Phosphorylation‐based regulation of mitochondrial metabolism

Abstract

Phosphorylation has long been appreciated to influence mitochondrial metabolism via the regulation of pyruvate dehydrogenase. However, the extent to which phosphorylation broadly influences mitochondrial function remains unclear, despite the presence of multiple protein phosphatases within the organelle. We recently demonstrated that deletion of the mitochondrial matrix phosphatase Pptc7 unexpectedly caused perinatal lethality in mice, suggesting that the regulation of mitochondrial phosphorylation is essential in mammalian development. Pptc7‐/‐ mice exhibit severe metabolic deficiencies, including hypoglycemia and lactic acidosis, and die within one day of birth. Biochemical and proteomic approaches revealed that Pptc7‐/‐ tissues have decreased mitochondrial function concomitant with a post‐transcriptional downregulation of mitochondrial proteins. Multiple elevated mitochondrial protein phosphorylation sites in Pptc7‐/‐tissues suggest novel functional connections between Pptc7‐mediated dephosphorylation and these observed metabolic consequences. Interestingly, these modifications occur on components of the import machinery of the mitochondria and within the mitochondrial targeting sequences of select nuclear‐encoded precursor proteins. Collectively, our data reveal an unappreciated role for a matrix‐localized phosphatase in the post‐translational regulation of the mitochondrial proteome and organismal metabolic homeostasis.