Risk Variants Impair Multiple Mitochondrial Pathways in a Metabolomics Analysis.

Background: Kidney risk variants (KRVs) in the gene are associated with mitochondrial dysfunction. However, the molecular spectrum of metabolites affected by the G1 and G2 KRVs, and the downstream mitochondrial pathways they affect, remain unknown.

Methods: We performed a metabolomics analysis using HEK293 Tet-on cells conditionally expressing G0, G1, and G2 KRVs to determine the patterns of metabolites and pathways potentially involved in nephropathy. The Welch two-sample test, matched-pairs test, and two-way repeated measures ANOVA were used to identify differential metabolites. Random forest, a supervised classification algorithm that uses an ensemble of decision trees, and the mean-decrease-accuracy metric were applied to prioritize top metabolites.

Results: Alterations in the tricarboxylic acid cycle, increased fatty acid oxidation, and compromised redox homeostasis were the major pathways affected by overexpression of KRVs.

Conclusions: Impairment of mitochondrial membrane respiratory chain complex I appeared to account for critical metabolic consequences of KRVs. This finding supports depletion of the mitochondrial membrane potential, as has been reported.