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The mitochondrial H(+)-ATP synthase synthesizes most of cellular ATP requirements by oxidative phosphorylation (OXPHOS). The ATPase Inhibitory Factor 1 (IF1) is known to inhibit the hydrolase activity of the H(+)-ATP synthase in situations that compromise OXPHOS. Herein, we demonstrate that phosphorylation of S39 in IF1 by mitochondrial protein kinase A abolishes its capacity to bind the H(+)-ATP synthase. Only dephosphorylated IF1 binds and inhibits both the hydrolase and synthase activities of the enzyme. The phosphorylation status of IF1 regulates the flux of aerobic glycolysis and ATP production through OXPHOS in hypoxia and during the cell cycle. Dephosphorylated IF1 is present in human carcinomas. Remarkably, mouse heart contains a large fraction of dephosphorylated IF1 that becomes phosphorylated and inactivated upon in vivo β-adrenergic stimulation. Overall, we demonstrate the essential function of the phosphorylation of IF1 in regulating energy metabolism and speculate that dephosho-IF1 might play a role in signaling mitohormesis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Significance: Since the signing of the National Cancer Act in 1971, cancer still remains a major cause of death despite significant progresses made in understanding the biology and treatment of the disease. After many years of ostracism, the peculiar energy metabolism of tumors has been recognized as an additional phenotypic trait of the cancer cell., Recent Advances: While the enhanced aerobic glycolysis of carcinomas has already been translated to bedside for precise tumor imaging and staging of cancer patients, accepting that an impaired bioenergetic function of mitochondria is pivotal to understand energy metabolism of tumors and in its progression is debated. However, mitochondrial bioenergetics and cell death are tightly connected., Critical Issues: Recent clinical findings indicate that H(+)-ATP synthase, a core component of mitochondrial oxidative phosphorylation, is repressed at both the protein and activity levels in human carcinomas. This review summarizes the relevance that mitochondrial function has to understand energy metabolism of tumors and explores the connection between the bioenergetic function of the organelle and the activity of mitochondria as tumor suppressors., Future Directions: The reversible nature of energy metabolism in tumors highlights the relevance that the microenvironment has for tumor progression. Moreover, the stimulation of mitochondrial activity or the inhibition of glycolysis suppresses tumor growth. Future research should elucidate the mechanisms promoting the silencing of oxidative phosphorylation in carcinomas. The aim is the development of new therapeutic strategies tackling energy metabolism to eradicate tumors or at least, to maintain tumor dormancy and transform cancer into a chronic disease.

The H(+)-ATP synthase is a reversible engine of mitochondria that synthesizes or hydrolyzes ATP upon changes in cell physiology. ATP synthase dysfunction is involved in the onset and progression of diverse human pathologies. During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1). The expression of IF1 in human tissues and its participation in the development of human pathology are unknown. Here, we have developed monoclonal antibodies against human IF1 and determined its expression in paired normal and tumor biopsies of human carcinomas. We show that the relative mitochondrial content of IF1 increases significantly in carcinomas, suggesting the participation of IF1 in oncogenesis. The expression of IF1 varies significantly in cancer cell lines. To investigate the functional activity of IF1 in cancer, we have manipulated its cellular content. Overexpression of IF1 or of its pH-insensitive H49K mutant in cells that express low levels of IF1 triggers the up-regulation of aerobic glycolysis and the inhibition of oxidative phosphorylation with concurrent mitochondrial hyperpolarization. Treatment of the cells with the H(+)-ATP synthase inhibitor oligomycin mimicked the effects of IF1 overexpression. Conversely, small interfering RNA-mediated silencing of IF1 in cells that express high levels of IF1 promotes the down-regulation of aerobic glycolysis and the increase in oxidative phosphorylation. Overall, these findings support that the mitochondrial content of IF1 controls the activity of oxidative phosphorylation mediating the shift of cancer cells to an enhanced aerobic glycolysis, thus supporting an oncogenic role for the de-regulated expression of IF1 in cancer.

The down-regulation of the catalytic subunit of the mitochondrial H+-ATP synthase (beta-F1-ATPase) is a hallmark of most human carcinomas. This characteristic of the cancer cell provides a proteomic signature of cellular bioenergetics that can predict the prognosis of colon, lung, and breast cancer patients. Here we show that the in vivo tumor glucose uptake of lung carcinomas, as assessed by positron emission tomography in 110 patients using 2-deoxy-2-[18F]fluoro-d-glucose as probe, inversely correlates with the bioenergetic signature determined by immunohistochemical analysis in tumor surgical specimens. Further, we show that inhibition of the activity of oxidative phosphorylation by incubation of cancer cells with oligomycin triggers a rapid increase in their rates of aerobic glycolysis. Moreover, we show that the cellular expression level of the beta-F1-ATPase protein of mitochondrial oxidative phosphorylation inversely correlates (P < 0.001) with the rates of aerobic glycolysis in cancer cells. The results highlight the relevance of the alteration of the bioenergetic function of mitochondria for glucose capture and consumption by aerobic glycolysis in carcinomas.