Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition.
Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition.
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DOI：
10.1038/s41418-018-0073-z
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发表时间：
2018-11
影响因子：
12.4
通讯作者：
Gordon JW
中科院分区：
文献类型：
--
作者：
Mughal W;Martens M;Field J;Chapman D;Huang J;Rattan S;Hai Y;Cheung KG;Kereliuk S;West AR;Cole LK;Hatch GM;Diehl-Jones W;Keijzer R;Dolinsky VW;Dixon IM;Parmacek MS;Gordon JW
肌心素是心血管发育所需的转录辅激活因子，但也通过尚不清楚的分子机制促进心肌细胞存活。线粒体渗透性转变与坏死有关，而孔闭合是心脏发育过程中线粒体成熟所必需的。我们发现，心肌蛋白功能的丧失导致E9.5时内膜下坏死，同时死亡基因Nix的表达升高。从机制上讲，我们证明了心肌蛋白敲低降低了microRNA-133 a水平，使Nix积累，导致线粒体通透性转换，减少线粒体呼吸和坏死。Myocardin敲低可通过线粒体钙积累促进钙从内质网/肌浆网释放，而microRNA-133 a功能的恢复或Nix的敲低可挽救钙扰动。我们观察到冠状动脉结扎后心肌梗死边缘区的心肌蛋白减少和Nix表达升高。这些发现确定了一个肌心蛋白调节途径，在发育过程中维持钙稳态和线粒体功能，并在缺血性心脏病期间减弱。鉴于Nix和microRNA-133 a的不同作用，这些发现可能对代谢疾病和癌症具有更广泛的意义。
Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis. Myocardin knockdown elicits calcium release from the endo/sarcoplasmic reticulum with mitochondrial calcium accumulation, while restoration of microRNA-133a function, or knockdown of Nix rescues calcium perturbations. We observed reduced myocardin and elevated Nix expression within the infarct border-zone following coronary ligation. These findings identify a myocardin-regulated pathway that maintains calcium homeostasis and mitochondrial function during development, and is attenuated during ischemic heart disease. Given the diverse role of Nix and microRNA-133a, these findings may have broader implications to metabolic disease and cancer.
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影响因子：
20.1
作者：
DIXON, IMC;LEE, SL;DHALLA, NS
通讯作者：
DHALLA, NS
影响因子：
5
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
8.8
作者：
Kwong JQ;Lu X;Correll RN;Schwanekamp JA;Vagnozzi RJ;Sargent MA;York AJ;Zhang J;Bers DM;Molkentin JD
通讯作者：
Molkentin JD
DOI：
10.1073/pnas.0914013107
发表时间：
2010-05-18
影响因子：
11.1
作者：
Chen, Yun;Lewis, William;Dorn, Gerald W., II
通讯作者：
Dorn, Gerald W., II
DOI：
10.1073/pnas.1233635100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Li, SJ;Wang, DZ;Olson, EN
通讯作者：
Olson, EN