Uncovering Mitochondrial Defects Induced by Chemicals: A Case Study of Low-Dose Medium-Chain Chlorinated Paraffin Exposure

Given the susceptibility of mitochondria
to environmental
pollutants,
mitochondrial defects are critical end points for chemical safety
evaluation. In this study, we present a comprehensive strategy for
assessing mitochondrial toxicity, exemplified through a case study
on medium-chain chlorinated paraffins (MCCPs, CxH2x+2–yCly with 14–17 carbon atoms),
one of the most abundant organic pollutants in the human body. Our
results demonstrate that MCCP exposure at levels commonly found in
humans significantly reduces cellular ATP content by impairing mitochondrial
respiration rather than glycolysis. Using an optimized mitochondrial
metabolomics approach combined with dose-resolved proteomics, we elucidated
the molecular mechanisms underlying MCCP-induced mitochondrial defects,
including inhibition of the electron transport chain, mitochondrial
membrane damage, accumulation of reactive oxygen species, and disruptions
in nucleotide metabolism. Notably, over 80% of the MCCP-regulated
mitochondrial proteins exhibited EC50 values below the
human internal levels of MCCPs, highlighting a significant threat
to human health. This proposed strategy for mitochondrial toxicity
assessment is expected to facilitate future research in mitochondrial
toxicology.