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Mitochondria of normal eukaryotic cells synthesize most ATP requirements needed to support cellular activity. They also par-ticipate in Ca2+ and reactive oxygen spe-cies (ROS) signaling and in the execution of cell death. The structure and molecu-lar composition of mitochondria vary largely among the different cellular types of mammals.1 The final mitochondrial phenotype results from gene expression programs that are regulated at both the transcriptional2 and post-transcriptional3 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 syn-thesis of ATP using as driving force the proton gradient generated by the respira-tory chain4 (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 bio-energetic signature of disease progression and of the response to chemotherapy.5 In carcinomas of the lung, colon and breast, the downregulation of β-F1-ATPase is also accompanied by an increased expres-sion of the ATPase inhibitory factor 1 (IF1),6 a physiological inhibitor of the H+-ATP synthase.7 IF1 is a highly conserved protein encoded in the nuclear ATPIF1 gene. Alternative splicing generates three dif-ferent isoforms of IF1. The expression of IF1 in different normal human tissues has been shown to vary largely,6 from very high levels in the heart, to intermediate expression in the liver and negligible lev-els in breast, colon and lung. In contrast, IF1 reprograms energy metabolism and signals the oncogenic phenotype in cance