An investigation of cellular responses to tetrafluoroethylcysteine-induced mitochondrial dysfunction

Abstract

Several disease states and chemical-induced toxicities are mediated through an early mitochondrial dysfunction. A better understanding of the molecular and biochemical events that transpire during such mitochondrial damage will help improve accuracy in preclinical screening of drug toxicities, and also in identifying potential drug targets for disease modulation. The studies described herein employ S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene (TFE), which covalently adducts a select subset of mitochondrial proteins, and causes mitochondrial stress. Results of these studies revealed that early mitochondrial changes, including the inhibition of the TCA cycle and ATP production, trigger a series of biochemical events that transcend organellar boundaries. The immediate impact of TFEC on the mitochondria is discussed in Chapter 2. The subsequent cascade of events are relayed through various signal transduction pathways that affect nuclear transcriptional responses and the induction of a number of cytosolic heat shock proteins (HSPs) as described in Chapter 3. An unexpected oxidative stress response, related to the activation of the Nrf2 transcriptional pathway was discovered and is described in Chapter 4. A further link between oxidative stress and a prior ER stress response is discussed. Finally, Chapter 5 speculates about a possible role for a critical TFEC adduct and explores new routes of toxicity based on other observations. Overall, the results support an important role for mitochondrial dysfunction in the initiation, progression and outcome of some chemical-induced toxicities. Multiple signaling pathways can emerge from a focal subcellular lesion, leading to a plethora of targeted cellular responses in various organelles. Future investigations are suggested to better characterize these responses for identifying potential toxicity biomarkers, and/or potential drug targets.