Metabolomics : Official journal of the Metabolomic Society · 2025
Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
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Terburgh Karin, Sweeney Nastassja, Louw Roan
Аннотация
INTRODUCTION: Mitochondrial complex (CI) deficiency frequently manifests as a severe neurometabolic disorder called Leigh syndrome (LS). Research on the Ndufs4 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 Ndufs4 KO on the liver is warranted.
OBJECTIVES: This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
METHODS: Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised 1H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
RESULTS: Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
CONCLUSION: Despite severe CI deficiency, respiration in the Ndufs4 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.
OBJECTIVES: This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
METHODS: Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised 1H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
RESULTS: Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
CONCLUSION: Despite severe CI deficiency, respiration in the Ndufs4 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.