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The\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    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\u2010associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole\u2010body CI deficiency affects cardiac bioenergetics and metabolism in late\u2010stage\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high\u2010resolution respirometry, respectively, in mitochondria isolated from\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    KO and wild\u2010type mouse hearts. Cardiometabolic profiling was performed on a well\u2010powered cohort, employing untargeted GC\u2010TOFMS,\n                    <jats:sup>1<\/jats:sup>\n                    H\u2010NMR and semi\u2010targeted LC\u2010MS\/MS.\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI\u2010driven respiration, halving CI's contribution to combined CI\u2009+\u2009II respiration and prompting a shift toward CII\u2010driven respiration. Cardiometabolic profiles revealed significant reductions in energy\u2010generating substrates, including long\u2010chain fatty acids, glucose, lactic acid and 3\u2010hydroxybutyric 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\u2010body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI\u2010dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI\u2010deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70142","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T10:04:21Z","timestamp":1768385061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Energy Metabolism Under Stress: Late\u2010Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in\n                    <i>Ndufs4<\/i>\n                    <scp>KO<\/scp>\n                    Mice"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5700-6890","authenticated-orcid":false,"given":"Karin","family":"Terburgh","sequence":"first","affiliation":[{"name":"Biomedical and Molecular Metabolism Research (BioMMet), Faculty of Natural and Agricultural Sciences North\u2010West University  Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-634X","authenticated-orcid":false,"given":"Nastassja","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Biomedical and Molecular Metabolism Research (BioMMet), Faculty of Natural and Agricultural Sciences North\u2010West University  Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-8644","authenticated-orcid":false,"given":"Roan","family":"Louw","sequence":"additional","affiliation":[{"name":"Biomedical and Molecular Metabolism Research (BioMMet), Faculty of Natural and Agricultural Sciences North\u2010West University  Potchefstroom South 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