ArticleMetabolomics : Official journal of the Metabolomic Society2025
Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
Article in Metabolomics : Official journal of the Metabolomic Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Metabolic adaptations of starving purple sea urchins (Strongylocentrotus purpuratus) surviving in the barrens.Scientific reports · 2026Article
- Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.Redox biology · 2026Article
- Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.Journal of inherited metabolic disease · 2026Article
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Abstract
introductionMitochondrial 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.
objectivesThis study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
methodsBioenergetic 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
resultsNdufs4 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.
conclusionDespite 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.
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