The H(+)-ATP synthase: a gate to ROS-mediated cell death or cell survival.

Cellular oxidative stress results from the increased generation of reactive oxygen species and/or the dysfunction of the antioxidant systems. Most intracellular reactive oxygen species derive from superoxide radical although the majority of the biological effects of reactive oxygen species are mediated by hydrogen peroxide. In this contribution we overview the major cellular sites of reactive oxygen species production, with special emphasis in the mitochondrial pathways. Reactive oxygen species regulate signaling pathways involved in promoting survival and cell death, proliferation, metabolic regulation, the activation of the antioxidant response, the control of iron metabolism and Ca(2+) signaling. The reversible oxidation of cysteines in transducers of reactive oxygen species is the primary mechanism of regulation of the activity of these proteins. Next, we present the mitochondrial H(+)-ATP synthase as a core hub in energy and cell death regulation, defining both the rate of energy metabolism and the reactive oxygen species-mediated cell death in response to chemotherapy. Two main mechanisms that affect the expression and activity of the H(+)-ATP synthase down-regulate oxidative phosphorylation in prevalent human carcinomas. In this context, we emphasize the prominent role played by the ATPase Inhibitory Factor 1 in human carcinogenesis as an inhibitor of the H(+)-ATP synthase activity and a mediator of cell survival. The ATPase Inhibitory Factor 1 promotes metabolic rewiring to an enhanced aerobic glycolysis and the subsequent production of mitochondrial reactive oxygen species. The generated reactive oxygen species are able to reprogram the nucleus to support tumor development by arresting cell death. Overall, we discuss the cross-talk between reactive oxygen species signaling and mitochondrial function that is crucial in determining the cellular fate. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.