• OBS binds with mitochondrial proteins DLST and GCDH to damage mitochondria. • OBS disrupts cascade of lysine metabolism, TCA cycle and methionine metabolism. • OBS induces distinct renal damage in mice. • The first study to prove the direct mitochondria–xenobiotics interaction. Chronic kidney disease is largely driven by environmental exposure such as per- and polyfluoroalkyl substances (PFAS). Mitochondrial proteins, whose homeostasis can be affected by PFAS, largely participate in the progression of renal damage. Despite this connection, the direct mitochondria–xenobiotics interaction and linking mechanisms are still lacking. In this study, integrative thermal proteome profiling and limited proteolysis-mass spectrometry was used to identify the direct protein targets of sodium p -perfluorous nonenoxybenzenesulfonate (OBS), a typical emerging PFAS, to pose nephrotoxicity. OBS elicited distinct renal injury phenotype in mice. Dihydrolipoamide succinyltransferase (DLST) and glutaryl-CoA dehydrogenase (GCDH) were identified as critical targets of OBS. Validation through cellular thermal shift assay, surface plasmon resonance and molecular docking confirmed that OBS bound with these two proteins. As a result, their expressions were significantly downregulated. Metabolomics revealed that the decrease in DLST and GCDH expressions subsequently inhibited tricarboxylic acid cycle and lysine degradation, which synergistically suppressed mitochondrial respiratory chain to hinder ATP production and depress methionine metabolism, eventually leading to the damage phenotype. Upon in situ overexpression of DLST and GCDH in kidney, mice exposed to OBS exhibited reduced level of mitochondrial damage and metabolic abnormalities, as well as mitigated kidney injury. This study discloses that OBS directly targets on mitochondrial proteins to disrupt the cascade of multiple metabolism processes and promotes renal impairment, proving evidence on the direct interaction between mitochondria and pollutants, and certifying mitochondrial proteins as potential therapeutic targets against environmental exposure induced toxicities.
Lyu et al. (Fri,) studied this question.