Tissue-specific expression and post-transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues

Abstract

The ATPase inhibitory factor 1 (IF1) is an intrinsically disordered protein that regulates the activity of the mitochondrialATP synthase. Phosphorylation of S39 in IF1 prevents it from binding to the enzyme and thus abolishes its inhibitory activity. Dysregulation of IF1 is linked to different human diseases, providing a relevant biomarker of cancer progression. However, the tissue content of IF1 relative to the abundance of the ATP synthase is unknown. In this study, we characterized the tissue-specific expression of IF1 in human and mouse tissues and quantitated the content of IF1 and of ATP synthase. We found relevant differences in IF1 expression between human and mouse tissues andfound that in high-energy-demanding tissues, the molar content of IF1 exceeds that of theATPsynthase. In these tissues, a fraction of IF1 is bound to the enzyme, and the other fraction is phosphorylated and hence is unable to bind the enzyme. Post-transcriptional control accounts formost of the regulated expression of IF1, especially inmouse heart, where IF1 mRNA translation is repressed by the leucine-rich pentatricopeptide repeat containing protein. Overall, these findings enlighten the cellularbiologyof IF1 andpave theway to development of additionalmodels that address its role in pathophysiology.