Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0758, USA.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1924-31. doi: 10.1152/ajpheart.00368.2011. Epub 2011 Sep 2.
The Bcl2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) is an atypical BH3-only protein that is associated with mitochondrial dysfunction and cell death. Bnip3 is also a potent inducer of mitochondrial autophagy, and in this study we have investigated the mechanisms by which Bnip3 induces autophagy in cardiac myocytes. We found that Bnip3 induced mitochondrial translocation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission in adult myocytes. Drp1-mediated mitochondrial fission correlated with increased autophagy, and inhibition of Drp1 reduced Bnip3-mediated autophagy. Overexpression of Drp1K38E, a dominant negative of Drp1, or mitofusin 1 prevented mitochondrial fission and autophagy by Bnip3. Also, inhibition of mitochondrial fission or autophagy resulted in increased death of myocytes overexpressing Bnip3. Moreover, Bnip3 promoted translocation of the E3 ubiquitin ligase Parkin to mitochondria, which was prevented in the presence of a Drp1 inhibitor. Interestingly, induction of autophagy by Bnip3 was reduced in Parkin-deficient myocytes. Thus our data suggest that induction of autophagy in response to Bnip3 is a protective response activated by the cell that involves Drp1-mediated mitochondrial fission and recruitment of Parkin.
Bcl2/腺病毒 E1B 19-kDa 相互作用蛋白 3（Bnip3）是一种非典型的 BH3 仅蛋白，与线粒体功能障碍和细胞死亡有关。Bnip3 也是线粒体自噬的有效诱导剂，在这项研究中，我们研究了 Bnip3 诱导心肌细胞自噬的机制。我们发现 Bnip3 诱导动力相关蛋白 1（Drp1）向线粒体易位，Drp1 是成年肌细胞中线粒体分裂的一种蛋白。Drp1 介导的线粒体分裂与自噬增加相关，抑制 Drp1 可减少 Bnip3 诱导的自噬。Drp1K38E 的过表达，一种 Drp1 的显性失活形式，或线粒体融合蛋白 1 可防止 Bnip3 引起的线粒体分裂和自噬。此外，抑制线粒体分裂或自噬可导致过度表达 Bnip3 的肌细胞死亡增加。此外，Bnip3 促进 E3 泛素连接酶 Parkin 向线粒体易位，而 Drp1 抑制剂可阻止这种易位。有趣的是，Bnip3 诱导的自噬在 Parkin 缺陷型肌细胞中减少。因此，我们的数据表明，Bnip3 诱导的自噬是一种细胞激活的保护反应，涉及 Drp1 介导的线粒体分裂和 Parkin 的募集。
