Modulation of cancer energy metabolism: the role of the ATPase inhibitor factor 1 (IF1) in the bioenergetics of cancer cells experiencing oxygen deprivation

IF1, the endogenous inhibitor protein of mitochondrial F1Fo-ATPase, has raised interest in cancer research due to its overexpression in solid tumours compared to normal tissues. Physiologically, IF1 protects cells from energy depletion by limiting the ATP hydrolytic activity of ATP synthase triggered by mitochondrial depolarization caused by oxygen deficiency as it occurs during ischemic episodes. Considering both the physiological function of IF1 and that cancer cells in solid tumour are frequently exposed to oxygen deprivation, we hypothesized that IF1 overexpression represents a strategy that cancer cells develop to protect themselves from energy depletion under conditions of low oxygen availability. To assess this, we assayed the bioenergetic changes in 143B and HCT116 cancer cells with different metabolic features following stable silencing of IF1. Interestingly, we found that in both cell lines exposed to oxygen deprivation conditions the presence of IF1 limits the energy dissipation due to the activation of the ATP hydrolytic activity of ATP synthase. Furthermore, the analyses of cellular growth and viability revealed that the IF1 silencing inhibited proliferation in the highly glycolytic 143B cells, while it induced more than 50% of cellular death in HCT116 OXPHOS-dependent cells, indicating that the energetic advantage conferred by IF1 is essential for cancer cell proliferation or survival depending on the energy metabolism of each cell line. Moreover, under mitochondrial depolarization conditions, both mitophagy and mitochondrial biogenesis markers were found up-regulated in IF1-expressing cells only, thus indicating a continuous renewal and preservation of the mitochondrial mass. Taken together, our results sustain the idea that IF1 overexpression supports cancer cell adaptation to hypoxic or anoxic conditions also favouring the proliferation of re-oxygenated cells by promptly providing functional mitochondria