The ATPase Inhibitory Factor 1 (IF1) Contributes to the Warburg Effect and Is Regulated by Its Phosphorylation in S39 by a Protein Kinase A-like Activity

Simple Summary The ATPase Inhibitory Factor 1 (IF1) plays a prominent role as an inhibitor of mitochondrial ATP synthase. Herein we review the role of IF1 in promoting the Warburg effect and the relevance of its phosphorylation by protein kinase A (PKA) to block its activity as inhibitor of ATP synthase. Our results are supported by other independent studies and highlight the involvement of IF1 in metabolic reprogramming to promote an augmented glycolytic phenotype under aerobic conditions by exerting its inhibitory action on a fraction of ATP synthase present in the mitochondrion. The phosphorylation in vivo of IF1 at S39 by a mitochondrial c-AMP-dependent PKA activity prevents its interaction with ATP synthase. Finally, we stress that IF1 not only can play a cancer-promoting role but also can prevent metastatic disease in some carcinomas.Abstract The relevant role played by the ATPase Inhibitory Factor 1 (IF1) as a physiological in vivo inhibitor of mitochondrial ATP synthase in cancer and non-cancer cells, and in the mitochondria of different mouse tissues, as assessed in different genetic loss- and gain-of-function models of IF1 has been extensively documented. In this review we summarize our findings and those of others that favor the implication of IF1 in metabolic reprogramming to an enhanced glycolytic phenotype, which is mediated by its binding and inhibition of the ATP synthase. Moreover, we emphasize that IF1 is phosphorylated in vivo in its S39 by the c-AMP-dependent PKA activity of mitochondria to render an inactive inhibitor that is unable to interact with the enzyme, thus triggering the activation of ATP synthase. Overall, we discuss and challenge the results that argue against the role of IF1 as in vivo inhibitor of mitochondrial ATP synthase and stress that IF1 cannot be regarded solely as a pro-oncogenic protein because in some prevalent carcinomas, it prevents metastatic disease.