Post-transcriptional regulation of the mitochondrial H(+)-ATP synthase: a key regulator of the metabolic phenotype in cancer.

A distinctive metabolic trait of tumors is their enforced aerobic glycolysis. This phenotype was first reported by Otto Warburg, who suggested that the increased glucose consumption of cancer cells under aerobic conditions might result from an impaired bioenergetic activity of their mitochondria. A central player in defining the bioenergetic activity of the cell is the mitochondrial H(+)-ATP synthase. The expression of its catalytic subunit β-F1-ATPase is tightly regulated at post-transcriptional levels during mammalian development and in the cell cycle. Moreover, the down-regulation of β-F1-ATPase is a hallmark of most human carcinomas. In this review we summarize our present understanding of the molecular mechanisms that participate in promoting the "abnormal" aerobic glycolysis of prevalent human carcinomas. The role of the ATPase Inhibitor Factor 1 (IF1) and of Ras-GAP SH3 binding protein 1 (G3BP1), controlling the activity of the H(+)-ATP synthase and the translation of β-F1-ATPase mRNA respectively in cancer cells is emphasized. Furthermore, we underline the role of mitochondrial dysfunction as a pivotal player of tumorigenesis.