Abstract:
The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, PRKN/Parkin facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this pathway contribute to the pathogenesis of numerous cardiometabolic and neurological diseases. Although dynamic actin remodeling has recently been shown to play an important role in governing spatiotemporal control of mitophagy, the mechanisms remain unclear. We recently found that the RhoGAP, ARHGAP26/GRAF1 is a PRKN-binding protein that is rapidly recruited to damaged mitochondria where upon phosphorylation by PINK1 it serves to coordinate phagophore capture by regulating mitochondrial-associated actin remodeling and by facilitating PRKN-LC3 interactions. Because ARHGAP26 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure and ARHGAP26 depletion in mouse hearts blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress, this enzyme may be a tractable target to treat the many diseases associated with mitochondrial dysfunction.
摘要:
丝氨酸/苏氨酸激酶,PINK1和E3泛素连接酶,PRKN/Parkin促进LC3依赖的自噬体包裹和功能失调的线粒体的溶酶体清除,这种通路的缺陷导致了许多心脏代谢和神经系统疾病的发病机制。尽管最近发现动态肌动蛋白重塑在调控线粒体自噬的时空控制中起重要作用,机制尚不清楚。我们最近发现RhoGAP,ARHGAP26/GRAF1是一种PRKN结合蛋白,可迅速募集到受损的线粒体中,在PINK1磷酸化后,它通过调节线粒体相关的肌动蛋白重塑和促进PRKN-LC3相互作用来协调吞噬团的捕获。由于PINK1依赖性位点上的ARHGAP26磷酸化在人类心力衰竭中失调,而小鼠心脏中的ARHGAP26耗竭会减弱线粒体清除并减弱对压力的代偿代谢适应,这种酶可能是治疗与线粒体功能障碍相关的许多疾病的一个可处理的靶标。