Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein.
Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein.
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DOI：
10.1091/mbc.e15-09-0678
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发表时间：
2016-01-15
影响因子：
3.3
通讯作者：
Karbowski M
中科院分区：
文献类型：
--
作者：
Xu S;Cherok E;Das S;Li S;Roelofs BA;Ge SX;Polster BM;Boyman L;Lederer WJ;Wang C;Karbowski M
所提供的数据支持 MARCH5 在线粒体裂变和细胞活力调节中的关键作用。通过泛素和蛋白酶体依赖性 MiD49 降解，MARCH5 充当线粒体裂变的负调节因子，从而启动一种机制，保护细胞免受应激诱导的细胞凋亡。泛素和蛋白酶体依赖性线粒体外膜 (OMM) 相关降解 (OMMAD) 对于线粒体和细胞稳态至关重要。然而，OMMAD 途径的范围和分子机制仍不清楚。我们报道 OMM 相关的 E3 泛素连接酶 MARCH5 控制动力相关蛋白 1 (Drp1) 依赖性线粒体裂变和细胞对应激诱导的细胞凋亡的敏感性。 MARCH5 敲除选择性抑制 MiD49（Drp1 的线粒体受体）的泛素化和蛋白酶体降解，从而导致线粒体断裂。 MARCH5−/− 细胞中的线粒体碎片与线粒体融合的抑制或生物能缺陷无关，这支持了 MARCH5 是线粒体裂变负调节因子的可能性。 MARCH5−/− 细胞中的 MARCH5 重新表达和 MiD49 敲除均逆转了线粒体断裂，并降低了对应激诱导的细胞凋亡的敏感性。这些发现和数据显示 MiD49 在应激时发生 MARCH5 依赖性降解，这支持了 MARCH5 对 MiD49 的调节是控制线粒体裂变以及细胞对应激的反应的新机制的可能性。
The data presented support a critical role for MARCH5 in the regulation of mitochondrial fission and cell viability. Through ubiquitin- and proteasome-dependent degradation of MiD49, MARCH5 acts as a negative regulator of mitochondrial fission and thereby initiates a mechanism that affords the cell protection from stress-induced apoptosis. Ubiquitin- and proteasome-dependent outer mitochondrial membrane (OMM)-associated degradation (OMMAD) is critical for mitochondrial and cellular homeostasis. However, the scope and molecular mechanisms of the OMMAD pathways are still not well understood. We report that the OMM-associated E3 ubiquitin ligase MARCH5 controls dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and cell sensitivity to stress-induced apoptosis. MARCH5 knockout selectively inhibited ubiquitination and proteasomal degradation of MiD49, a mitochondrial receptor of Drp1, and consequently led to mitochondrial fragmentation. Mitochondrial fragmentation in MARCH5−/− cells was not associated with inhibition of mitochondrial fusion or bioenergetic defects, supporting the possibility that MARCH5 is a negative regulator of mitochondrial fission. Both MARCH5 re-expression and MiD49 knockout in MARCH5−/− cells reversed mitochondrial fragmentation and reduced sensitivity to stress-induced apoptosis. These findings and data showing MARCH5-dependent degradation of MiD49 upon stress support the possibility that MARCH5 regulation of MiD49 is a novel mechanism controlling mitochondrial fission and, consequently, the cellular response to stress.