52. Nat Cell Biol. 2025 Oct 07.
    Senescence-coupled differentiation selectively eliminates cancer-prone stem cells.
      
    DOI:  https://doi.org/10.1038/s41556-025-01783-x
  53. Cell Rep. 2025 Oct 04. pii: S2211-1247(25)01128-3. [Epub ahead of print]44(10): 116357
    P-Rex1 limits glucose clearance and suppresses hepatocyte glucose uptake and mitochondrial metabolism independently of its Rac-GEF activity.
    Julia Y Chu, Elpida Tsonou, Polly A Machin, Kirsty MacLellan-Gibson, Anna G Roberts, Stephen A Chetwynd, Adam T McCormack, John C Stephens, Elisa Benetti, Gemma K Kinsella, David Baker, David C Hornigold, Heidi C E Welch.
      We investigated the roles of Rac guanine-nucleotide exchange factor (Rac-GEF) P-Rex1 in glucose homeostasis using Prex1-/- and catalytically inactive Prex1GD mice. P-Rex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout aging. Prex1-/- mice on a high-fat diet are protected from diabetes. The increased glucose clearance in Prex1-/- mice may stem in part from constitutively enhanced hepatic glucose uptake. P-Rex1 controls Glut2 surface levels and mitochondrial morphology, membrane potential, and ATP production in hepatocytes, independently of its catalytic activity. The inverse agonist GRA2 showed that P-Rex1 suppresses glucose uptake and mitochondrial ATP production in hepatocytes through the orphan GPCR Gpr21. Cell fractionation showed that P-Rex1 controls Gpr21 trafficking, independently of its catalytic activity. We propose that P-Rex1 limits hepatocyte glucose uptake by retaining Gpr21 at the plasma membrane. These findings delineate new strategies for controlling glucose homeostasis.
    Keywords:  CP: Cell biology; CP: Metabolism; G protein-coupled receptor; GEF; GPCR; Gpr21; P-Rex1; glucose homeostasis; guanine nucleotide exchange factor; liver; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2025.116357
  54. Front Cell Neurosci. 2025 ;19 1636185
    Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
    Peizhu Lv, Xia Chen, Shiping Liu, Yu Zhang, Yan Bai, Shun Wang, Yulin Wang.
      This article conducts a systematic search of literature in the fields of neuroscience, cell biology, immunometabolism, etc. from 1990 to 2025, with PubMed/WebofScience as the core database. Experimental and clinical studies covering the core mechanisms of the preprophase of PD (mitochondrial imbalance → NLRP3 activation → lactation modification → α -SYN pathology) were included, and non-interaction mechanisms and clinical-phase studies were excluded. The pathological interaction network of mitochondrial dynamic imbalance, lysosomes - mitochondrial interaction disorder and neuroinflammation in Parkinson's disease (PD) was explained. Construct a three-dimensional pathological network of "energy-inflammation-protein homeostasis" to provide a theoretical basis for early intervention. The imbalance of mitochondrial fission/fusion leads to the accumulation of fragmented mitochondria, triggering energy metabolism disorders and oxidative stress; abnormal aggregation of α-synuclein (α-syn) disrupts mitochondrial-endoplasmic reticulum membrane (MAM) calcium signaling, upregulates Miro protein to inhibit mitochondrial autophagy clearance, forming a vicious cycle of neuronal damage. Defects in the PINK1/Parkin pathway and LRRK2 mutations interfere with the turnover of mitochondrial fission complexes, causing mtDNA leakage, activating the NLRP3 inflammasome, and driving neuroinflammatory cascades. Additionally, lysosomal dysfunction caused by GBA1 mutations exacerbates mitochondrial quality control defects through Rab7 activity imbalance. Abnormal lactate metabolism may influence inflammasome activity through epigenetic regulation, but its role in PD needs further validation. Based on the above mechanisms, a diagnostic strategy for the prodromal phase integrating dynamic monitoring of mitochondrial fragmentation index, lysosomal function markers, and inflammatory factors is proposed, along with new intervention directions targeting Drp1, NLRP3, and the lysosome-mitochondria interface.
    Keywords:  NLRP3 inflammasome; Parkinson’s disease; lactylation modification; mitochondrial dynamics; prodromal phase
    DOI:  https://doi.org/10.3389/fncel.2025.1636185
  55. Genetics. 2025 Oct 06. pii: iyaf215. [Epub ahead of print]
    Mondo: Integrating Disease Terminology Across Communities.
    Nicole A Vasilevsky, Sabrina Toro, Nicolas Matentzoglu, Joseph E Flack, Kathleen R Mullen, Harshad Hegde, Sarah Gehrke, Patricia L Whetzel, Yousif Shwetar, Nomi L Harris, Mee S Ngu, Gioconda L Alyea, Megan S Kane, Paola Roncaglia, Eric Sid, Courtney L Thaxton, Valerie Wood, Roshini S Abraham, Maria Isabel Achatz, Pamela Ajuyah, Joanna S Amberger, Lawrence Babb, Jasmine Baker, James P Balhoff, Jonathan S Berg, Amol Bhalla, Xavier Bofill-De Ros, Ian R Braun, Eleanor C Broeren, Blake K Byer, Alicia B Byrne, Tiffany J Callahan, Leigh C Carmody, Lauren E Chan, Amanda R Clause, Julie S Cohen, Marcello DeLuca, Natalie T Deuitch, May Flowers, Jamie Fraser, Toyofumi Fujiwara, Vanessa Gitau, Jennifer L Goldstein, Dylan Gration, Tudor Groza, Benjamin M Gyori, William Hankey, Jason A Hilton, Daniel S Himmelstein, Stephanie S Hong, Charles T Hoyt, Robert Huether, Eric Hurwitz, Julius O B Jacobsen, Atsuo Kikuchi, Sebastian Köhler, Daniel R Korn, David Lagorce, Bryan J Laraway, Jane Y Li, Adriana J Malheiro, James McLaughlin, Birgit H M Meldal, Shruthi Mohan, Sierra A T Moxon, Monica C Munoz-Torres, Tristan H Nelson, Frank W Nicholas, David Ochoa, Daniel Olson, Tudor I Oprea, Tomiko T Oskotsky, David Osumi-Sutherland, Kelley Paris, Helen E Parkinson, Zoë M Pendlington, Xiao P Peng, Amy Pizzino, Sharon E Plon, Bradford C Powell, Julie C Ratliff, Heidi L Rehm, Lyubov Remennik, Erin R Riggs, Sean Roberts, Peter N Robinson, Justyne E Ross, Kevin Schaper, Brian M Schilder, Johanna L Schmidt, Elliott W Sharp, Morgan N Similuk, Damian Smedley, Tam P Sneddon, Rachel Sparks, Ray Stefancsik, Gregory S Stupp, Shilpa Sundar, Terue Takatsuki, Imke Tammen, Kezang C Tshering, Deepak R Unni, Eloise Valasek, Adeline Vanderver, Alex H Wagner, Ryan F Webb, Danielle Welter, Doron Yaya-Stupp, Andreas Zankl, Xingmin Aaron Zhang, Julie A McMurry, Christopher G Chute, Ada Hamosh, Christopher J Mungall, Melissa A Haendel.
      Precision medicine aims to enhance diagnosis, treatment, and prognosis by integrating multimodal data at the point of care. However, challenges arise due to the vast number of diseases, differing methods of classification, and conflicting terminological coding systems and practices used to represent molecular definitions of disease. This lack of interoperability artificially constrains the potential for diagnosis, clinical decision support, care outcome analysis, as well as data linkage across research domains to support the development or repurposing of therapeutics. There is a clear and pressing need for a unified system for managing disease entities ⁠- including identifiers, synonyms, and definitions. To address these issues, we created the Mondo disease ontology-a community-driven, open-source, unified disease classification system that harmonizes diverse terminologies into a consistent, computable framework. Mondo integrates key medical and biomedical terminologies, including Online Mendelian Inheritance in Man (OMIM), Orphanet, Medical Subject Headings (MeSH), National Cancer Institute Thesaurus (NCIt), and more, to provide a comprehensive and accurate representation of disease concepts with fully provenanced and attributed links back to the sources. Mondo can be used as the handle for curation of gene-disease associations utilized in diagnostic applications, research applications such as computational phenotyping, and in clinical coding systems in clinical decision support by pointing the clinician to the numerous knowledge resources linked to the Mondo identifier. Mondo's community-centric approach, stewarded by the Monarch Initiative's expertise in ontologies, ensures that the ontology remains adaptable to the evolving needs of biomedical research and clinical communities, as well as the knowledge providers.
    Keywords:  biomedical informatics; community-driven ontology; disease classification; disease integration; disease ontology; disease terminology; rare disease
    DOI:  https://doi.org/10.1093/genetics/iyaf215
  56. Nat Chem. 2025 Oct 09.
    Thermochemical heterolytic hydrogenation catalysis proceeds through polarization-driven hydride transfer.
    Hai-Xu Wang, Yogesh Surendranath.
      Heterolytic hydrogenations, which split H2 across a hydride acceptor and proton acceptor, comprise a key reaction class that spans the chemical value chain, including CO2 hydrogenation to formate and NADH regeneration from nicotinamide adenine dinucleotide (NAD+). The dominant mechanistic models for heterogeneous catalysis of these reactions invoke classical surface reaction steps, largely ignoring the role of interfacial charge separation. Here we quantify the electrochemical potential of the catalyst during turnover and uncover evidence supporting an interfacial electrochemical hydride transfer mechanism for this overall thermochemical reaction class. We find that the proton acceptor induces spontaneous electrochemical polarization of the metal catalyst surface, thereby controlling the thermodynamic hydricity of the surface M-H intermediates and driving rate-determining electrochemical hydride transfer to the hydride acceptor substrate. This mechanistic framework, which applies across diverse reaction media and for the hydrogenation of CO2 to formate and NAD+ to NADH, enables the determination of intrinsic reaction kinetics and exposes design principles for the future development of sustainable hydrogenation reactivity.
    DOI:  https://doi.org/10.1038/s41557-025-01939-0
  57. Mov Disord. 2025 Oct 08.
    RRP12 Variants Are Associated With Autosomal Recessive Brain Calcifications.
    Edoardo Monfrini, Paola Rinchetti, Mathieu Anheim, Anna Klingseisen, Ouhaid Lagha-Boukbiza, Zhidong Cen, Dehao Yang, Xinhui Chen, Reza Maroofian, Henry Houlden, Gioia Cappelletti, Anne-Claire Richard, Olivier Quenez, Camilo Toro, Steven J Frucht, Francesco Lotti, Wei Luo, David Hunt, Gael Nicolas, Giulietta M Riboldi.
       BACKGROUND: Primary brain calcifications are observed in several inherited diseases due to different pathogenic mechanisms, including the disruption of the neurovascular unit, mitochondrial dysfunction, and impaired nucleic acid metabolism.
    OBJECTIVE: The aim of the study was to identify a novel genetic cause of brain calcifications in genetically unresolved cases.
    METHODS: Exome sequencing data from two unrelated Pakistani patients with generalized dystonia and primary brain calcifications were analyzed. The best candidate gene (ie, RRP12) was then investigated in two large cohorts of patients with brain calcifications from France (n = 111) and China (n = 543). RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model.
    RESULTS: A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Screening of two large cohorts of patients with unresolved brain calcifications revealed two affected French siblings and one unrelated Chinese individual, each carrying rare, biallelic, missense variants in the RRP12 gene (c.1429G>A, p.E477K and c.2634T>G, p.F878L, respectively). Molecular studies revealed a significant reduction in RRP12 protein and abnormal nucleolar morphology in patient'derived fibroblasts. Consistent with its essential role in RNA metabolism, rrp12 knockdown in zebrafish caused severe developmental delay, crimping, and early lethality.
    CONCLUSIONS: RRP12 is a novel candidate gene for autosomal recessive brain calcifications, possibly associated with a wide clinical spectrum ranging from early-onset severe forms to adult-onset paucisymptomatic presentations. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  PFBC; RRP12; brain calcifications; dystonia; primary familial brain calcification
    DOI:  https://doi.org/10.1002/mds.70058
  58. Ann Neurol. 2025 Oct 06.
    Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism.
    Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad ElGhazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth.
       OBJECTIVE: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.
    METHODS: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.
    RESULTS: Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.
    INTERPRETATION: Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025 ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.78013
  59. Cell Death Dis. 2025 Oct 06. 16(1): 676
    Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.
    Aravindan Narayanan, Souvik Guha, Avinash Mali, Sharmila A Bapat.
      Ex vivo stem cell self-renewal and maintenance is supported by absence of serum-derived mitogens. In the present study, we sought to elucidate the proteomes of stem-like cells grown in serum-free media across a panel of high-grade serous ovarian cancer cell lines, which encompass a gradient from epithelial, intermediate and mesenchymal cell phenotypes to recapitulate the heterogeneity of the disease. MaxQuant-based label-free quantification of proteins identified that despite their different cellular and molecular architectures, all phenotypes exhibited mitochondria- and stemness-related pathways under conditions of serum starvation, although the specific proteins involved were discrete to each phenotype. This suggests that common cellular programs in a disease can be mediated through variable biological networks that generates molecular heterogeneity. We further explored if these pathways are inter-related, co-regulated or just incidentally associated in response to an environment depleted of growth factors and mitogens. Irrespective of their phenotype, cell lines on serum-starvation displayed an increased amount of mitochondrial DNA, mitochondrial biogenesis and mitochondrial activity with a switch from glycolysis to oxidative phosphorylation fuelled by the fatty acid oxidation. Ultra-structural studies implicated this metabolic fluctuation was regulated by dynamic mitochondrial remodelling. This also led us to explore a possible therapeutic strategy of targeting mitochondrial function to restrict tumor regenerative potential and disease recurrence. Conclusively, these new avenues contribute to a more comprehensive understanding of ovarian cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07987-1
  60. Mol Syndromol. 2025 Jun 23.
    A Novel Compound Heterozygous CYP27A1 Variant in Cerebrotendinous Xanthomatosis: A Case Report from a Non-Consanguineous Family.
    Hande Nur Cesur Baltacı, Burcu Sağlam Ada, Nüket Yürür Kutlay, Ajlan Tükün, Serap Tıraş Teber, Turgay Coşkun.
       Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid storage disorder characterized by the accumulation of cholesterol and cholestanol in various tissues. It is caused by pathogenic variants in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase.
    Case Presentation: Here, we present an 8-year-old boy with attention-deficit/hyperactivity disorder, born to non-consanguineous parents. He was referred to our center for CYP27A1 gene analysis and genetic counseling, following the identification of a homozygous deletion in exon 6 of the CYP27A1 gene in his mother. His plasma cholestanol levels were also elevated, supporting a diagnosis of CTX. The proband's father had a history of epilepsy and mild intellectual disability. Genetic analysis of the father revealed a novel heterozygous p.(Glu170Valfs*16) variant in the CYP27A1 gene. Based on these findings, the proband was found to carry a compound heterozygous variant in CYP27A1, confirming the molecular diagnosis of CTX. After genetic counseling, treatment with chenodeoxycholic acid (CDCA) was initiated. Plasma cholestanol levels normalized, and some clinical symptoms showed improvement after 2 months of treatment.
    Conclusions: Early genetic screening of presymptomatic family members is critical, as timely initiation of CDCA therapy can prevent or significantly attenuate the clinical progression of CTX.
    Keywords:  CYP27A1; Cerebrotendinous xanthomatosis
    DOI:  https://doi.org/10.1159/000547016
  61. Pediatr Int. 2025 Jan-Dec;67(1):67(1): e70211
    Primary systemic carnitine deficiency: Phenotypic variability, diagnostic challenges, and long-term outcomes.
    Eymen Pınar, Tanyel Zubarioglu, Hanım Babazade, Kağan Çalışgan, Mehmet Şerif Cansever, Ertuğrul Kıykım, Çiğdem Aktuğlu Zeybek.
       BACKGROUND: Primary systemic carnitine deficiency (CDSP) is a rare inherited metabolic disorder characterized by impaired carnitine transport due to mutations in the SLC22A5 gene, leading to impaired mitochondrial fatty acid oxidation. The aim of this retrospective, descriptive study was to investigate the clinical, biochemical, and molecular features of CDSP in Turkey, where the lack of a national expanded metabolic screening program contributes to delayed diagnosis and severe complications.
    METHODS: The clinical, biochemical, and molecular profiles of 12 patients from eight families diagnosed between 2003 and 2025 were retrospectively analyzed. Data on family history, consanguinity, clinical manifestations-including cardiomyopathy, muscle weakness, neurological symptoms, and liver dysfunction-plasma free carnitine levels, and echocardiographic measurements were collected and analyzed.
    RESULTS: The majority of patients (92%) were from consanguineous families. Cardiomyopathy was the most common clinical feature (75%), followed by muscle weakness (50%), neurological symptoms (42%), and liver dysfunction (33%). A novel SLC22A5 variant (c.125T>C; p.Leu42Pro) was identified that expands the known genetic spectrum of CDSP. Oral carnitine supplementation significantly increased plasma free carnitine levels (p = 0.01) and improved long-term interventricular septal thickness Z-scores (p = 0.045). In addition, cholestasis was observed in two patients, suggesting an expanded disease phenotype.
    CONCLUSION: These results emphasize the crucial role of early detection and family screening in the prevention of life-threatening complications associated with CDSP. Long-term carnitine therapy improves metabolic and cardiac outcomes, underscoring the need for early intervention and inclusion of CDSP in national newborn screening programs.
    Keywords:   SCL22A5 ; cardiomyopathies; cholestasis; echocardiography; systemic carnitine deficiency
    DOI:  https://doi.org/10.1111/ped.70211
  62. Nat Rev Genet. 2025 Oct 10.
    Clinical use of polygenic risk scores: current status, barriers and future directions.
    Iftikhar J Kullo.
      Genome-wide association studies have identified thousands of single-nucleotide variants that are associated with complex traits, including cardiometabolic diseases, cancers and neurological disorders. Polygenic risk scores (PRSs), which aggregate the effects of these variants, can help to identify individuals who are at increased risk of developing such diseases. As PRSs are typically only weakly associated with conventional risk factors for these diseases, they have incremental predictive value and are beginning to be incorporated into clinical practice to guide early detection and preventive strategies. However, challenges to their use - such as suboptimal precision, poor transferability across diverse populations and low familiarity among patients and providers with the concept of polygenic risk - must be addressed before their broader clinical adoption. This Review explores the current state of the field, highlights key challenges and outlines future directions for the use of PRSs to improve risk prediction and to advance personalized prevention in clinical care.
    DOI:  https://doi.org/10.1038/s41576-025-00900-8
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