The xenobiotic detoxification pathway - glycine conjugation - is downregulated in a mouse model of Leigh syndrome.

Leigh syndrome (LS), a primary mitochondrial disease frequently caused by complex I (CI) deficiency, has been associated with hepatic dysfunction and impaired metabolic homeostasis. Despite this, the impact of mitochondrial dysfunction on hepatic xenobiotic detoxification pathways remains poorly understood. This study investigated the glycine conjugation pathway-central to the metabolism of dietary xenobiotics such as benzoate, salicylate, and medium-chain fatty acids (MCFAs)-in a whole-body Ndufs4 knockout (Ndufs4-/-) mouse model of LS. Transcriptomic analysis revealed a significant downregulation of the xenobiotic/medium chain fatty acid: CoA ligases (Acsm1 and Acsm2) and glycine N-acyltransferase (Glyat) in the livers of Ndufs4-/- mice, suggesting impaired activation and conjugation of xenobiotics. This was corroborated by reduced GLYAT (EC2.3.1.13) enzymatic activity and a marked decrease in hepatic hexanoylglycine levels. These findings imply that CI deficiency attenuates glycine conjugation capacity, potentially compromising the liver's ability to metabolise xenobiotic and dietary substrates. Given the role of glycine conjugation in detoxification, our data highlight a metabolic vulnerability in LS that may influence dietary and pharmacological interventions. Adjusting dietary intake of conjugation substrates may therefore be crucial in the clinical management of mitochondrial disease.