Phosphorylation-dependent mitochondrial translocation of MAP4 is an early step in hypoxia-induced apoptosis in cardiomyocytes.
Phosphorylation-dependent mitochondrial translocation of MAP4 is an early step in hypoxia-induced apoptosis in cardiomyocytes.
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MAP4 磷酸化依赖性线粒体易位是缺氧诱导心肌细胞凋亡的早期步骤。
DOI：
10.1038/cddis.2014.369
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发表时间：
2014-09-18
影响因子：
9
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Hu J;Chu Z;Han J;Zhang Q;Zhang D;Dang Y;Ren J;Chan HC;Zhang J;Huang Y
缺血性或缺氧性细胞凋亡通常与线粒体通透性转换孔（mPTP）的开放密切相关;然而，调节mPTP并因此导致细胞依赖性细胞凋亡的分子机制仍然是不清楚的。新出现的证据表明，关键蛋白质进出线粒体的运动在细胞凋亡中起着关键的调节作用。在这里，我们报告说，出乎意料的是，微管相关蛋白4（MAP 4）易位从胞浆线粒体磷酸化后缺氧处理后，在新生心肌细胞。当靶向线粒体时，发现MAP 4导致mPTP开放并诱导细胞凋亡。通过对MAP 4磷酸化的遗传抑制，可以逆转MAP 4的线粒体积累和促凋亡功能。MAP 4（Ala）突变体，模仿去磷酸化形式，抑制线粒体易位和凋亡。我们的数据揭示了MAP 4在心脏细胞凋亡中的新作用，并提出了一种潜在的治疗策略，靶向MAP 4的线粒体易位对凋亡性心脏病。
Hypoxic or ischemic apoptosis is often tightly associated with the opening of mitochondrial permeability transition pore (mPTP); however, the molecular mechanisms regulating mPTP and thus mitochondrial-dependent apoptosis remain elusive. Emerging evidence indicates that the movement of key proteins in or out of mitochondria play a critical regulatory role in apoptosis. Here, we reported that, unexpectedly, the microtubule-associated protein 4 (MAP4) translocated from cytosol to mitochondria upon phosphorylation after hypoxia treatment in neonatal cardiomyocytes. When targeted to mitochondria, MAP4 was found to lead to mPTP opening and induce apoptosis. Mitochondrial accumulation and pro-apoptotic function of MAP4 could be reversed through the genetic inhibition of MAP4 phosphorylation. The MAP4(Ala) mutant, which mimicked the dephosphorylated form, suppressed mitochondrial translocation and apoptosis. Our data reveal a novel role of MAP4 in cardiac apoptosis and suggest a potential therapeutic strategy targeting mitochondrial translocation of MAP4 against apoptotic heart diseases.