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Research on the <jats:italic>Ndufs4<\/jats:italic> knockout (KO) mouse model has identified neuronal vulnerability to CI deficiency as a major driver of the disease, yet its effects on hepatic function remain unclear. Considering the importance of the liver, and its interconnection with the brain, in regulating whole-body metabolic balance, further investigation into the effects of whole-body <jats:italic>Ndufs4<\/jats:italic> KO on the liver is warranted.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objectives<\/jats:title>\n            <jats:p>This study investigated liver bioenergetics and metabolism in <jats:italic>Ndufs4<\/jats:italic> KO and WT mice at the late stage of LS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Bioenergetic investigations of liver mitochondria (<jats:italic>n<\/jats:italic>\u2009\u2265\u20093) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (<jats:italic>n<\/jats:italic>\u2009\u2265\u200919) utilised <jats:sup>1<\/jats:sup>H-NMR, GC-TOFMS, and LC-MS\/MS. Significant alterations were identified via t-tests and effect size calculations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              <jats:italic>Ndufs4<\/jats:italic> KO livers displayed a significant\u2009~\u200986% reduction in CI activity and a\u2009~\u200943% decrease in CI contribution to CI\u2009+\u2009II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in <jats:italic>Ndufs4<\/jats:italic> KO hepatic metabolism including glucose-, amino acid-, purine\/pyrimidine metabolism and the TCA-cycle.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Despite severe CI deficiency, respiration in the <jats:italic>Ndufs4<\/jats:italic> KO liver remains largely unaffected due to reliance on CII. Nonetheless, advanced LS significantly disrupts liver metabolism, with O-GlcNAcylation and mTOR signalling suggestsed as key areas for future investigation. Altogether, our findings underscore the importance of interorgan metabolic dynamics and the liver-brain axis in neurometabolic disorders like LS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11306-025-02275-7","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T04:48:35Z","timestamp":1749617315000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5700-6890","authenticated-orcid":false,"given":"Karin","family":"Terburgh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-634X","authenticated-orcid":false,"given":"Nastassja","family":"Sweeney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-8644","authenticated-orcid":false,"given":"Roan","family":"Louw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"2275_CR1","doi-asserted-by":"publisher","first-page":"148213","DOI":"10.1016\/j.bbabio.2020.148213","volume":"1861","author":"MJW Adjobo-Hermans","year":"2020","unstructured":"Adjobo-Hermans, M. 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