APOL1 risk variants impair multiple mitochondrial pathways in a metabolomics analysis

Background: Kidney risk variants (KRVs) in the apolipoprotein L1 gene (APOL1) are associated with mitochondrial dysfunction. However, the molecular spectrum of metabolites impacted 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 APOL1 G0, and G1 and G2 KRVs to determine the patterns of metabolites and pathways potentially involved in nephropathy. Welch9s two-sample t-test, matched pairs t-test, and two-way repeated measures ANOVA were employed to identify differential metabolites. Random Forest, a supervised classification algorithm that uses an ensemble of decision trees, and the mean decrease accuracy (MDA) 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 impacted by overexpression of APOL1 KRVs. Conclusion: Impairment of mitochondrial membrane respiratory chain complex I appeared to account for critical metabolic consequences of APOL1 KRVs. This finding supports depletion of the mitochondrial membrane potential, as has been reported.