IF1 reprograms energy metabolism and signals the oncogenic phenotype in cancer

Mitochondria of normal eukaryotic cells synthesize most ATP requirements needed to support cellular activity. They also participate in Ca and reactive oxygen species (ROS) signaling and in the execution of cell death. The structure and molecular composition of mitochondria vary largely among the different cellular types of mammals. The final mitochondrial phenotype results from gene expression programs that are regulated at both the transcriptional and post-transcriptional levels. A key component of mitochondria in energy conservation, ROS signaling and the execution of cell death is the H-ATP synthase, a reversible engine of oxidative phosphorylation that catalyzes the synthesis of ATP using as driving force the proton gradient generated by the respiratory chain (Fig. 1A). Its catalytic subunit (β-F1-ATPase, dark blue in Fig. 1) forms part of the soluble F1-ATPase domain (Fig. 1A). β-F1-ATPase is significantly diminished in cancer and provides a bioenergetic signature of disease progression and of the response to chemotherapy. In carcinomas of the lung, colon and breast, the downregulation of β-F1-ATPase is also accompanied by an increased expression of the ATPase inhibitory factor 1 (IF1), a physiological inhibitor of the H-ATP synthase. IF1 is a highly conserved protein encoded in the nuclear ATPIF1 gene. Alternative splicing generates three different isoforms of IF1. The expression of IF1 in different normal human tissues has been shown to vary largely, from very high levels in the heart, to intermediate expression in the liver and negligible levels in breast, colon and lung. In contrast, IF1 reprograms energy metabolism and signals the oncogenic phenotype in cancer