MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.
MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.
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MICU1 可以防止心肌缺血/再灌注损伤，并通过输入受体 Tom70 对其进行控制。
DOI：
10.1038/cddis.2017.280
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发表时间：
2017-07-13
影响因子：
9
通讯作者：
Tao L
中科院分区：
文献类型：
--
作者：
Xue Q;Pei H;Liu Q;Zhao M;Sun J;Gao E;Ma X;Tao L
线粒体Ca2+超载是心肌缺血/再灌注（MI/R）损伤中线粒体损伤导致心肌细胞死亡的主要原因。MICU1最近被确定为线粒体Ca2+稳态的重要调节因子。在这里，我们试图确定MICU1在MI/R中的作用，并研究线粒体进口受体Tom70是否在MICU1和MI/R的线粒体易位中起关键作用。通过心肌内注射，给药MICU1和Tom70特异性小干扰RNA (20 μg)，以及携带Tom70a序列（3.3 × 107 TU）的慢病毒载体。注射72小时后，小鼠进行30分钟心肌梗死，然后进行3小时（用于细胞凋亡和线粒体损伤评估）或24小时（用于心功能和梗死面积测定）再灌注。MI/R对MICU1总表达无显著影响，但导致线粒体MICU1显著降低。MICU1表达下调可显著加重心肌梗死/R损伤，表现为梗死面积增大、心功能下降和心肌凋亡增加。此外，MICU1缺陷导致线粒体Ca2+超载明显加重，从而破坏线粒体形态，抑制线粒体功能（ATP产生减少）。有趣的是，线粒体Tom70在MI/R中也减少。基因功能缺失研究显示，Tom70消融可抑制线粒体MICU1表达。此外，Tom70缺乏显著加重了MI/R损伤，加重了线粒体Ca2+超载。然而，补充Tom70可显著减轻MI/R损伤，保留线粒体形态和功能，并抑制线粒体Ca2+超载，这些都被MICU1抑制所消除。线粒体Tom70/MICU1通路对MI/R损伤具有保护作用，其中MICU1的线粒体定位受Tom70调控，MICU1在Tom70的心脏保护中起着不可或缺的作用。
Mitochondrial Ca2+ overload is a main contributor to mitochondrial damage hence cardiomyocyte death in myocardial ischemia/reperfusion (MI/R) injury. MICU1 has been recently identified as an important regulator of mitochondrial Ca2+ homeostasis. Here we try to identify the role of MICU1 in MI/R, and to investigate whether the mitochondrial importer receptor Tom70 possesses critical roles in the mitochondrial translocation of MICU1 and MI/R. Specific small interfering RNA (20 μg) against MICU1 and Tom70, and lentivirus vectors carrying the Tom70a sequences (3.3 × 107 TU) were delivered through intramyocardial injection. Seventy-two hours after injection, mice were subjected to 30 min of MI followed by 3 h (for cell apoptosis and mitochondrial damage assessment) or 24 h (for cardiac function and infarct size determination) of reperfusion. MI/R had no significant effect on total MICU1 expression, but caused significant reduction of MICU1 in mitochondria. Knockdown of MICU1 significantly aggravated MI/R injury, as evidenced by enlarged infarct size, depressed cardiac function and increased myocardial apoptosis. Moreover, MICU1 deficiency resulted in markedly aggravated mitochondrial Ca2+ overload, consequently destructed mitochondrial morphology and suppressed mitochondrial function (evidenced by decreased ATP production). Interestingly, mitochondrial Tom70 was also decreased in MI/R. Genetic loss-function study revealed that mitochondrial MICU1 expression was depressed by Tom70 ablation. Furthermore, Tom70 deficiency significantly aggravated MI/R injury and worsened mitochondrial Ca2+ overload. However, supplementation of Tom70 significantly attenuated MI/R injury, preserved mitochondrial morphology and function, and inhibited mitochondrial Ca2+ overload, all of which were abolished by MICU1 suppression. Mitochondrial Tom70/MICU1 pathway protects against MI/R injury, in which mitochondrial localization of MICU1 is governed by Tom70, and MICU1 serves as an indispensable factor in Tom70’s cardioprotection.
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影响因子：
64.5
作者：
Mallilankaraman K;Doonan P;Cárdenas C;Chandramoorthy HC;Müller M;Miller R;Hoffman NE;Gandhirajan RK;Molgó J;Birnbaum MJ;Rothberg BS;Mak DO;Foskett JK;Madesh M
通讯作者：
Madesh M
DOI：
10.1073/pnas.0705891104
发表时间：
2007-09-25
影响因子：
11.1
作者：
Elrod, John W.;Calvert, John W.;Lefer, David J.
通讯作者：
Lefer, David J.
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
影响因子：
64.8
作者：
Baughman, Joshua M.;Perocchi, Fabiana;Girgis, Hany S.;Plovanich, Molly;Belcher-Timme, Casey A.;Sancak, Yasemin;Bao, X. Robert;Strittmatter, Laura;Goldberger, Olga;Bogorad, Roman L.;Koteliansky, Victor;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.