Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in atherosclerotic mice.
Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in atherosclerotic mice.
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匹伐他汀通过钙依赖性 CAMK1-PINK1 通路激活动脉粥样硬化小鼠线粒体自噬以保护 EPC 增殖
DOI：
10.1038/s42003-022-03081-w
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发表时间：
2022-02-10
影响因子：
5.9
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Yang J;Sun M;Cheng R;Tan H;Liu C;Chen R;Zhang J;Yang Y;Gao X;Huang L
Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE−/− mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis. Endothelial progenitor cell (EPCs) proliferation decreased, accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway in atherosclerosis. Statins induce mitophagy to protect EPCs by mitochondrial calcium release and CAMK1-mediated PINK1 phosphorylation.
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影响因子：
14.9
作者：
Cisneros-Barroso E;Yance-Chávez T;Kito A;Sugiura R;Gómez-Hierro A;Giménez-Zaragoza D;Aligue R
通讯作者：
Aligue R
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
DOI：
10.4049/jimmunol.1102975
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guo L;Stripay JL;Zhang X;Collage RD;Hulver M;Carchman EH;Howell GM;Zuckerbraun BS;Lee JS;Rosengart MR
通讯作者：
Rosengart MR
线粒体通透性过渡孔是线粒体钙外排的可分配元件。
影响因子：
4
作者：
De Marchi E;Bonora M;Giorgi C;Pinton P
通讯作者：
Pinton P
影响因子：
15.9
作者：
Dimmeler, S;Aicher, A;Zeiher, AM
通讯作者：
Zeiher, AM