Mitochondria are a critical target the cellular source of most of the cell’s supply of adenosine triphosphate (ATP) and are also involved in other tasks such as signaling, cellular differentiation, and cell cycle, growth and death. Mitochondria dysfunction is increasingly implicated in many systems, including the hepatoxicity and cardiotoxicity of humans.
In line with the principles of the Toxicity Testing in the 21st Century (TT21C), this project is investigating chemical-induced perturbations of two critical mitochondrial toxicity pathways: Nrf2 [Nuclear factor erythroid-derived factor 2 - related factor 2] and PGC-1? [Peroxisome proliferator-activated receptor-? coactivator-1?] in the onset and development of mitochondrial toxicity in human cells. The aim is to:
1) Review existing research on chemical-induced mitochondrial toxicity linking the two pathways
2) in-vitro assay development/optimization with multiple levels of readout from cell populations and individual cells (both time- and dose-dependent)
3) Understanding of antioxidant defence mechanism, through the data generated and computational network mapping (modelling) of key species (mRNA, proteins).
Ultimately, we intend to explore the knowledge gained from the two mitochondrial toxicity pathways as part of evidence to develop novel mechanism-based non-animal pathway approaches for risk assessment. This project is in collaboration with the Chinese Academy of Military Medical Sciences (AMMS) with a commitment of three full-time scientists.