bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–11–16
72 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
  2. Alternative start codon selection shapes mitochondrial function and rare human diseases.
  3. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  4. Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy.
  5. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  6. Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
  7. Perioperative Care of a Child With Combined Oxidative Phosphorylation Deficiency 6: Total Intravenous Anesthesia With Remimazolam.
  8. Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.
  9. The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.
  10. CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.
  11. STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
  12. Monitoring the complexity and dynamics of mitochondrial translation.
  13. The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
  14. GREGoR: accelerating genomics for rare diseases.
  15. Unlocking extracellular mitochondria from bench to clinical application in stroke.
  16. Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
  17. Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.
  18. Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
  19. MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.
  20. Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
  21. Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
  22. PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
  23. Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.
  24. Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
  25. UPRmt-regulated mitokines: novel strategies for myocardial injury repair.
  26. Therapeutic remodeling of the ceramide backbone prevents kidney injury.
  27. ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.
  28. M3Hep: A Multimodal Hepatotoxicity Prediction Model Combining Mitochondrial Toxicity and Masking Strategy.
  29. Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
  30. RNA sequencing provides functional insights and diagnostic resolution in previously unsolved rare disease cases.
  31. Mitochondrial Genome Variants and Nuclear Mitochondrial DNA Segments in 7331 Individuals from NyuWa and 1KGP.
  32. Identification of a novel MIPEP splice variant with altered substrate-binding properties.
  33. Developmental bioenergetics: a comparative perspective on mitochondrial efficiency in paediatric physiology.
  34. Aberrant Splicing of Dnm1l Impairs Cardiac Bioenergetics and Mitochondrial Dynamics in Myotonic Dystrophy Type I (DM1).
  35. A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.
  36. Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics.
  37. Beyond Folding: Expanding the Functional Landscape of Hsp90 Chaperone Machinery in Health and Disease.
  38. Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.
  39. Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
  40. iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
  41. Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.
  42. CRISPR vs cholesterol: can gene editing prevent heart disease?
  43. The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.
  44. Calcium Regulation of Mitochondrial Metabolism.
  45. Interactions of Arachidonic Acid with AAC1 and UCP1.
  46. Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.
  47. The legacy of Bruce Ames and mitochondrial DNA mutagenicity: integrating oxidative stress, aging, and modern perspectives.
  48. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  49. Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.
  50. iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
  51. Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.
  52. Clinical Feasibility of Long-Read WGS for DNA Methylation Signature Analysis.
  53. New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse.
  54. A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.
  55. TEDD: a comprehensive database for translation efficiency dynamics.
  56. Programmed axon degeneration: mechanism, inhibition and therapeutic potential.
  57. Consensus guidelines for cellular label-free optical metabolic imaging: ensuring accuracy and reproducibility in metabolic profiling.
  58. From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
  59. Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.
  60. Estimation and mapping of the missing heritability of human phenotypes.
  61. A combined genomic arrhythmia propensity score delineates cumulative risk.
  62. 5-Formylcytosine is not a prevalent RNA modification in mammalian cells.
  63. Somatic mutations at scale.
  64. Protocol for in vivo assessment of glucose metabolism in mouse models.
  65. PCNA is a nucleotide exchange factor for the clamp loader ATPase complex.
  66. The function of Mak16 in ribosome biogenesis depends on its [4Fe-4S] cluster.
  67. Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.
  68. The effect of triclosan uncovers the possible involvement of complex II in the oxidation of glycerol-3-phosphate in brain mitochondria.
  69. Drug discovery research with the iPSC models of neurodegenerative diseases.
  70. The mind-bending power of placebo.
  71. GroEL/ES chaperonin unfolds then encapsulates a nascent protein on the ribosome.
  72. Uncommon yet impactful - case-based reflections on rare neurologic disorders.
  1. Int J Mol Sci. 2025 Oct 22. pii: 10275. [Epub ahead of print]26(21):
    Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
    Shruti Somai, Chioma H Aloh, Dillon E King, William C Copeland.
      Mitochondria are vital for cellular energy production, as these organelles generate most of the cellular energy required for various metabolic processes. Mitochondria contain their own circular DNA, which is present in multiple copies and is exclusively maternally inherited. Cellular energy in the form of adenosine 5'-triphosphate is produced via oxidative phosphorylation and involves the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. Mitochondrial DNA itself is replicated by a dedicated set of nuclear-encoded proteins composed of the DNA polymerase gamma, the Twinkle helicase, the mitochondrial single-stranded DNA binding protein, as well as several accessory factors. Mutations in these genes, as well as in the genes involved in nucleotide metabolism, are associated with a spectrum of mitochondrial disorders that can affect individuals from infancy to old age. Additionally, mitochondrial disease can arise as a result of point mutations, deletions, or depletion in the mitochondrial DNA or in genes involved in mitochondrial transcription, replication, maintenance, and repair. Although a cure for mitochondrial diseases is currently elusive, several treatment options have been explored. In this review, we explore the molecular insights of the core mitochondrial replisome proteins that have aided our understanding of mitochondrial diseases and influenced current therapies.
    Keywords:  DNA polymerase γ; PolG; PolG2; Twinkle; mitochondria; mitochondrial diseases; mtDNA; mtDNA replication; mtSSB
    DOI:  https://doi.org/10.3390/ijms262110275
  2. Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]
    Alternative start codon selection shapes mitochondrial function and rare human diseases.
    Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.
      Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.
    Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
  3. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  4. Brain. 2025 Nov 14. pii: awaf422. [Epub ahead of print]
    Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy.
    Claudio Fiorini, Neringa Jurkute, Alessandra Torraco, Chiara La Morgia, Daniele Ghezzi, Gaia Tioli, Laura Rigobello, Danara Ormanbekova, Alessandro Berghella, Alberto Pietro Pasti, Flavia Palombo, Piero Barboni, Maria Lucia Cascavilla, Federico Sadun, Annamaria De Negri, Enrico Bertini, Olimpia Musumeci, Anna Ardissone, Teresa Rizza, Giancarlo Iarossi, Gabriella Silvestri, Salvatore Rossi, Anastasia Altobelli, Antony T Moore, Thomas Cullup, Andrew R Webster, Indran Davagnanam, Michel Michaelides, Samantha Malka, Hana Ptackova, Hana Stufkova, Marketa Tesarova, Petra Liskova, Leopold Zeng, Thomas Klopstock, Robert Kopajtich, Christiane Neuhofer, Holger Prokisch, Costanza Lamperti, Alfredo A Sadun, Patrick Yu-Wai-Man, Valerio Carelli, Francesco Musiani, Luisa Iommarini, Rosalba Carrozzo, Gavin Arno, Leonardo Caporali.
      Our understanding of the genetic landscape of inherited optic neuropathies has grown significantly over the past decades, and it is now known to involve many genes found in both the nuclear and mitochondrial genomes, exhibiting all possible inheritance patterns. Furthermore, pathogenic variants in nuclear genes of mitochondrial respiratory Complex I (CI) subunits have been identified in some cases of ION, in addition to the more common severe presentation of CI deficiencies, usually with early onset. We conducted NGS screening of CI genes to identify potential causative variants in patients with optic atrophy, also performing comprehensive clinical assessments, including neuroimaging studies (MRI) and neurological evaluations. Detailed molecular structure modeling was performed to better evaluate the damaging effects of both novel and previously reported variants in the relevant CI subunits. We identified and characterized candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear CI-related genes encoding polypeptides involved in the structure of CI, including 3 core subunits (NDUFS7, NDUFV1, NDUFV2), 4 accessory subunits (NDUFA1, NDUFA10, NDUFA12, NDUFB11), and 4 assembly factors (NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF8). Notably, defects in core CI subunits in this cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defects. Our case series broadens the genetic spectrum of inherited optic neuropathies, emphasizing the crucial role of nuclear CI genes in its pathogenesis. The arLHON phenotype emerges as linked to numerous nuclear CI genes for which an insidious onset of optic atrophy is also reported, and in some cases the same variant may underlie both phenotypes. Overall, we highlight the possibly so far underestimated prevalence of CI nuclear subunits in the molecular diagnosis of ION, prompting to include all CI-related genes in the standard diagnostic screening.
    DOI:  https://doi.org/10.1093/brain/awaf422
  5. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  6. Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):
    Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
    Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.
      Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.
    Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane
    DOI:  https://doi.org/10.3390/cells14211657
  7. J Med Cases. 2025 Nov;16(11): 434-439
    Perioperative Care of a Child With Combined Oxidative Phosphorylation Deficiency 6: Total Intravenous Anesthesia With Remimazolam.
    Ifeoluwa C Olakunle, Joseph D Tobias.
      Combined oxidative phosphorylation deficiency 6 (COXPD6) is a severe mitochondrial encephalomyopathy resulting from a mutation in the X-linked apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) gene. The AIFM1 gene located on chromosome Xq26.1, encodes apoptosis inducing factor (AIF), a flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide (NADH) oxidoreductase, which is involved in the process of oxidative phosphorylation and mitochondrial-derived programmed cell death in the nucleus. COXPD6 patients have significant end-organ involvement of the central nervous, peripheral nervous, respiratory, and gastrointestinal systems, manifested by seizures, hypotonia, psychomotor delay, muscle weakness, and wasting. We present an 11-year-old child with AIFM1-related COXPD6 who underwent posterior spinal fusion for progressive neuromuscular kyphoscoliosis. We explore the genetic history of this mitochondrial disorder, review a detailed anesthetic approach to perioperative management including use of the novel benzodiazepine, remimazolam, and discuss anesthetic considerations in these patients.
    Keywords:  AIFM1 gene; AIFM1-related combined oxidative phosphorylation deficiency 6; Mitochondrial disease; Pediatric anesthesiology
    DOI:  https://doi.org/10.14740/jmc5179
  8. Brain Behav. 2025 Nov;15(11): e71045
    Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.
    Fanjing Zhou, Jiang Chen, Tingzheng Zhang, Fengnan Niu, Jinglong Hu, Yun Xu, Meijuan Zhang.
       INTRODUCTION/AIMS: Mitochondrial encephalomyopathies are multisystem disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome is a rare manifestation, often associated with POLG mutations. This study identifies a novel POLG mutation in a SANDO patient, validates its pathogenicity, and analyzes the molecular genetics of 61 reported POLG-SANDO cases.
    METHODS: After obtaining informed consent, the proband underwent neurological examination, electromyography, muscle/nerve biopsies (histochemical/ultrastructural analyses), and genetic testing (whole-exome sequencing, mtDNA analysis). Pathogenicity of identified POLG variants was assessed in Cas9-mediated primary neuronal models expressing mutant proteins by measuring reactive oxygen species (ROS) levels and mtDNA copy number (qRT-PCR, ND1/APP ratio). Literature searches (PubMed, CNKI, Wanfang, and ClinVar) identified reported POLG mutations and clinical features in SANDO.
    RESULTS: Clinical and biopsy findings confirmed SANDO syndrome. Genetic analysis revealed compound heterozygous POLG mutations: a novel c.3297G>C (p.W1099C) and a known c.1774C>T (p.L592F). Neurons expressing either mutant exhibited elevated ROS levels (p < 0.05) and reduced mtDNA copy number compared with controls. Literature synthesis identified over 30 SANDO-associated POLG mutations, with p.A467T (31.2%) and p.W748S (22.1%) being the most frequent. The mean age of onset was 31.6 years.
    CONCLUSIONS: We identify a novel pathogenic POLG variant (p.W1099C) causing mitochondrial dysfunction via impaired mtDNA maintenance, expanding the SANDO genetic spectrum. Functional studies confirmed both mutations induce mitochondrial dysfunction (elevated ROS and decreased mtDNA Copy Number), validating their pathogenicity. The compiled mutation profile aids diagnosis of this phenotypically heterogeneous, frequently misdiagnosed disorder.
    Keywords:  POLG mutation; SANDO; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.1002/brb3.71045
  9. Brain. 2025 Nov 14. pii: awaf430. [Epub ahead of print]
    The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.
    Kajus Merkevicius, Dmitrii Smirnov, Lea D Schlieben, Rebecca Ganetzky, René G Feichtinger, Huafang Jiang, Fang Fang, Tomohiro Ebihara, Kei Murayama, Giulia Ferrera, Anna Ardissone, Dariusz Rokicki, Dorota Wesol-Kucharska, Sabine Schröder, Peter Bauer, Aida Bertoli-Avella, Elsebeth Østergaard, Peter Freisinger, Mirian C H Janssen, Matias Wagner, Omar Abouyousef, Bader Alhaddad, Lama AlAbdi, Fowzan Alkuraya, Charlotte L Alston, Anna Baghdasaryan, Diana Barca, Ivo Barić, Marcello Bellusci, Andrea Bevot, Eugen Boltshauser, Ingo Borggraefe, Juliette Bouchereau, Claudio Bruno, Birute Burnyte, Amy Calhoun, Kari Casas, Mahmut Coker, Ellen Crushell, Pascal De Lonlay, Carlo Dionisi-Vici, Felix Distelmaier, Marni J Falk, Ana Cristina Ferreira, Carlos R Ferreira, Can Ficicioglu, Gulden Fatma Gokçay, Johannes Häberle, Oliver Heath, Albrecht Hellenschmidt, Julia Hoefele, Georg F Hoffmann, Tomas Honzik, Martina Huemer, Patrícia Janeiro, Amel Karaa, Çiğdem Seher Kasapkara, Ilse Kern, Joerg Klepper, Thomas Klopstock, Ina Knerr, Johannes Koch, Zita Krumina, Costanza Lamperti, Elise Lebigot, Zhimei Liu, Esther M Maier, Diego Martinelli, Robert McFarland, Bryce Mendelsohn, Maria Judits Molnar, Helen Mundy, Marie-Cecile Nassogne, Anabela Oliveira, Katrin Õunap, Chiara Panicucci, Sumit Parikh, Heidi Peters, Samia Pichard, Barbara Plecko, Danijela P Ramadža, Gabriela M Repetto, Isabel Rivera, Richard J Rodenburg, Alessandro Rossi, Manuel Schiff, Kathrin Seidemann, Wendy E Smith, Sérgia Soares, Barbara Siri, Katja Steinbrucker, Pasquale Striano, Jolanta Sykut-Cegielska, Galit Tal, Robert W Taylor, Kostas Tsiakas, Sema Kalkan Ucar, Eva Hoytema van Konijnenburg, Mathias Woidy, Joy Yaplito-Lee, Yilmaz Yildiz, Martin Zenker, Petra Zsidegh, Dominik Westphal, Wolfgang Sperl, Thomas Meitinger, Garry K Brown, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann.
      This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.
    Keywords:  genotype-phenotype correlation; inborn errors of metabolism; inborn metabolic disease; ketogenic diet; mitochondrial disease; treatment
    DOI:  https://doi.org/10.1093/brain/awaf430
  10. Sci Adv. 2025 Nov 14. 11(46): eadu0726
    CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.
    Szu-Chi Liao, Kohei Kano, Sadhna Phanse, Mai Nguyen, Elyssa Margolis, YuHong Fu, Jonathan X Meng, Mohamed Taha Moutaoufik, Zac Chatterton, Tatiana Saccon, Kirsten Broderick, Hiroyuki Aoki, Jeffrey Simms, Felicia Xaveria Suteja, Yoshitaka Sei, Eric J Huang, Kevin McAvoy, Giovanni Manfredi, Glenda Halliday, Mohan Babu, Ken Nakamura.
      Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.
    DOI:  https://doi.org/10.1126/sciadv.adu0726
  11. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113
    STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
    Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.
       BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
    METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
    RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
    CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.
    Keywords:  STX4; mitochondria; muscle; quality control
    DOI:  https://doi.org/10.1002/jcsm.70113
  12. Mol Cell. 2025 Nov 12. pii: S1097-2765(25)00863-9. [Epub ahead of print]
    Monitoring the complexity and dynamics of mitochondrial translation.
    Taisei Wakigawa, Mari Mito, Yushin Ando, Haruna Yamashiro, Kotaro Tomuro, Haruna Tani, Kazuhito Tomizawa, Takeshi Chujo, Asuteka Nagao, Takeo Suzuki, Osamu Nureki, Fan-Yan Wei, Yuichi Shichino, Yuzuru Itoh, Tsutomu Suzuki, Shintaro Iwasaki.
      Since mitochondrial translation leads to the synthesis of the essential oxidative phosphorylation (OXPHOS) subunits, exhaustive and quantitative delineation of mitoribosome traversal is needed. Here, we developed a variety of high-resolution mitochondrial ribosome profiling derivatives and revealed the intricate regulation of mammalian mitochondrial translation. Harnessing a translation inhibitor, retapamulin, our approach assessed the stoichiometry and kinetics of mitochondrial translation flux, such as the number of mitoribosomes on a transcript, the elongation rate, and the initiation rate. We also surveyed the impacts of modifications at the anticodon stem loop in mitochondrial tRNAs (mt-tRNAs), including all possible modifications at the 34th position, in cells deleting the corresponding enzymes and derived from patients, as well as in mouse tissues. Moreover, a retapamulin-assisted derivative and mito-disome profiling revealed mitochondrial translation initiation factor (mtIF) 3-mediated translation initiation from internal open reading frames (ORFs) and programmed mitoribosome collision sites across the mitochondrial transcriptome. Our work provides a useful platform for investigating protein synthesis within the energy powerhouse of the cell.
    Keywords:  MELAS; Ribo-Seq; disome; kinetics; mitochondria; mitoribosomes; mtIF3; ribosome profiling; tRNA modification; translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.022
  13. Sci Adv. 2025 Nov 14. 11(46): eadx7809
    The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
    Sukrut C Kamerkar, Taewook Kang, Radu V Stan, Edward J Usherwood, Henry N Higgs.
      Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx7809
  14. Nature. 2025 Nov;647(8089): 331-342
    GREGoR: accelerating genomics for rare diseases.
    GREGoR Partner Members
      Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Furthermore, all data generated, currently representing over 7,500 individuals from over 3,000 families, are rapidly made available to researchers worldwide through the Analysis, Visualization and Informatics Lab-space (AnVIL) to catalyse global efforts to develop approaches for genetic diagnoses in rare diseases. Most of these families have undergone previous clinical genetic testing but remained unsolved, with most being exome-negative. Here we describe the collaborative research framework, datasets and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.
    DOI:  https://doi.org/10.1038/s41586-025-09613-8
  15. Stem Cells Transl Med. 2025 Nov 14. pii: szaf060. [Epub ahead of print]14(11):
    Unlocking extracellular mitochondria from bench to clinical application in stroke.
    Gen Hamanaka, Dong-Bin Back, Ji-Hyun Park, Shin Ishikane, Kazuhide Hayakawa.
      Within the central nervous system (CNS), mitochondria serve as vital energy sources for neurons, glial cells, and vascular functions, maintaining intracellular metabolic balance. Recent studies involving cellular models, rodents, and humans reveal that metabolically active mitochondria can be released into the extracellular space, playing roles in intercellular communication within the CNS. When taken up by neurons, these extracellular mitochondria may provide neuroprotective effects. Conversely, damaged mitochondria and their released components during severe tissue injury or inflammation can contribute to neurodegenerative processes. Thus, mitochondria secreted under pathological conditions in the CNS hold promise as biomarkers indicative of recovery. Additionally, transplantation of external mitochondria shows potential as a therapeutic approach for various CNS disorders. This mini review focuses on recent advances in the transfer of mitochondria between cells, the use of extracellular mitochondria as biomarkers, and the prospects of mitochondria transplantation from experimental research to clinical application, particularly in diseases like stroke.
    Keywords:  biomarkers; central nervous system; extracellular mitochondria; mitochondria transplantation; mitochondrial modification; stroke
    DOI:  https://doi.org/10.1093/stcltm/szaf060
  16. Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):
    Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
    Margherita Zamberlan, Martina Semenzato.
      Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.
    Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms262110581
  17. Neurochem Res. 2025 Nov 15. 50(6): 361
    Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.
    Bingjie Han, Jie Bai.
      Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.
    Keywords:  Calcium homeostasis; Mitochondria; Mitochondrial endoplasmic reticulum-associated membrane; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s11064-025-04591-9
  18. Cells. 2025 Oct 27. pii: 1678. [Epub ahead of print]14(21):
    Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
    Patrice X Petit.
      Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players.
    Keywords:  BH3 interacting domain death agonist (also BID-FL); BID; CLOOH; Cell death; DISC; GUV; MTCH2; Mitochondria; Mitochondrial Carrier Homolog 2; OMM outer mitochondrial membrane; cardiolipin peroxidized; death inducing signalling complex; giant unilamellar-vesicles; p15); tBID (truncated BID at the n terminal end
    DOI:  https://doi.org/10.3390/cells14211678
  19. J Neuromuscul Dis. 2025 Nov 12. 22143602251391068
    MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.
    Care4Rare Canada Consortium
      BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial MT-ATP6 gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of MT-ATP6 pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of MT-ATP6 in undiagnosed cases of sporadic or maternally inherited HSP.
    Keywords:  gait ataxia; genome; heteroplasmy; maternal transmission; mitochondrial diseases; muscle spasticity; polyneuropathy
    DOI:  https://doi.org/10.1177/22143602251391068
  20. Dis Model Mech. 2025 Nov 14. pii: dmm.052146. [Epub ahead of print]
    Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
    Mrudula Dileep, Anamika Sharma, Nandashree Kasturacharya, Syed Kavish Nizami, Steffy Manjila, Ashita Bhan, Gaiti Hasan.
      Our understanding of mechanisms underlying familial Parkinson's Disease (PD) have benefitted from studies in Drosophila models of PD. However, in a majority of PD patients the disease occurs sporadically and cellular phenotypes that arise early in sporadic PD remain to be understood. A genetic predisposition, arising from mutations in pathways that impact dopaminergic neuron health could be one cause of sporadic PD. Here, we studied Drosophila with single copies of recessive IP3R gene (itpr) mutants placed in combination with a recessive null mutant for the parkin gene. Whereas individual mutants appear normal, in combination they synergise to exhibit flight motor deficits with a focus in a subset of central dopaminergic neurons. Surprisingly, mitophagy and mitochondrial Ca2+ are barely affected. Instead, flight motor deficits correlate with elevated levels of mitochondrial H2O2 and reducing H2O2 levels by genetic means restored mitochondrial function and flight to a significant extent. This study underlines the importance of mitochondrial oxidative stress as an early phenotype in PD and suggests that humans with recessive mutations in either pathway have a higher chance of developing sporadic PD.
    Keywords:  Calcium homeostasis; Dopaminergic neurons; Flight; Motor function; PPL1
    DOI:  https://doi.org/10.1242/dmm.052146
  21. Nat Metab. 2025 Nov 14.
    Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
    Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner.
      Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD.
    DOI:  https://doi.org/10.1038/s42255-025-01399-3
  22. J Am Heart Assoc. 2025 Nov 11. e043921
    PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.
       BACKGROUND: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here, we examined how cardiac mitochondrial flexibility and the posttranslational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
    METHODS: cKO and litter-matched controls were euthanized in the fed or fasted (12 hours) states, with or without a 20-minute stimulant stress of caffeine and epinephrine. Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
    RESULTS: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and carnitine palmitoyl transferase 1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
    CONCLUSIONS: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.
    Keywords:  O‐GlcNAc; O‐GlcNAcylation; PFK‐2; glycolysis; metabolic flexibility
    DOI:  https://doi.org/10.1161/JAHA.125.043921
  23. J Inherit Metab Dis. 2025 Nov;48(6): e70112
    Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.
    Erle Kristensen, Karin Naess, Martin Engvall, Claus Klingenberg, Magnhild Rasmussen, Eylert Brodtkorb, Elsebet Ostergaard, Irenaeus de Coo, Leticia Pias-Peleteiro, Pirjo Isohanni, Johanna Uusimaa, Kari Majamaa, Mikko Kärppä, Mika H Martikainen, Juan Dario Ortigoza-Escobar, Trine Tangeraas, Siren Berland, Carolyn M Sue, Judith Sylvia Walker, Emma Harrison, Heather Biggs, Rita Horvath, Niklas Darin, Shamima Rahman, Omar Hikmat.
      Liver involvement in POLG disease is common and associated with high morbidity and mortality. Detailed, large-scale, systematic studies of liver involvement are lacking. This study aims to describe the onset, clinical course and prognostic implications of liver involvement in POLG disease. We conducted a multinational, retrospective study including clinical, genetic and biochemical data from patients with confirmed POLG disease. Patients were stratified according to age of disease onset: early-onset (< 12 years), juvenile/adult-onset (12-40 years), and late-onset (> 40 years). Of the 202 patients, 110 (54%) had liver involvement. This could present at any time during the lifespan, but occurred more frequently in patients with early-onset disease (76/98, 78%). Median onset age for liver involvement in females was 7 years (range: 1 month to 50 years), and 21 months in males (birth to 71 years). Infection-triggered disease onset carried a significantly higher risk of liver involvement than spontaneous or other disease triggers. Eighty-five percent of those with liver involvement also had epilepsy. Liver involvement was an indicator of poor prognosis and was significantly associated with worse survival. This study provides a comprehensive description of liver involvement in a large cohort of POLG disease patients. Liver involvement is common in this disease and associated with significantly worse survival. POLG disease should be considered in children presenting with liver involvement, and rapid genetic testing may guide management decisions. Our findings emphasize the need for early vigilance in monitoring liver involvement in all patients with confirmed POLG disease, particularly those with early-onset disease and during intercurrent infection.
    Keywords:  hepatopathy; liver disease; liver transplantation; mitochondrial disorder; mitochondriopathy; valproate
    DOI:  https://doi.org/10.1002/jimd.70112
  24. Nat Commun. 2025 Nov 10. 16(1): 9868
    Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
    Marco Scalabrin, Eloisa Turco, Ilaria Davigo, Riccardo Filadi, Leonardo Nogara, Gaia Gherardi, Lucia Barazzuol, Andrea Armani, Giulia Trani, Samuele Negro, Anais Franco-Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Paola Pizzo, Marco Sandri, Stephan Kemp, Vanina Romanello.
      Skeletal muscles, which constitute 40-50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.
    DOI:  https://doi.org/10.1038/s41467-025-64833-w
  25. Front Cell Dev Biol. 2025 ;13 1652353
    UPRmt-regulated mitokines: novel strategies for myocardial injury repair.
    Weinan Gao, Jia Liu, Wenda Zhang, Bin Liu, Luyan Shen.
      Cardiac mitochondria generate ATP, via oxidative phosphorylation (OXPHOS) to sustain continuous and forceful myocardial contraction, thereby meeting systemic metabolic demands. Mitochondrial biogenesis and energy metabolism depend on proteostasis, which can be disrupted by stressors such as hypoxia, leading to impaired cardiac function. As a result, the study of mitochondrial energy metabolism and proteostasis under stress has become a key focus in cardiovascular research. The mitochondrial unfolded protein response (UPRmt) plays a "double-edged sword" role-either protective or detrimental-depending on the type, intensity, and duration of the stressor. This has sparked interest in strategies aimed at enhancing its adaptive signaling while inhibiting maladaptive pathways. Acting as mediators of intercellular communication, mitokines may transmit local mitochondrial stress signals to mitochondria in distant cells and tissues. This review analyzes and summarizes the role of UPRmt in regulating mitochondrial factors and explores the mechanisms through which fibroblast growth factor 21 (FGF21), secreted by the liver and skeletal muscle, influences protein homeostasis in cardiac myocytes. These insights aim to offer new avenues for the development of targeted UPRmt therapies and rehabilitation strategies for heart diseases.
    Keywords:  cardiac diseases; fibroblast growth factor 21 (FGF21); mitochondrial stress; mitochondrial unfolded protein response (UPRmt); mitokines
    DOI:  https://doi.org/10.3389/fcell.2025.1652353
  26. Cell Metab. 2025 Nov 12. pii: S1550-4131(25)00440-1. [Epub ahead of print]
    Therapeutic remodeling of the ceramide backbone prevents kidney injury.
    Rebekah J Nicholson, Luis Cedeño-Rosario, J Alan Maschek, Trevor Lonergan, Jonathan G Van Vranken, Angela R S Kruse, Chris J Stubben, Liping Wang, Deborah Stuart, Queren A Alcantara, Monica P Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J Clark, Samir Parikh, Jeffrey Spraggins, Donna Romero, Jeremy T Blitzer, Steven P Gygi, Jared Rutter, William L Holland, Nirupama Ramkumar, Scott A Summers.
      Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.
    Keywords:  ETC; MICOS; acute kidney injury; ceramides; cristae; lipid metabolism; lipidomics; metabolism; mitochondria; proximal tubule; sphingolipids
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.006
  27. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Nov 10. pii: S1388-1981(25)00111-8. [Epub ahead of print]1871(1): 159703
    ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.
    Anne Gemmink, Tineke van de Weijer, Gert Schaart, Gernot F Grabner, Esther Kornips, Kèvin Knoops, Rudolf Zechner, Martina Schweiger, Matthijs K C Hesselink.
      Defects in Adipose tissue TriGlyceride Lipase (ATGL)-mediated myocellular lipid droplet (LD) lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine if ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPARα and/or PPARδ transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the gene encoding for ATGL. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contact, mitochondrial network connectivity, and mitochondrial membrane potential were affected. Using a humanized ATGL inhibitor in myotubes (cultured form healthy donors) revealed similar results. Upon stimulating PPARδ transcriptional activity, mitochondrial respiration improved by more than 50 % in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPARδ transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network connectivity, and mitochondrial membrane potential. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial network connectivity, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPARδ transcriptional activity.
    Keywords:  ATGL; Lipid droplets; Microscopy; Mitochondrial networks; NLSDM; PPAR transcriptional activity; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159703
  28. Toxicol Mech Methods. 2025 Nov 11. 1-24
    M3Hep: A Multimodal Hepatotoxicity Prediction Model Combining Mitochondrial Toxicity and Masking Strategy.
    Yang Liu, Yu Xie, Xiao Wang, Yingxu Liu, Simeng Zhang, Lidan Zheng, Qian Ge, Lingxi Gu, Yanmin Zhang, Jinfeng Liu, Yadong Chen, Mengyi Lu, Haichun Liu.
      Drug hepatotoxicity is one of the primary reasons for drug clinical trial failures and market withdrawals, with mitochondrial dysfunction being one of the mechanisms inducing drug hepatotoxicity. Manifestation of mitochondrial toxicity occurs when mitochondria are damaged or their functions are inhibited. This study introduces M3Hep, a novel multimodal framework that integrates SMILES, molecular graphs, and mitochondrial toxicity through a masking strategy to improve hepatotoxicity prediction. A total of 8,459 mitochondrial toxicity samples and 6,418 hepatotoxicity samples were collected for constructing the mitochondrial toxicity prediction model and M3Hep, respectively. To fully utilize the collected hepatotoxicity samples, this study developed a mitochondrial toxicity prediction model to predict mitochondrial toxicity for molecules without experimental mitochondrial toxicity data, achieving an AUC of 0.96 for the mitochondrial toxicity prediction model. The ablation study results of M3Hep indicate that incorporating mitochondrial toxicity enhances the performance of hepatotoxicity prediction models, further demonstrating the connection between mitochondrial toxicity and hepatotoxicity. M3Hep outperforms most baseline models across all metrics, with its AUC reaching up to 0.81. Moreover, in terms of the MCC metric, M3Hep surpasses all commonly used hepatotoxicity prediction tools collected, with a value of 0.49. In order to better understand the prediction mechanism of M3Hep, we conducted an interpretability analysis based on the GNNExplainer and SHAP methods.
    Keywords:  Deep learning; Hepatotoxicity; Masking strategy; Mitochondrial toxicity; Multimodal model
    DOI:  https://doi.org/10.1080/15376516.2025.2588277
  29. Nat Metab. 2025 Nov 13.
    Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
    Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.
      Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01419-2
  30. BMC Med Genomics. 2025 Nov 14. 18(1): 182
    RNA sequencing provides functional insights and diagnostic resolution in previously unsolved rare disease cases.
    Undiagnosed Diseases Network
      Exome and genome sequencing have greatly improved the diagnosis of rare genetic disorders but remain limited in their ability to identify and classify non-coding variants, including intronic variants, cryptic splice-site alterations, and disruptions in regulatory regions. RNA sequencing (RNA-seq) has emerged as a powerful tool to bridge this gap by providing functional insights into genomic variants that disrupt splicing or gene expression, thereby aiding in variant interpretation and classification. We retrospectively reviewed 30 cases from the Utah Penelope Program and the Undiagnosed Diseases Network over a three-year period, in which RNA-seq was performed on whole blood and/or fibroblasts following either negative DNA sequencing or the identification of candidate variants requiring functional assessment. In these cases, RNA-seq identified exon skipping, cryptic splice-site activation, and intron retention, leading to transcript disruption. Additionally, positional enrichment analysis clarified X-inactivation patterns and dosage effects, confirming the pathogenicity of copy number variants. By detecting these transcript-level alterations, RNA-seq provided functional evidence supporting the reclassification of multiple variants of uncertain significance, contributing to diagnostic resolution in selected cases. This study underscores the clinical utility of RNA-seq in detecting splicing and regulatory defects that DNA sequencing and predictive tools alone cannot resolve. Integrating RNA-seq into clinical workflows can support variant classification, aid in diagnostic resolution for selected cases, and provide mechanistic insights into genetic disorders, contributing to patient care and genetic counseling.
    Keywords:  Genomics; RNA sequencing; Rare disease; Splicing; Variant reclassification
    DOI:  https://doi.org/10.1186/s12920-025-02227-z
  31. Genomics Proteomics Bioinformatics. 2025 Nov 05. pii: qzaf098. [Epub ahead of print]
    Mitochondrial Genome Variants and Nuclear Mitochondrial DNA Segments in 7331 Individuals from NyuWa and 1KGP.
    Yuanxin Wang, Jiajia Wang, Yanyan Li, Peng Zhang, Zhonglong Wang, Shuai Liu, Yiwei Niu, Yirong Shi, Sijia Zhang, Tingrui Song, Tao Xu, Shunmin He.
      Dysfunctional mitochondria are implicated in various diseases, however comprehensive characterization of mitochondrial DNA (mtDNA) in the Chinese population remains limited. Here, we conducted a systematic analysis of mtDNA from 7331 samples, comprising 4129 Chinese samples (NyuWa) and 3202 samples from the 1000 Genomes Project (1KGP). We identified 7216 distinct high-quality mtDNA variants, classified them into 22 macro-haplogroups, and detected 1466 distinct nuclear mitochondrial DNA segments (NUMTs). Among these, 88 mtDNA variants and 642 NUMTs were specific to NyuWa. Genome-wide association analyses revealed significant correlations between 12 mtDNA variants and 199 nuclear DNA (nDNA) variants. Our findings demonstrated that all individuals in both NyuWa and 1KGP harbored common NUMTs, while one-fifth possessed ultra-rare NUMTs that tended to insert into nuclear gene regions. Notably, rare NUMTs in the NyuWa cohort showed significant enrichment of nuclear breakpoints in long interspersed nuclear elements (LINEs) compared to 1KGP. Overall, this study provides the first comprehensive profile of NUMTs in the Chinese population and establishes the most extensive resource of Chinese mtDNA variants and NUMTs based on high-depth whole genome sequencing (WGS) to date, providing valuable reference resources for genetic research on mtDNA-related diseases.
    Keywords:  Mitochondrial DNA; NUMTs; Whole genome sequencing; mtDNA variants; mtDNA-nDNA variant association
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf098
  32. Biochem Biophys Rep. 2025 Dec;44 102329
    Identification of a novel MIPEP splice variant with altered substrate-binding properties.
    Yuina Otani, Michiya Kawarai, Masaki Kobayashi, Yuka Nozaki, Rio Uchida, Kyo Tezuka, Miku Yokoyama, Yuhei Mizunoe, Takumi Narita, Hiroshi Haeno, Kanako Miyano, Yasuhito Uezono, Yoshikazu Higami.
      Mitochondrial intermediate peptidase (MIPEP) is a mitochondrial signal peptidase that removes N-terminal amino acids from mitochondrial matrix proteins. We have identified a novel Mipep splice variant that lacks exons 15 and 16, which we termed "ΔMIPEP". We characterized the molecular features of ΔMIPEP by investigating its expression level in numerous mouse tissues and by performing a computer simulation that allows the prediction of protein structures and substrate-binding properties. ΔMipep mRNA was detected in all mouse tissues examined but at much lower levels than full-length Mipep. Structure prediction and docking simulation of full-length MIPEP and ΔMIPEP with substrates of MIPEP, such as malate dehydrogenase 2 (MDH2) and cytochrome c oxidase subunit 4, showed that entry of these substrates into ΔMIPEP with a low binding energy was greatly restricted. To determine levels of MIPEP substrates in the presence or absence of full-length MIPEP or ΔMIPEP, we created Mipep and ΔMipep overexpression 3T3-L1 cells and Mipep knockout (KO) cells. Western blotting showed that in Mipep KO cells Mipep overexpression slightly decreased the molecular weight of MDH2 and Sirtuin 3, another MIPEP substrate, whereas ΔMipep overexpression did not. These results indicate that ΔMIPEP fails to recognize MIPEP substrate proteins. Together, our findings indicate that ΔMIPEP is a novel splice variant that can contribute to mitochondrial signal peptidase-mediated regulation of mitochondrial protein homeostasis.
    Keywords:  AlphaFold2; Mitochondrial intermediate peptidase; Processing; Splice variant; ΔMIPEP
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102329
  33. J Physiol. 2025 Nov 10.
    Developmental bioenergetics: a comparative perspective on mitochondrial efficiency in paediatric physiology.
    Sébastien Ratel, Joffrey Bardin, Anthony J Blazevich.
      
    Keywords:  efficiency; growth; metabolism; mitochondria; plasticity
    DOI:  https://doi.org/10.1113/JP289900
  34. Circ Genom Precis Med. 2025 Nov 10.
    Aberrant Splicing of Dnm1l Impairs Cardiac Bioenergetics and Mitochondrial Dynamics in Myotonic Dystrophy Type I (DM1).
    Oluwafolajimi Adesanya, Pouya Nabie, Alexandra Betancourt, Auinash Kalsotra.
      Background: DM1 is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA form toxic hairpins that sequester the muscle blind-like (MBNL) family of splicing factors. This disrupts tissue alternative splicing landscape, triggering multisystemic manifestations - myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurologic disturbances. While impaired mitochondrial function has been reported in brain, skeletal muscle, and fibroblasts of DM1 patients, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects. Methods: Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides (ASO) to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. Results: DM1 induced a multi-state decrease in oxygen consumption rate (OCR) with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor (Mff, encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. ASO-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild type HL-1 cardiomyocytes. Conclusions: Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.
    DOI:  https://doi.org/10.1161/CIRCGEN.125.005492
  35. Cell Rep. 2025 Nov 07. pii: S2211-1247(25)01293-8. [Epub ahead of print]44(11): 116522
    A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.
    Megumi Mori, Grant Kauwe, Ammar Aly, Edward H Liao, Gary Scott, A Pejmun Haghighi.
      Neuronal response to changes in nutrient availability is critical for maintaining metabolic homeostasis and organismal survival. Nevertheless, we know little about the molecular players that regulate and maintain neurotransmission under nutritional stress. We demonstrate that, under acute amino acid restriction, the maintenance of normal synaptic strength at the Drosophila larval neuromuscular junction critically depends on the integrated stress response (ISR) machinery. Our findings indicate that amino acid restriction triggers a non-canonical ISR cascade in muscle via GCN2 and eIF2α phosphorylation but independently of ATF4. We have identified Still life (Sif), an ortholog of human TIAM1, as a translational target of the ISR and show that it is required in muscle for mediating the action of the ISR. Our results reveal an intricate non-canonical ISR signaling cascade at the synapse and offer a new framework to separate the role of the ISR in proteostasis from its synaptic actions.
    Keywords:  CP: metabolism; CP: neuroscience; GCN2; amino acid sensing; eIF2alpha; integrated stress response; presynaptic release; regulation of translation; retrograde signaling; synaptic set point
    DOI:  https://doi.org/10.1016/j.celrep.2025.116522
  36. J Neurochem. 2025 Nov;169(11): e70272
    Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics.
    María S Marcora, Maximiliano J Katz, Azul Galo, Pablo Bochicchio, Vinicius Bongiovanni, Diego H Bodín, Mario R Pagani, Jorge D Correale, María J Pasquini.
      Iron deficiency (ID) is the most common micronutrient deficiency globally. ID in pre- and post-natal periods has been associated with impaired neurological development and altered behavior, which may persist despite iron supplementation. However, the neurobiological changes responsible for these findings have not been fully identified yet. Here, we develop an invertebrate experimental model using Drosophila melanogaster to study the impact of ID on glial cells. ID induced by dietary deferoxamine altered locomotor activity in adult flies. Glial-specific downregulation of the iron transporter Malvolio (Mvl) resulted in reduced locomotion, an effect prevented by iron supplementation in the fly medium. We confirmed that Mvl downregulation led to ID in the brain, where Mvl is partially expressed. Interestingly, Mvl reduction in ensheathing glia replicated locomotor activity deficits, which suggests that this glial subpopulation is particularly sensitive to iron levels. Mvl downregulation also altered mitochondrial morphology and size, in correlation with altered expression of mitochondrial fission and fusion genes, and mitochondrial electron transport chain complex genes. These results suggest that glial ID impairs normal mitochondrial dynamics and impacts energy production. Additionally, glial overexpression of mitochondrial ferritin, Fer3HCH, known to induce ID in the cytosol and mitochondria, also impaired locomotor activity, which highlights the importance of iron availability in both compartments. These findings demonstrate, for the first time, the importance of iron availability in Drosophila glial cells and its impact on behavior and mitochondrial dynamics. Most importantly, the Drosophila model proves useful in unveiling previously unknown cellular and molecular mechanisms associated with ID in glial cells.
    Keywords:   Drosophila ; Malvolio; glia; iron; mitochondria
    DOI:  https://doi.org/10.1111/jnc.70272
  37. Int J Mol Sci. 2025 Oct 22. pii: 10279. [Epub ahead of print]26(21):
    Beyond Folding: Expanding the Functional Landscape of Hsp90 Chaperone Machinery in Health and Disease.
    Manish Kumar Singh, Jyotsna S Ranbhise, Minghao Fu, Songhyun Ju, Sunhee Han, Hyeong Rok Yun, Wonchae Choe, Sung Soo Kim, Insug Kang.
      Molecular chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding, stabilization, and function of proteins. Among them, Heat shock protein 90 (Hsp90), represents a highly conserved protein family of molecular chaperones that plays an essential role in diverse biological processes and is fundamental to cellular health and survival. As a highly abundant molecular chaperone, Hsp90 comprises 1-2% of cellular proteins, increasing to 4-6% under stress conditions. It interacts with client proteins, assisting them in proper folding and stability. Unlike classical chaperonins, Hsp90 operates through a highly regulated, ATP-dependent cycle that involves multiple co-chaperones. This process allows Hsp90 to selectively engage with numerous client proteins, including signaling proteins, kinases, hormone receptors, and transcription factors. Recent discoveries have revealed its involvement in processes beyond protein folding, demonstrating its role in diverse cellular functions such as epigenetic regulation, immune signaling, and oncogenic transformation. This current review highlighted the specific characteristics of cytoplasmic and endoplasmic reticulum (ER) as well as mitochondrial paralogs and functions, focusing on its contribution to buffering genetic variation, facilitating oncogene addiction, and modulating disease phenotypes in conditions such as cancer, neurodegeneration, cardiovascular diseases (CVD), and diabetes. We also discuss the therapeutic potential of targeting Hsp90 and its co-chaperones, outlining the challenges and prospects in drug development. These insights not only reshape our understanding of chaperone biology but also present opportunities for precision medicine in various human diseases.
    Keywords:  ATPase; Hsp90; cancer; cardiac disease; client proteins; co-chaperone; diabetes
    DOI:  https://doi.org/10.3390/ijms262110279
  38. Biomed Pharmacother. 2025 Nov 13. pii: S0753-3322(25)00945-X. [Epub ahead of print]193 118751
    Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.
    Zahid A Manzar, Lucas J Davis, Karl F Swanson, Erik Muñoz, Hazel H Szeto, Hans Minderman, B Rita Alevriadou.
      Cell-derived extracellular vesicles (EV) are mediators of intercellular communication with increased circulating levels of endothelial cell-derived EV (EC-EV) reported in cardiovascular diseases (CVD). The EC-EV ability to elicit either detrimental or restorative effects on target EC is thought to be, in part, due to horizontal transfer of their mitochondrial cargo. To understand the role of mitochondrial cargo in EC-EV paracrine effects, large EV were collected from media of cultured human EC, and the number of mitochondria-carrying EV (mitoEV), EV mitochondrial cargo mass, and mitoEV quality/polarization were quantified. EC activation with tumor necrosis factor (TNF)-α caused an increased release rate of EV (TNF-EV), including mitoEV that carried a larger and more depolarized mitochondrial cargo, compared to EV released from control EC (C-EV). EC co-treatment with TNF-α and the mitochondria-targeted antioxidant MitoTEMPO restored both the mitochondrial cargo quality and the number of mitoEV carrying polarized mitochondria to levels similar to C-EV. TNF-EV, but not C-EV, dose-dependently upregulated inflammatory gene expression in target naïve EC. Fluorescence microscopy showed the EV mitochondrial cargo to transfer and colocalize with the target EC mitochondrial network. Mitochondrial cargo depolarization of C-EV using carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone was sufficient for those EV to trigger inflammation in target naïve EC. In conclusion, the mitochondrial redox state of donor EC regulates mitoEV mitochondrial cargo quality that, at least in part, determines their capacity to cause target EC dysfunction and promote CVD. The mitochondrial membrane potential (ΔΨm) in EC-mitoEV may be a new biomarker and therapeutic target in vascular biology and medicine.
    Keywords:  Extracellular vesicles; Inflammation; Mitochondria; Mitochondrial membrane potential; Mitochondrial transfer; Vascular endothelial cell
    DOI:  https://doi.org/10.1016/j.biopha.2025.118751
  39. Mitochondrion. 2025 Nov 12. pii: S1567-7249(25)00095-9. [Epub ahead of print] 102098
    Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
    Melody Toosky, Arash Kheradvar.
      Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia-reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings. Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3  mM), sub-physiologic (0.65  mM), and supraphysiologic (2.6  mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course. Mitochondria exposed to 1.3  mM calcium retained 90-95 % membrane potential by 12 h, while 2.6  mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels. These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further in vivo studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.
    Keywords:  Calcium overload; Cardioprotection; Extracellular mitochondria; Intracoronary Delivery; Ischemia-reperfusion injury; Mitochondrial membrane potential; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.mito.2025.102098
  40. Sci Adv. 2025 Nov 14. 11(46): eadz3889
    iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
    Jonathan S Marvin, Philipp Mächler, Chengbo Meng, Tayfun Ates, Ronak H Patel, Raghabendra Adhikari, Monika A Makurath, Zaneta Ku, Daniel Feliciano, Deniz Atasoy, Guohong Cui, David Kleinfeld, Timothy A Brown.
      Continuous glucose monitors have proven invaluable for monitoring blood glucose levels for diabetics, but they are of limited use for observing glucose dynamics at the cellular (or subcellular) level. We have developed a second generation, genetically encoded intensity-based glucose sensing fluorescent reporter (iGlucoSnFR2). We show that when it is targeted to the cytosol, it reports intracellular glucose consumption and gluconeogenesis in cell culture, along with efflux from the endoplasmic reticulum. It outperforms the original iGlucoSnFR in vivo when observed by fiber photometry in mouse brain and reports transient increase in glucose concentration when stimulated by noradrenaline or electrical stimulation. Last, we demonstrate that membrane localized iGlucoSnFR2 can be calibrated in vivo to indicate absolute changes in extracellular glucose concentration in awake mice. We anticipate iGlucoSnFR2 facilitating previously unobservable measurements of glucose dynamics with high spatial and temporal resolution in living mammals and other experimental organisms.
    DOI:  https://doi.org/10.1126/sciadv.adz3889
  41. Mol Neurobiol. 2025 Nov 13. 63(1): 37
    Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.
    Šárka Danačíková, Petr Pecina, Alena Pecinová, Jan Svoboda, David Vondrášek, Davide Alessandro Basello, Tomáš Čajka, Daniel Hadraba, Tomáš Mráček, Vladimír Kořínek, Jakub Otáhal.
      Neuronal differentiation requires extensive metabolic remodeling to support increased energetic and biosynthetic demands. Here, we present an integrated multi-omics and functional characterization of metabolic transitions during early differentiation of human induced pluripotent stem cells (iPSCs) into excitatory cortical neurons using doxycycline-inducible overexpression of neurogenin-2 (NGN2). We analyzed parental iPSCs and induced neurons (iNs) at days 7 and 14 of differentiation, integrating gene expression profiling, label-free quantitative proteomics, high-resolution respirometry, fluorescence lifetime imaging microscopy (FLIM), and 13C₆-glucose metabolic flux analysis. Our data reveal progressive metabolic remodeling associated with neuronal maturation, including enhanced oxidative phosphorylation, increased mitochondrial content, and respiratory capacity. Proteomic analyses showed upregulation of mitochondrial and antioxidant pathways, while FLIM indicated a progressive increase in enzyme-bound NAD(P)H, consistent with a shift toward oxidative metabolism. Notably, 13C₆-glucose tracing revealed delayed labeling of the intracellular pool of fully labeled glucose and tricarboxylic acid cycle metabolites, together with enhanced labeling of pentose phosphate pathway intermediates and glutathione in iNs, indicating a shift toward biosynthetic and antioxidant glucose utilization during differentiation. Despite this enhancement in mitochondrial function, differentiated neurons maintained glycolytic activity, suggesting metabolic flexibility. Our results define the first week of differentiation as a critical window of metabolic specialization and establish NGN2-iPSC-derived cortical neurons as a versatile and well-characterized model system for investigating bioenergetic remodeling during early human neurodevelopment. It provides a robust foundation for mechanistic insights and high-throughput evaluation of metabolic pathways relevant to human disease.
    Keywords:  Cellular bioenergetics; Human iPSCs; Metabolic flux analysis; Neuronal differentiation; Proteomics; Respirometry
    DOI:  https://doi.org/10.1007/s12035-025-05284-8
  42. Nature. 2025 Nov 13.
    CRISPR vs cholesterol: can gene editing prevent heart disease?
    Heidi Ledford.
      
    Keywords:  CRISPR-Cas9 genome editing; Diseases; Gene therapy
    DOI:  https://doi.org/10.1038/d41586-025-03711-3
  43. Cell Mol Life Sci. 2025 Nov 14. 82(1): 400
    The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites.
    Kai Jürgens, Lena Menzel, Nora Klinke, Lisa Schäper, Leonhard Breitsprecher, Michael Holtmannspötter, Olympia-Ekaterini Psathaki, Stefan Walter, Sandra Ratnavadivel, Anders Malmendal, Heiko Meyer, Hendrik Milting, Achim Paululat.
      Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC-5) is a fully penetrant form of ARVC caused by the missense mutation in the gene TMEM43p.S358L. Despite extensive research, the molecular basis underlying the detrimental effects of TMEM43p.S358L still needs to be discovered. TMEM43 is a phylogenetically conserved protein. We previously analysed the Drosophila homologue (CG8111 or Dmel\Tmem43) to understand the protein's physiological relevance and the mutation p.S358L. Drosophila Tmem43 is localised at the ER/SR membrane and interacts with the outer mitochondrial membrane protein Porin/VDAC. This interaction is lost in a Tmem43p.S333L mutant that resembles the human p.S358L mutation. In addition, Tmem43p.S333L caused a breakdown in mitochondrial membrane potential and increased cellular reactive oxygen species, suggesting impaired mitochondrial function as a major pathomechanism. Complementary ultrastructural analyses revealed severe structural defects in the affected mitochondria, including degeneration of the organelles. Highly similar ultrastructural defects were observed in the human right ventricular myocardium of a TMEM43p.S358L trait carrier, suggesting a common molecular basis for the detrimental effects of the mutation in flies and humans. We propose that both the p.S358L mutation in humans and the p.S333L mutation in Drosophila impair TMEM43/VDAC interaction, which affects the stability of ER/SR-mitochondrial contact sites and, thus, proper mitochondrial function and oxidative phosphorylation rates. The consequential undersupply of ATP likely results in cardiac cell death and, ultimately, heart failure.
    Keywords:  ARVC type 5; Cardiogenesis; Cardiomyopathy; Drosophila model; TMEM43
    DOI:  https://doi.org/10.1007/s00018-025-05942-z
  44. Annu Rev Physiol. 2025 Nov 10.
    Calcium Regulation of Mitochondrial Metabolism.
    Carmen A Mannella, Pawel Swietach, Liron Boyman.
      Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca2+) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca2+ ([Ca2+]m) sensitivity in key energy metabolic pathways, highlighting the [Ca2+]m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca2+]m-sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca2+ entry pathway into the matrix, the mitochondrial Ca2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca2+. Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.
    DOI:  https://doi.org/10.1146/annurev-physiol-052424-082740
  45. Int J Mol Sci. 2025 Oct 29. pii: 10504. [Epub ahead of print]26(21):
    Interactions of Arachidonic Acid with AAC1 and UCP1.
    Jonathan H Borowsky, Michael Grabe.
      The inner mitochondrial membrane proteins ATP/ADP carrier protein 1 (AAC1) and Uncoupling protein 1 (UCP1) belong to the SLC25 mitochondrial carrier family. AAC1 is responsible for ATP/ADP exchange, while UCP1-dependent proton transport, which also requires small molecules known as activators, is the basis of brown fat thermogenesis. Arachidonic acid (AA) is an endogenous activator capable of inducing proton transport in both proteins. As such, both AAC1- and UCP1-dependent proton transport are potential targets of weight loss drugs. While AAC1 structures have long been available, only recently have structures of UCP1 been determined. Unfortunately, no AA-bound structure of either protein is available. To explore their interactions with AA, we performed molecular dynamics (MD) simulations of both proteins. Six parallel simulations of each protein were run with an average length of just over 6 μs, for a total of 75 μs of aggregate simulation across both proteins. AA bound deeply between transmembrane helix (TM) helices or in the central cavity of AAC1 in 14 events and between TM helices of UCP1 in 6 events. All AA involved in these deep binding events came from the intermembrane space-facing (C) leaflet. In AAC1, AA most often bound between TM1/TM2 and TM5/TM6. In four cases the fatty acid bound at the bottom of the central cavity rather than in an interhelical groove. In UCP1, all but one deeply bound AA sat between TM5 and TM6. No AA fully entered the cavity as observed in AAC1. In addition to entering the proteins, AAs were enriched around them in the surrounding membrane adjacent to the TM helices. While both protein structures exhibit hydrophobic stretches separating the intermembrane space (IMS) from the matrix, water wires formed through both AAC1 and UCP1, connecting the bulk water in both regions. Grotthuss shuttling along water wires has been proposed as a possible mechanism of AAC1/UCP1-dependent proton transport, but water wires are not present in experimental structures and have not previously been reported in MD simulations. Calculations of electric potentials along these water wires find a large 0.75-1 V electrostatic barrier along water wires through AAC1 and a substantially smaller such barrier of ~0.5 V through UCP1.
    Keywords:  AAC1; MD simulation; UCP1; electrostatics; proton uncoupling
    DOI:  https://doi.org/10.3390/ijms262110504
  46. Nat Commun. 2025 Nov 10. 16(1): 9875
    Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.
    Ghayda M Mirzaa, Keqin Yan, Raissa Relator, Mathieu Levesque, Pranisha Jayasinghe, Sara Timpano, Binnaz Yalcin, Stephan Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux-Boucher, Juliette Piard, Kristin G Monaghan, Maria J Guillen Sacoto, William B Dobyns, Kristen L Park, Daniel Martin Fernández-Mayoralas, Alberto Fernández-Jaén, Parul Jayakar, María Palomares-Bralo, Fernando Santos-Simarro, Alfredo Brusco, Vincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, Kyra E Stuurman, Katalin Štěrbová, Noor Smal, Sarah Weckhuysen, Renske Oegema, A Micheil Innes, Daniel C Koboldt, Tawfeg Ben-Omran, Rebecca C Yeh, Michael C Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah A Paolucci, Kait Miller, Barbara Burton, Katherine Kim, Emily O'Heir, Zandre Bruwer, Kirsten A Donald, Tjitske Kleefstra, Amy Goldstein, Brad Angle, Kelly Bontempo, Peter Miny, Pascal Joset, Florence Demurger, Emma Hobson, Lewis Pang, Lori Carpenter, Dong Li, Dominique Bonneau, Bekim Sadikovic, David J Picketts.
      Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.
    DOI:  https://doi.org/10.1038/s41467-025-64838-5
  47. Front Mol Biosci. 2025 ;12 1710944
    The legacy of Bruce Ames and mitochondrial DNA mutagenicity: integrating oxidative stress, aging, and modern perspectives.
    Jennifer Dang, Jia Yu Liou, Rida Mullah, Cecilia Giulivi.
      
    Keywords:  Ames bacterial mutagenicity test; aging; mitochondrial dysfunction; mtDNA mutagenesis; nutrition; oxidative stress; triage theory
    DOI:  https://doi.org/10.3389/fmolb.2025.1710944
  48. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
  49. Int J Mol Sci. 2025 Oct 29. pii: 10497. [Epub ahead of print]26(21):
    Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.
    Ganna Nevoit, Maksim Potyazhenko, Ozar Mintser, Gediminas Jarusevicius, Alfonsas Vainoras.
      This perspective piece extrapolates knowledge of mitochondriology to the clinical aspects of cardiovascular disease (CVDs) development. The aim was to deepen the understanding of the etiopathogenesis of CVDs by conceptualizing the systemic involvement of mitochondrial dysfunction mechanisms in their follow-up. A theoretical comparison of mitochondrial status and mitochondrial dysfunction across stages of the cardiovascular continuum was performed based on a systematic analysis of the scientific literature data using general scientific, theoretical, and logical methods and normative rules. Conceptual aspects of the involvement of mitochondrial dysfunction (MD) mechanisms at each stage of the CVDs continuum were identified. MD is a dynamic, complex, multifactorial process that is characterized by quantitative and qualitative changes in the mitochondrial pool of human body cells during the development of CVDs. MD is a fundamental participant in the pathogenesis of CVDs, predetermining the nature and features of the clinical manifestation and course of the disease in each patient. MD has distinctive features at each stage of the catamnesis of CVDs and can be classified according to this principle. The development of objective methods for assessing the degree of MD and its classification criteria is a promising task for future scientific research.
    Keywords:  cardiovascular continuum; cardiovascular diseases; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms262110497
  50. Nature. 2025 Nov 12.
    iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
    Fengxiang Wang, Cuiji Sun, Tianshu William Wu, Yuting Fu, Yujing Fan, Shuchang Zhao, Kaiyin Huang, Zijian Pan, Yang Lu, Jingrong Regina Han, Shikai Jia, Lizhou Zeng, Sheng Zhang, Ting Chen, Shaowei An, Shuang Susie Meng, Xun Guo, Weizhe Li, Heyuan Lian, Xiaoting Sun, Jin Hu, Chuanzhen Yang, Shan Feng, Pengfei Li, Liyuan Du, Xiaodong Liu, Kiryl D Piatkevich, Yilong Zou.
      The number of spatial omics technologies being developed is increasing1. However, a missing tool is one that can locate proteins in tissues in an untargeted manner at high spatial resolution and coverage. Here we present in situ imaging proteomics via expansion (iPEX), which integrates isotropic tissue magnification2 with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. iPEX provides scalable spatial resolution down to the micrometre scale and substantially increases the sensitivity of protein identification by 10-100-fold. Using the retina as a model, iPEX enabled the construction of spatial proteomic maps with high precision, the visualization of single-cell layers and extrasomatic structures and the identification of colocalized proteins. iPEX was readily applied to diverse tissues, including brain, intestine, liver and organoids, detecting 600-1,500 proteins at 1-5-µm effective pixel size. The application of iPEX to depict spatial proteomic maps in brains of mice with 5xFAD Alzheimer's disease revealed an early-onset mitochondrial aberrancy. Notably, in young mice, the peroxisomal acetyl-CoA acyltransferase ACAA1A-of which the N392S mutant is a monogenic risk factor in Alzheimer's disease3-was downregulated. ACAA1 depletion blocked the biosynthesis of long-chain polyunsaturated fatty acids, including docosahexaenoic acid, in multiple cellular contexts. These lipidome alterations were restored in cells overexpressing wild-type ACAA1 but not ACAA1(N392S), which suggests that the dysregulation of long-chain polyunsaturated fatty acids has an early role in neurodegeneration. Together, these results demonstrate that iPEX facilitates untargeted spatial proteomics at micrometre resolution for diverse applications.
    DOI:  https://doi.org/10.1038/s41586-025-09734-0
  51. Cell Mol Neurobiol. 2025 Nov 10. 45(1): 101
    Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.
    Li Zhang, Ying Ge, Jingjing Wu, Mei Wang, Nanqu Huang, Yong Luo.
      Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.
    Keywords:  Mesenchymal stem cells; Mitochondrial damage; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s10571-025-01624-3
  52. Clin Genet. 2025 Nov 12.
    Clinical Feasibility of Long-Read WGS for DNA Methylation Signature Analysis.
    Mathis Hildonen, Luca Mariani, Jonas Dalsberg, Mads Bak, Rosanna Weksberg, Sanaa Choufani, Zeynep Tümer.
      DNA methylation (DNAm) signatures have emerged as valuable diagnostic biomarkers for rare genetic disorders. To date, the most widely used approach for establishing and validating these signatures has relied on array-based technologies. However, in clinical diagnostics, there is a growing shift from short-read sequencing (SRS) toward long-read sequencing (LRS) technologies. Recent advances in platforms such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) enable direct assessment of DNAm from native DNA, offering improved resolution and reduced technical bias compared to array-based technologies. In this study, we compared DNAm profiles generated by LRS with those obtained from DNAm arrays. DNAm profiles of two individuals with pathogenic KMT2D variants were analyzed using DNAm arrays, LRS using PacBio and ONT, and ONT multiplexed sequencing with adaptive sampling. A support vector machine (SVM) classifier trained on array data, as well as the public classification platform EpigenCentral, yielded correct predictions for all LRS samples, underscoring the potential of LRS platforms in DNAm-based diagnostics. Our results suggest that DNAm profiles generated by LRS align well with DNAm signatures established using DNAm arrays, supporting their feasibility in clinical and research applications with the added benefit of simultaneous methylation and sequence analysis.
    Keywords:  DNAm signature; Kabuki syndrome; PacBio; epigenetic; episignature; long‐read sequencing; methylation; nanopore
    DOI:  https://doi.org/10.1111/cge.70108
  53. Brain Commun. 2025 ;7(6): fcaf397
    New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse.
    Clara D M van Karnebeek, Valérie Gailus-Durner, Udo F Engelke, Claudia Seisenberger, Susan Marschall, Nathalia R V Dragano, Patricia da Silva-Buttkus, Stefanie Leuchtenberger, Helmut Fuchs, Martin Hrabě de Angelis, Ron A Wevers, Curtis R Coughlin, Dirk J Lefeber.
      Pyridoxine-dependent epilepsy (PDE) due to recessive ALDH7A1 mutations is characterized by intractable epilepsy that is often unresponsive to antiseizure medications. Irrespective of pyridoxine (vitamin B6) supplementation and lysine reduction therapy, patients present severe residual neurocognitive deficits. We evaluated upstream inhibition of 2-aminoadipic semialdehyde synthase (AASS) as a novel therapeutic strategy to reduce the accumulating metabolites (α-aminoadipic semialdehyde, Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboxylic acid) considered neurotoxic. We utilized an existing mouse knockout model of hyperlysinaemia (Aass-knockout) and generated a PDE model, a Aldh7a1 single knockout model via CRISPR/Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein) and generated the double-knockout Aass/Aldh7a1 mice. Next-generation metabolomics screening was performed to measure all known biomarkers in brain, liver and plasma of wild-type and mutant mice. Metabolomics confirmed the known metabolite markers for Aldh7a1-knockout and Aass knockout mice in all samples. The potentially neurotoxic metabolites (Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboxylic acid) significantly decreased in double-knockout Aass/Aldh7a1 mice brain and liver tissues compared to Aldh7a1-knockout mice. Plasma analysis revealed a significant reduction of known biomarkers, suggesting a reliable monitoring option in human patients. We demonstrate the first mammalian evidence that AASS inhibition is a viable strategy to rescue abnormal brain metabolism associated with PDE. This may target the intellectual disability and neurologic deficits caused by persistent lysine catabolic-related neurotoxicity despite adequate vitamin B6 supplementation.
    Keywords:  2-aminoadipic semialdehyde synthase inhibition; lysine biochemistry; metabolic epilepsy; mouse model; therapy
    DOI:  https://doi.org/10.1093/braincomms/fcaf397
  54. Am J Hum Genet. 2025 Nov 12. pii: S0002-9297(25)00403-3. [Epub ahead of print]
    A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.
    David Wang, Matthew R Gazzara, San Jewell, Benjamin D Wales-McGrath, Kevin Yang, Christopher D Brown, Peter S Choi, Yoseph Barash.
      Genome-wide association studies (GWASs) have identified thousands of putative disease-causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show that current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a pipeline for sQTL discovery. MAJIQTL includes two statistical methods: a weighted multiple-testing approach for sGene discovery and a model for sQTL effect-size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the variant rs528823 in Alzheimer disease. Using antisense oligonucleotides, we test this variant's effect by blocking the implicated YBX3 binding site, leading to exon skipping in MS4A3.
    Keywords:  Alzheimer; MAJIQ; MS4A3; Parkinson; RNA splicing; RNA-seq; effect size; sQTL; statistical genetics; weighted hypothesis testing
    DOI:  https://doi.org/10.1016/j.ajhg.2025.10.012
  55. Nucleic Acids Res. 2025 Nov 11. pii: gkaf1125. [Epub ahead of print]
    TEDD: a comprehensive database for translation efficiency dynamics.
    Wenyan Lei, Cuidan Li, Hengyu Zhou, Zhi Nie, Anke Wang, Pan Li, Zhuojing Fan, Rongxi Zhu, Haoyu Cheng, Yuxian Guo, Liya Yue, Xiaoyuan Jiang, Renjun Gao, Yongjie Sheng, Haitao Niu, Tuohetaerbaike Bahetibieke, Wenbao Zhang, Wenming Zhao, Jingfa Xiao, Fei Chen.
      Translation, a core process in central dogma, is essential for gene expression and determination of biological phenotypes. High-throughput RNA-seq, Ribo-seq, and RNC-seq have enabled large-scale measurement of translation efficiency dynamics, yet systematic quantification and integration of translation efficiency (TE), initiation efficiency (translation ratio, TR), and elongation speed (elongation velocity index, EVI) at both gene and transcript levels across diverse biological contexts remain limited, even though their context-specific regulation-together with associated UTR features-plays key roles in development, homeostasis, and disease. To address this gap, we present TEDD (https://ngdc.cncb.ac.cn/tedd), a comprehensive database for exploring human TE, TR, and EVI with a focus on regulatory 5'/3' UTR features. TEDD integrates 1518 RNA-seq, Ribo-seq, and RNC-seq samples from 143 human projects (279 datasets) covering 24 tissues/cell types, 74 cell lines, and 52 conditions. Metrics are calculated at both gene and transcript levels, paired with detailed UTR annotations for fine-grained investigation of translational regulation. With user-friendly browsing, search, and download functions, TEDD offers an integrated online platform for multi-dimensional comparisons across genes, transcripts, Kyoto Encyclopedia of Genes and Genomes/Gene Ontology-defined gene sets, and UTR elements, providing a valuable resource for studying translational control and supporting basic and translational applications in messenger RNA vaccine design, synthetic biology, gene therapy, and enzyme engineering.
    DOI:  https://doi.org/10.1093/nar/gkaf1125
  56. Nat Rev Neurosci. 2025 Nov 12.
    Programmed axon degeneration: mechanism, inhibition and therapeutic potential.
    Andrea Loreto, Lukas J Neukomm.
      Programmed axon degeneration (PAxD) is an evolutionarily conserved mechanism in the nervous system that is activated by axonal injury (axotomy) to execute the self-destruction of a severed distal axon. It can also be triggered by non-axotomy insults, resulting in the loss of axons connected to their cell bodies. PAxD is therefore a promising target for therapeutic intervention and drugs that inhibit it are currently being tested in clinical trials. In this Review, we summarize the molecular mechanism of PAxD, focusing on its regulation by nicotinamide adenine dinucleotide (NAD+) metabolism and how it dictates Ca2+-mediated axonal demise. We examine its involvement in human disease and its potential as a therapeutic target by dissecting its role in various non-axotomy disease models. Finally, we address key challenges for its clinical translation, including the need for relevant biomarkers and safety considerations. Further advancements in understanding PAxD will pave the way for new therapeutic strategies targeting human axonopathies.
    DOI:  https://doi.org/10.1038/s41583-025-00986-3
  57. J Biomed Opt. 2025 Feb;30(Suppl 2): S23901
    Consensus guidelines for cellular label-free optical metabolic imaging: ensuring accuracy and reproducibility in metabolic profiling.
    Irene Georgakoudi, Melissa C Skala, Kyle P Quinn, Chiara Stringari, Janet E Sorrells, Ahmed A Heikal, Lin Z Li, He N Xu, Sixian You, Alex J Walsh, Rupsa Datta, Kayvan Samimi, Amani A Gillette, Kevin W Eliceiri, Mihaela Balu, Stephen A Boppart, Michelle A Digman, Kylie R Dunning, Conor L Evans, Alba Alfonso Garcia, Jessica P Houston, Wonsang Hwang, Matthew M Lindley, Xingde Li, Zhiyi Liu, Laura Marcu, Sangeeta Murugkar, Michael G Nichols, Raluca Niesner, Sapun H Parekh, Narasimhan Rajaram, Suman Ranjit, Keyue Shen, Lingyan Shi, Belén Torrado, Alexander Vallmitjana, Michael Wang-Evers, Roger Zemp.
       Significance: Cellular metabolism plays a central role in health and disease, making its study critical for advancing diagnostics and therapies. Label-free optical metabolic imaging using endogenous fluorescence from reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and flavin adenine dinucleotide (FAD) provides nondestructive, high-resolution insights into metabolic function and heterogeneity from the sub-cellular to the tissue level. Standardized approaches are essential to ensure reproducibility and comparability across studies.
    Aim: We aim to establish a consensus framework for the acquisition, calibration, and reporting of microscopic imaging metabolic function assessments based on fluorescence intensity and lifetime measurements of NAD(P)H and FAD.
    Approach: We present best practices for calibrating, analyzing, and reporting fluorescence intensity-based optical redox ratios and fluorescence lifetime data using multiexponential fitting and phasor analysis. Guidelines for validation experiments and cross-system standardization are provided to improve accuracy and reproducibility.
    Results: We demonstrate the importance of calibration procedures and normalization strategies for intensity-based optical redox measurements. We highlight needed calibration, signal-to-noise ratio considerations, and the impact of distinct analytical approaches on fluorescence lifetime-based metabolic function metrics.
    Conclusion: We recommend a consistent, practical framework for reproducible, label-free, optical metabolic imaging, facilitating robust comparisons across studies and supporting the broader adoption of optical metabolic imaging technologies for biomedical research and clinical translation.
    Keywords:  bound fraction; calibration; endogenous fluorescence; flavin adenine dinucleotide; fluorescence lifetime imaging microscopy; metabolic imaging; nicotinamide adenine dinucleotide; nicotinamide adenine dinucleotide phosphate; redox ratio
    DOI:  https://doi.org/10.1117/1.JBO.30.S2.S23901
  58. J Extracell Vesicles. 2025 Nov;14(11): e70192
    From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
    Rostyslav Horbay, Vasyl Syrvatka, Artem Bedzay, Mikaela van der Merwe, Dylan Burger, Shawn T Beug.
      According to the endosymbiotic theory of mitochondrial origin, an α-proteobacterium entered a prokaryotic cell and, through symbiosis, evolved into the mitochondria-the powerhouse of the cell. Like other bacteria, the α-proteobacteria generate their own extracellular vesicles (EVs), a trait that was passed onto the mitochondria, enabling them to generate mitochondria-derived vesicles (MDVs). MDVs, similar to small EVs (sEVs), are vesicles ranging from 30 to 200 nm in diameter and carry cargo for degradation by lysosomes and peroxisomes. MDVs share several features with sEVs, including targeted cargo degradation, biogenesis, packaging into multivesicular bodies, nucleic acid and protein transportation, induction of immune responses, and surface antigen presentation. MDVs may also be released from the cell in a manner similar to sEVs, potentially influencing intercellular communication and immune responses. Furthermore, the presence of MDVs presents opportunities for early disease detection, including neurodegenerative disorders and cancer. In this review, we explore the differences and similarities between MDVs and EVs, including their roles in immunity.
    Keywords:  endosomal sorting complex required for transportation (ESCRT); endosome; lysosome; mitochondria‐derived vesicles (MDVs); mitophagy; multivesicular body (MVB); peroxisome; small extracellular vesicles (sEVs)
    DOI:  https://doi.org/10.1002/jev2.70192
  59. Neurochem Res. 2025 Nov 10. 50(6): 354
    Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.
    Rujie Zhong, Hailin Yang, Xiaoyu Li, Feiyu Wang, Li Zhai, Jing Gao.
      Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.
    Keywords:  Ferroptosis; Mitochondria; Neurological diseases; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11064-025-04605-6
  60. Nature. 2025 Nov 12.
    Estimation and mapping of the missing heritability of human phenotypes.
    Pierrick Wainschtein, Yuanxiang Zhang, Jeremy Schwartzentruber, Irfahan Kassam, Julia Sidorenko, Petko P Fiziev, Huanwei Wang, Jeremy McRae, Richard Border, Noah Zaitlen, Sriram Sankararaman, Michael E Goddard, Jian Zeng, Peter M Visscher, Kyle Kai-How Farh, Loic Yengo.
      Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3 to quantify the relative contribution of 40 million single-nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability: that is, 20% from rare variants (MAF < 1%) and 68% from common variants (MAF ≥ 1%). We show that coding and non-coding genetic variants account for 21% and 79% of the rare-variant WGS-based heritability, respectively. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data. Finally, we performed genome-wide association analyses of all 34 phenotypes and, overall, identified 11,243 common-variant associations and 886 rare-variant associations. Altogether, our study provides high-precision estimates of rare-variant heritability, explains the heritability of many phenotypes and demonstrates for lipid traits that more than 25% of rare-variant heritability can be mapped to specific loci using fewer than 500,000 fully sequenced genomes.
    DOI:  https://doi.org/10.1038/s41586-025-09720-6
  61. Cell Rep Med. 2025 Nov 11. pii: S2666-3791(25)00528-2. [Epub ahead of print] 102455
    A combined genomic arrhythmia propensity score delineates cumulative risk.
    Tanner O Monroe, Megan J Puckelwartz, Lorenzo L Pesce, Samuel D Kearns, Patrick Page, Nora Ibrahim, Zachary T Weber, Emmanuel I Ugwor, Marcelo A Nóbrega, Prince Kannankeril, Laura J Rasmussen-Torvik, Lisa M Dellefave-Castillo, Alfred L George, Gregory Webster, Elizabeth M McNally.
      Cardiac ventricular arrhythmias can cause sudden death. Despite known genomic contributions, multigenic risk predictors are limited. The genetics of arrhythmias and cardiomyopathies overlap, with additional overlap with epilepsy. To improve genetic risk prediction, we assemble a cohort with non-ischemic ventricular arrhythmias and controls lacking cardiac diagnoses. Here, we integrate 18 polygenic scores; variants from clinical gene panels for coding regions of cardiomyopathy, arrhythmia, and epilepsy genes; and noncoding regulatory regions mapping to those genes. Polygenic scores alone hold prognostic value. Rare coding variants identify cumulative risk extending beyond known pathogenic/likely pathogenic variants. We also find enrichment of ultrarare regulatory variation. A risk predictor that combines all variant classes outperforms any single class or subset and replicates in a validation cohort. This combined genomic arrhythmia propensity score (GAPS) identifies high-risk individuals even among those who lack known primary pathogenic variants. This integrated approach serves as a model for other complex traits.
    Keywords:  arrythmia; cardiomyopathy; common variants; genetic burden; genetic risk; heart; noncoding variants; polygenic score; rare variants; sudden cardiac death
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102455
  62. Nat Commun. 2025 Nov 11. 16(1): 9925
    5-Formylcytosine is not a prevalent RNA modification in mammalian cells.
    Jasmin A Dehnen, Alexander V Gopanenko, Carola Scholz, Michael U Musheev, Christof Niehrs.
      The RNA modification 5-formylcytidine (f5C) is poorly explored in mammals. Low f5C levels reported in mRNA may reflect spurious 5-methylcytidine (m5C) oxidation or targeted demethylation by TET or ALKBH1 dioxygenases. We analyzed f5C in RNA of mouse embryonic stem cells (mESCs) using LC-MS/MS and chemical-assisted sequencing. We reveal that the previously reported pyridine-borane-sequencing misidentifies N4-acetylcytidine (ac4C) and unmodified, hyper-reactive cytidines in a CUMC context as f5C. To overcome these limitations, we developed FIBo-seq with enhanced specificity and sensitivity for f5C-sequencing. We find no evidence for a role of TET enzymes in generating f5C, unlike for ALKBH1. Moreover, no f5C sites are detectable in mRNA. Instead, the bulk of mammalian f5C resides in the well-established mitochondrial tRNA Methionine (mt-tRNAMet) and is mediated by ALKBH1. The results argue against an instructive function for f5C outside tRNA in mammals.
    DOI:  https://doi.org/10.1038/s41467-025-66090-3
  63. Nat Genet. 2025 Nov;57(11): 2620
    Somatic mutations at scale.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02438-1
  64. STAR Protoc. 2025 Nov 07. pii: S2666-1667(25)00598-2. [Epub ahead of print]6(4): 104192
    Protocol for in vivo assessment of glucose metabolism in mouse models.
    Titaya Lerskiatiphanich, Cedric S Cui, John D Lee.
      Metabolic disturbances are common in motor neuron disease (MND), and elucidating their mechanisms may reveal therapies. Here, we present a protocol to assess glucose homeostasis in mice, including glucose tolerance, insulin tolerance, and glucagon challenge tests. We describe steps for fasting, intraperitoneal injections, and serial blood glucose measurements. The protocol also includes plasma collection for catecholamine analysis using matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging and immunofluorescence of pancreatic hormones, enabling comprehensive metabolic profiling in aged and neurodegenerative mouse models. For complete details on the use and execution of this protocol, please refer to McDonald et al.1 and McDonald et al.2.
    Keywords:  Metabolism; Metabolomics; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2025.104192
  65. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2518834122
    PCNA is a nucleotide exchange factor for the clamp loader ATPase complex.
    Joshua Pajak, Jacob T Landeck, Xingchen Liu, Krishna Anand, Sasha Litvak, Brian A Kelch.
      All life requires loading ring-shaped sliding clamp protein complexes onto DNA. The sliding clamp loader is a conserved AAA+ ATPase that binds the sliding clamp, opens the ring, and places it onto DNA. While recent structural work on both the canonical and "alternative" clamp loaders has shed light into how these machines perform their task once, it remains unclear how clamp loaders are recycled to load multiple sliding clamps. Here, we present structures of the Saccharomyces cerevisiae clamp loader Replication Factor C (RFC) in absence of sliding clamp or supplemented nucleotide. Our structures indicate that RFC holds onto ADP tightly in at least two of its four ATPase active sites, suggesting that nucleotide exchange is regulated. Our molecular dynamics simulations and biochemical data indicate that binding of the sliding clamp Proliferating Cell Nuclear Antigen (PCNA) causes rapid exchange of tightly bound ADP. Our data suggest that PCNA acts as a nucleotide exchange factor (NEF) by prying apart adjacent subunits, providing a pathway for ADP release. We propose that, by using its own substrate as a NEF, RFC excludes off-pathway states that would arise from binding DNA prior to PCNA.
    Keywords:  AAA+ ATPase; clamp loader; cryo-EM
    DOI:  https://doi.org/10.1073/pnas.2518834122
  66. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2513844122
    The function of Mak16 in ribosome biogenesis depends on its [4Fe-4S] cluster.
    Nadine Duppe, Lukas Knauer, Marc Hagebölling, Lena Langner, Martin Stümpfig, Volker Schünemann, Antonio J Pierik, Daili J Netz.
      Mak16 and its interacting partner Rpf1 play a critical role at an early step in the maturation of the ribosomal 60S subunit of eukaryotes, as revealed by cryoelectron microscopy structures. While these studies suggested no metal participation or the presence of a Zn2+ ion in Mak16, we identify a previously unexplored iron-sulfur (Fe/S) cluster in yeast Mak16 through both in vivo and in vitro methods. We demonstrate a functional link between mitochondrial and cytosolic Fe/S protein biogenesis and ribosome assembly, highlighting an overlooked aspect of 60S ribosomal biogenesis. Characterization of human and yeast Mak16 revealed a redox-active [4Fe-4S]2+/1+ cluster with a midpoint potential below -500 mV. Oxidative stress destabilizes Mak16 and disrupts its interaction with Rpf1 in vivo, while in vitro H2O2 causes [3Fe-4S]1+ cluster formation. Our findings also reveal that upon binding to rRNA expansion segment 7 the redox properties of the nearby Fe/S cluster largely remain unchanged. However, disruption of Fe/S cluster coordination destabilized Mak16, impaired the Mak16-Rpf1 complex formation and decreased the 25S rRNA level. The critical role of Fe/S proteins in eukaryotic DNA replication and repair, mitoribosomal function, and maturation has now been extended to nuclear ribosomal assembly. Relying on a vulnerable cofactor comes at a cost, as cluster loss can severely disrupt essential cellular processes. The inherent biosynthetic complexity and instability of the Fe/S cluster of Mak16 allows it to function as sensor for redox imbalance, creating the possibility to regulate cellular homeostasis under stress.
    Keywords:  iron–sulfur; metallocofactor; ribosome biogenesis
    DOI:  https://doi.org/10.1073/pnas.2513844122
  67. Nat Struct Mol Biol. 2025 Nov 10.
    Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.
    Zhaoxiang He, Fei Teng, Yanqing Yang, Ruiyang Guo, Mengchen Wu, Fangzhu Han, Hongtao Tian, Jiawei Wang, Yiqi Hu, Yangwei Jiang, Leili Zhang, Chenyang Xu, Fan Yang, Jiancang Zhou, Shan Zhang, James A Letts, Ruhong Zhou, Long Zhou.
      Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has been proposed for hydrophobic biguanides, it remains elusive for the hydrophilic metformin, whose excellent pharmacological tolerance depends on weak complex I inhibition without competitive nature. Here we solved cryo-electron microscopy structures of the metformin-bound porcine respirasome. Our structural and kinetic data are consistent with a model in which metformin enters complex I only in its open state and becomes trapped at the ubiquinone redox site by ubiquinone-induced conformational closing of the enzyme. By contrast, the hydrophobic proguanil alone occupies both the entrance and the redox site of the ubiquinone channel in open and closed complex I and is kinetically consistent with competitive inhibition with conformation-dependent affinities. Our data provide the molecular basis for metformin's well-known superior properties, such as a wide therapeutic window and positive ubiquinone cooperativity, leading to its clinical success and facilitating future therapeutic developments.
    DOI:  https://doi.org/10.1038/s41594-025-01710-6
  68. Free Radic Biol Med. 2025 Nov 06. pii: S0891-5849(25)01343-7. [Epub ahead of print]242 589-600
    The effect of triclosan uncovers the possible involvement of complex II in the oxidation of glycerol-3-phosphate in brain mitochondria.
    Alexey G Kruglov, Anna B Nikiforova, Marina V Akulenko.
      Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) links the oxidative phosphorylation, glycolysis, and phospholipid biosynthesis and essentially contributes to ROS production by mitochondria in certain tissues. The pattern of biological effects of mGPDH dysregulation resembles that of chronic exposure to triclosan (Tcs), an unusual complex II inhibitor. Here we propose a hypothesis that the membrane-embedded regions of mGPDH and complex II form a common ubiquinone-binding center, which would be disturbed by Tcs. In this context, we test the potential of Tcs to inhibit mGPDH-related activities (respiration and ROS production) in isolated rat brain mitochondria (RBM). In the presence of moderate concentrations of glycerol-3-phosphate (G3P) and Ca2+, RBM demonstrated a limited ability to support oxidative phosphorylation and generation of superoxide anion and H2O2 via the reversed and transmembrane electron transport (from mGPDH to the flavins of complexes I and II). Tcs suppressed G3P- and 3-hydroxybutyrate (3-HB)-supported respiration and induced high-amplitude mitochondrial swelling. Exogenous cytochrome c restored the respiration in the presence of 3-HB but not G3P. In the presence of rotenone and thenoyltrifluoroacetone, the inhibitors of complexes I and II, Tcs inhibited antimycin A-activated and G3P-supported ROS production, which was accompanied by the oxidation of cytochromes b/heme b of complexes III/II. The 3-HB-supported ROS production and the extent of the reduction of cytochromes b were not affected by Tcs directly. These data confirm our hypothesis. However, for its rigorous assessment, we propose several approaches. Confirmation of this hypothesis will be of great importance for the development of promising mGPDH-targeted anticancer drugs.
    Keywords:  Common ubiquinone-binding site; GPD2; ROS; Succinate dehydrogenase; Superoxide anion; Triclosan
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.008
  69. Neurosci Res. 2025 Nov 08. pii: S0168-0102(25)00168-3. [Epub ahead of print] 104985
    Drug discovery research with the iPSC models of neurodegenerative diseases.
    Masahiro Adachi, Haruhiko Banno, Haruhisa Inoue.
      Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. Recently, it has become recognized that the use of iPSCs for screening can promote drug discovery research. Additionally, research is being conducted to develop high-quality models for drug discovery and to link translational research with clinical studies. The present work focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and broadly introduces the latest research using iPSCs, from disease mechanism studies to drug discovery research. In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI).
    Keywords:  ALS with frontotemporal dementia (ALS/FTD); Alzheimer's disease (AD); amyotrophic lateral sclerosis (ALS); drug discovery research; induced pluripotent stem cells (iPSCs); neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.neures.2025.104985
  70. Nat Med. 2025 Nov;31(11): 3575-3578
    The mind-bending power of placebo.
    Paul Webster.
      
    DOI:  https://doi.org/10.1038/s41591-025-04047-1
  71. Nat Commun. 2025 Nov 13. 16(1): 9976
    GroEL/ES chaperonin unfolds then encapsulates a nascent protein on the ribosome.
    Alžběta Roeselová, Sarah L Maslen, Jessica Zhiyun He, Gabija Jurkeviciute, Aleksandra Pajak, J Mark Skehel, Radoslav I Enchev, David Balchin.
      The bacterial chaperonin GroEL/ES promotes protein folding post-translation by transiently encapsulating client proteins within a central chamber. GroEL also binds translating ribosomes in vivo, implying an additional role in cotranslational folding. However, how GroEL/ES recognises and modulates ribosome-tethered nascent proteins is unclear. Here, we used biochemical reconstitution, structural proteomics and electron microscopy to study the mechanism by which GroEL/ES engages nascent polypeptides. We show that GroEL binds nascent chains on the inside of its cavity via the apical domains and disordered C-terminal tails, resulting in local structural destabilization of the client. Ribosome-tethered nascent domains are partially encapsulated upon GroES binding to GroEL, and recover their original conformation in the chaperonin cavity. Reconstitution of chaperone competition at the ribosome shows that both Trigger factor and GroEL can be accommodated on long nascent chains, but GroEL and DnaK are mutually antagonistic. Our findings extend the role of GroEL/ES in de novo protein folding, and reveal a plasticity of the chaperonin mechanism that allows cotranslational client encapsulation.
    DOI:  https://doi.org/10.1038/s41467-025-64968-w
  72. Neurol Neurochir Pol. 2025 Nov 13.
    Uncommon yet impactful - case-based reflections on rare neurologic disorders.
    Tomasz Chmiela, Zbigniew K Wszolek.
      Rare diseases (RDs) are a heterogeneous group of disorders defined by their low prevalence - affecting fewer than 1 in 2,000 individuals in Europe and fewer than 200,000 people in the US. Although individually uncommon, rare diseases collectively impact an estimated 263 to 446 million people worldwide. Early recognition and diagnosis remain major challenges, particularly in neurology, where overlapping phenotypes and limited awareness often delay appropriate management. We present 3 illustrative case studies highlighting the diagnostic and therapeutic complexities associated with rare neurologic disorders. The first case describes a patient with CSF1R-related disorder; diagnosis was significantly delayed due to initial misattribution of symptoms to traumatic brain injury. This delay ultimately precluded timely intervention with disease-modifying therapies such as hematopoietic stem cell transplantation. The second case involves a patient with frontotemporal dementia and parkinsonism linked to chromosome 17 with a pathogenic c.837T>G, p.N279K variant in the MAPT gene, also known as pallidopontonigral degeneration. Although a strong family history facilitated early diagnosis, the case underscores the broader challenges of managing hereditary neurodegenerative diseases within affected families. The third case presents an exceptionally rare scenario of dual pathogenic mutations in ATXN3 and ATXN8OS, resulting in concurrent diagnoses of spinocerebellar ataxia types 3 and 8. This case exemplifies the clinical ambiguity and interpretive difficulty posed by co-occurring rare variants with overlapping symptomatology. Collectively, these 3 cases emphasize the importance of accurate, timely diagnosis to avoid unnecessary testing in rare neurologic diseases. Timely recognition enables access to emerging personalized therapies and support systems.
    Keywords:  CSF1R-RD; MAPT; PPND; SCA; SCA3; SCA8; rare diseases
    DOI:  https://doi.org/10.5603/pjnns.108495
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