| First Author | Terburgh K | Year | 2025 |
| Journal | Metabolomics | Volume | 21 |
| Issue | 4 | Pages | 76 |
| PubMed ID | 40498175 | Mgi Jnum | J:389912 |
| Mgi Id | MGI:8369424 | Doi | 10.1007/s11306-025-02275-7 |
| Citation | Terburgh K, et al. (2025) Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model. Metabolomics 21(4):76 |
| abstractText | 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 (1)H-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. |
