Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein.

Journal of molecular and cellular cardiology (2021-02-08)
Sriram Aravamudhan, Clara Türk, Theresa Bock, Lena Keufgens, Hendrik Nolte, Franziska Lang, Ramesh Kumar Krishnan, Tim König, Philipp Hammerschmidt, Natalie Schindler, Susanne Brodesser, Dieu Hien Rozsivalova, Elena Rugarli, Aleksandra Trifunovic, Jens Brüning, Thomas Langer, Thomas Braun, Marcus Krüger

Heart development relies on PTMs that control cardiomyocyte proliferation, differentiation and cardiac morphogenesis. We generated a map of phosphorylation sites during the early stages of cardiac postnatal development in mice; we quantified over 10,000 phosphorylation sites and 5000 proteins that were assigned to different pathways. Analysis of mitochondrial proteins led to the identification of PGC-1- and ERR-induced regulator in muscle 1 (PERM1), which is specifically expressed in skeletal muscle and heart tissue and associates with the outer mitochondrial membrane. We demonstrate PERM1 is subject to rapid changes mediated by the UPS through phosphorylation of its PEST motif by casein kinase 2. Ablation of Perm1 in mice results in reduced protein expression of lipin-1 accompanied by accumulation of specific phospholipid species. Isolation of Perm1-deficient mitochondria revealed significant downregulation of mitochondrial transport proteins for amino acids and carnitines, including SLC25A12/13/29/34 and CPT2. Consistently, we observed altered levels of various lipid species, amino acids, and acylcarnitines in Perm1-/- mitochondria. We conclude that the outer mitochondrial membrane protein PERM1 regulates homeostasis of lipid and amino acid metabolites in mitochondria.

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