Phosphoproteomics of the developing heart identifies PERM1-An outer mitochondrial membrane protein
Phosphoproteomics of the developing heart identifies PERM1-An outer mitochondrial membrane protein
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DOI：
10.1016/j.yjmcc.2021.01.010
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发表时间：
2021-02-09
影响因子：
5
通讯作者：
Krueger, Marcus
中科院分区：
文献类型：
--
作者：
Aravamudhan, Sriram;Turk, Clara;Krueger, Marcus
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。我们绘制了小鼠出生后心脏发育早期阶段磷酸化位点的图谱；我们量化了超过10000个磷酸化位点和5000个分配给不同途径的蛋白质。通过对线粒体蛋白的分析，鉴定出PGC-1-和err诱导的肌肉1调节因子（PERM1），它在骨骼肌和心脏组织中特异性表达，并与线粒体外膜有关。我们证明PERM1受到UPS通过酪蛋白激酶2磷酸化其PEST基序介导的快速变化。小鼠中Perm1的消融导致脂素-1蛋白表达减少，并伴有特定磷脂种类的积累。对perm1缺陷线粒体的分离发现，氨基酸和肉毒碱的线粒体转运蛋白SLC25A12/13/29/34和CPT2显著下调。一致地，我们观察到Perm1-/-线粒体中各种脂类、氨基酸和酰基肉碱的水平发生了变化。我们得出结论，线粒体外膜蛋白PERM1调节线粒体中脂质和氨基酸代谢物的稳态。
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.