Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation

Abstract

This Adverse Outcome Pathway (AOP) describes the linkage between uncoupling of oxidative phosphorylation (OXPHOS) and growth inhibition via decreased cell proliferation. The mitochondrial OXPHOS machinery is a key physiological process responsible for producing the primary cellular energy, adenosine triphosphate (ATP). Uncoupling of OXPHOS is a well-known mechanism of action of many chemicals and can affect many ATP-dependent biological functions. Cell proliferation in particular, as a major process to achieve organismal growth, is positively correlated with the cellular ATP level and highly susceptible to energy depletion. This AOP causally links uncoupling of OXPHOS to growth inhibition, through ATP depletion and reduced cell proliferation with strong weight of evidence support. This AOP is of high regulatory relevance, as it is considered applicable to both human health and ecological risk assessments. The AOP also forms the core of a larger AOP network addressing uncoupling of OXPHOS mediated growth inhibition. This AOP is referred to as AOP 263 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).