The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention

SIMPLE SUMMARY: Cancer is a global health problem with high personal and economic burden worldwide. The reprogramming of metabolism experienced by carcinomas offers a large set of enzymes that could be exploited to prevent cancer growth and metastasis. This review emphasizes the interplay between mitochondrial ATP synthase and its physiological inhibitor, the ATPase Inhibitory Factor 1 (IF1), in the metabolic reprogramming of OXPHOS in cancer cells to an enhanced glycolytic phenotype. We highlight the cell-type specificity by which the ATP synthase/IF1 axis exerts its activity as a tumor promotor or signals an anti-metastatic phenotype. Moreover, the implication of the ATP synthase/IF1 axis in cell death, and as a promising target for cancer therapy, is also stressed. We think that investigations aimed at characterizing the posttranscriptional mechanisms that regulate the activity of ATP synthase/IF1 axis will provide additional promising biomarkers for effective treatment of the disease. ABSTRACT: Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment.