Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome

The value of metabolomics in multi-systemic mitochondrial disease research has been increasingly recognized, with the ability to investigate a variety of biofluids and tissues considered a particular advantage. Although minimally invasive biofluids are the generally favored sample type, it remains unknown whether systemic metabolomes provide a clear reflection of tissue-specific metabolic alterations.

Here we cross-compare urine and tissue-specific metabolomes in the Ndufs4 knockout mouse model of Leigh syndrome-a complex neurometabolic MD defined by progressive focal lesions in specific brain regions-to identify and evaluate the extent of common and unique metabolic alterations on a systemic and brain regional level.

Untargeted and semi-targeted multi-platform metabolomics were performed on urine, four brain regions, and two muscle types of Ndufs4 KO (n≥19) vs wildtype (n≥20) mice.

Widespread alterations were evident in alanine, aspartate, glutamate, and arginine metabolism in Ndufs4 KO mice; while brain-region specific metabolic signatures include the accumulation of branched-chain amino acids, proline, and glycolytic intermediates. Furthermore, we describe a systemic dysregulation in one-carbon metabolism and the tricarboxylic acid cycle, which was not clearly reflected in the Ndufs4 KO brain.

Our results confirm the value of urinary metabolomics when evaluating MD-associated metabolites, while cautioning against mechanistic studies relying solely on systemic biofluids.