Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USA.
Cells. 2022 Apr 27;11(9):1469. doi: 10.3390/cells11091469.
Myeloid cell leukemia-1 () is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that 's functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether regulates autophagy in the heart. We found that cardiac-specific overexpression of had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via 's LC3-interacting regions and mutation of these sites significantly reduced -mediated mitochondrial clearance. We also found that interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor.
髓样细胞白血病-1 () 是一种独特的抗凋亡 Bcl-2 家族成员，对线粒体稳态至关重要。最近的研究表明， 的功能超出了其在防止细胞凋亡死亡中的传统作用。具体来说，数据表明 在自噬中发挥调节作用，自噬是一种涉及回收和消除功能失调细胞器的基本降解途径。在这里，我们研究了 是否调节心脏中的自噬。我们发现，心脏特异性过表达 对基础自噬活性几乎没有影响，但强烈抑制饥饿诱导的自噬。相比之下， 在心肌梗死或线粒体去极化期间并不抑制自噬的激活。相反， 的过表达增加了依赖于 Parkin 的线粒体去极化的清除。噬作用的增加部分是通过 的 LC3 相互作用区域介导的，并且这些位点的突变显著降低了 - 介导的线粒体清除。我们还发现 与自噬受体 Bnip3 相互作用，并且该相互作用在响应线粒体应激时增加。总的来说，这些发现表明在营养限制条件下， 抑制非选择性自噬，而通过作为自噬受体增强功能失调线粒体的选择性自噬。
