Cell Signaling Technology, Dellaertweg 9b, 2316 WZ Leiden, Netherlands.
CECAD Research Center, Institute for Genetics, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
J Mol Cell Cardiol. 2021 May;154:41-59. doi: 10.1016/j.yjmcc.2021.01.010. Epub 2021 Feb 5.
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.
心脏发育依赖于控制心肌细胞增殖、分化和心脏形态发生的 PTMs。我们生成了一张在小鼠心脏出生后发育早期的磷酸化位点图谱；我们定量了超过 10000 个磷酸化位点和 5000 个被分配到不同途径的蛋白质。对线粒体蛋白质的分析导致了 PGC-1-和 ERR 诱导的肌肉 1 调节因子（PERM1）的鉴定，它在骨骼肌和心脏组织中特异性表达，并与外线粒体膜结合。我们证明 PERM1 易受 UPS 通过其 PEST 基序被酪蛋白激酶 2 磷酸化介导的快速变化的影响。在小鼠中敲除 Perm1 会导致脂肪酶 1 的蛋白表达减少，同时伴有特定磷脂种类的积累。分离缺乏 Perm1 的线粒体表明，氨基酸和肉碱的线粒体转运蛋白（包括 SLC25A12/13/29/34 和 CPT2）显著下调。一致地，我们观察到 Perm1 线粒体中各种脂质、氨基酸和酰基辅酶 A 的水平发生改变。我们得出结论，外线粒体膜蛋白 PERM1 调节线粒体中脂质和氨基酸代谢物的稳态。
