The F₁F_o-ATPase inhibitor, IF₁, is a critical regulator of energy metabolism in cancer cells

In the last two decades, IF₁, the endogenous inhibitor of the mitochondrial F₁F_o-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF₁ is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF₁ remains elusive. Here, we recall the main features of the mechanism of the action of IF₁ when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF₁ is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF₁ as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF₁ as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF₁ as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF₁ on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF₁ in cancer and in developing related anticancer strategies.