The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, 1H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.

Mutations in the Ndufs4 gene encoding the accessory subunit of complex I (CI) of the mitochondrial oxidative phosphorylation (OXPHOS) system, are the most common causes of Leigh Syndrome (LS). LS is a severe infantile neurodegenerative disorder characterised by various clinical phenotypes ranging from ataxia, cardiomyopathy, swallowing difficulties, visual problems, psychomotor regression to fatal respiratory failure. The mechanistic processes contributing to the onset and progression of these clinical manifestations remain poorly understood. This study investigates tissue-specific proteomic changes in a mouse model of LS using quantitative proteomics as a hypothesis-generating technique. Six distinct tissues, namely three brain regions (brainstem, cerebellum, olfactory bulb), heart, kidney, and liver, were collected from the LS mouse model (Ndufs4 KO mice) and compared to wild type (WT) controls using SWATH-MS analysis as a data acquisition method. Functional enrichment analysis revealed distinct tissue-specific cellular responses which include a shift toward amino acid metabolism in the heart, increased mitochondrial translation in the kidney, and alterations in phase II detoxification pathways in the liver. Our results unravel candidate mechanisms for tissue-specific vulnerability and highlight the regulation of PTEN gene transcription as potential driver of neurodegeneration. These findings provide data-driven hypotheses for tissue-specific vulnerability in LS, highlighting potential mechanisms and therapeutic targets. This study established a foundation for future hypothesis-driven research into the tissue-specific pathophysiology of mitochondrial disease.

Mitochondrial tRNA genes are critical hotspots for pathogenic mutations and several mitochondrial diseases. They account for approximately 70-75% of disease-causing mtDNA variants despite comprising only 5-10% of the mitochondrial genome. These mutations interfere with mitochondrial translation and affect oxidative phosphorylation, resulting in remarkably heterogeneous multisystem disorders. Under this light, we systematically reviewed PubMed, Scopus, and MITOMAP databases through October 2025, indexing all clinically relevant pathogenic mt-tRNA mutations classified by affected organ systems and underlying molecular mechanisms. Approximately 500 distinct pathogenic variants were identified across all 22 mt-tRNA genes. Beyond typical syndromes like MELAS, MERRF, Leigh syndrome, and Kearns-Sayre syndrome that are linked to mt-tRNA mutations, they increasingly implicate cardiovascular diseases (cardiomyopathy, hypertension), neuromuscular disorders (myopathies, encephalopathies), sensory impairment (hearing loss, optic neuropathy), metabolic dysfunction (diabetes, polycystic ovary syndrome), renal disease, neuropsychiatric conditions, and cancer. Beyond sequence mutations, defects in post-transcriptional modification systems emerge as critical disease mechanisms affecting mt-tRNA function and stability. The mutations on tRNA genes described herein represent potential targets for emerging genome editing therapies, although several translational challenges remain. However, targeted correction of pathogenic mt-tRNA mutations holds transformative potential for precision intervention on mitochondrial diseases.

Mitochondria have emerged as a significant and promising area of research in hypertrophic cardiomyopathy (HCM). However, there is a notable scarcity of bibliometric studies in this field. Our aim is to conduct a bibliometric analysis of mitochondrial research in HCM, delineating research hotspots and trends to aid in understanding the focal points and evolving trajectories of both basic and clinical research. Articles and reviews related to mitochondrial research in hypertrophic cardiomyopathy (HCM) from 2003 to 2023 were filtered from the Web of Science database. CiteSpace software was utilized to generate knowledge maps including keyword analysis, authorship networks, countries of origin, and journal distributions. A total of 285 relevant articles on HCM and mitochondria were included, with publication output steadily increasing over the years. These publications originated from 47 countries and regions, with the United States and China contributing the most publications. Primary research institutions included UDICE-French Research Universities, Centro de Investigacion Biomedica en Red, and Institut National de la Sante et de la Recherche Medicale (Inserm). J BIOL CHEM and P NATL ACAD SCI USA emerged as prominent journals with substantial research output and authority. We identified 520 authors, with Rachid Boutoual and Scot C Leary having the highest publication outputs, while BJ Maron and D Ghezzi were cited most frequently. Through hotspot analysis, we identified frequently occurring keywords such as Hypertrophic cardiomyopathy, Oxidative stress, Heart failure, Lactic acidosis, Mutations, Disease, Dilated cardiomyopathy, Cardiomyopathy, Deficiency, and Cardiac hypertrophy. Mitochondrial diseases associated with HCM, including Leigh syndrome, Barth syndrome (BTHS), heart failure, arrhythmias, and cardiovascular diseases, represent current and evolving research areas. Through bibliometric methods, we have elucidated the research hotspots and trends concerning hypertrophic cardiomyopathy (HCM) and mitochondria. The investigation of mitochondria, particularly in the context of cardiovascular medicine and HCM, demonstrates an unstoppable momentum. Research on mitochondria in HCM predominantly focuses on mechanisms, cardiovascular diseases, and therapeutic approaches, which will serve as pivotal areas for future exploration.

We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting a highly conserved amino acid position (p.Ser297Pro) in the cytochrome b (MT-CYB) gene on a haplogroup K1c1a background, which includes a set of four non-synonymous polymorphisms also present in the same gene. Biochemical studies documented respiratory chain impairment due to complex III defect. This variant fulfils the criteria for being pathogenic and was previously reported in a sporadic case of fatal neonatal polyvisceral failure.