线粒体在质量控制中与自噬体的互作研究

线粒体是真核细胞内重要的细胞器，其健康状态直接影响到细胞的生存，因而，对其质量控制非常关键。线粒体内的蛋白酶和分子伴侣、线粒体融合和分裂的动态平衡、线粒体衍生小泡以及线粒体特异性自噬都是线粒体质量控制的重要环节。这些控制机制的相互关系还有待于进一步的厘清。申请人前期的研究发现，线粒体内膜上的i-AAA蛋白酶功能丧失导致的线粒体缺陷不能被线粒体特异性的细胞自噬所清除，更有甚者，该蛋白酶的缺失还导致年龄依赖性的细胞自噬受阻。本项目以此为基础，提出线粒体i-AAA蛋白酶介导了线粒体与自噬体在线粒体质量控制过程中的相互作用，从分子水平、细胞水平和组织水平研究其具体的作用机制、致病机理。本项目的实施，将有助于我们进一步加深对线粒体质量控制这一生物学过程中细胞器互作的认识，为与之相关的人类疾病治疗提供新的、重要的理论基础和实践指导。

Mitochondrion figures big in eukaryotic cells and its fitness dictates the cell survival and wellbeing. Thus, the mitochondrial quality control is of primary importance. The mitochondrial proteases and chaperons, the dynamic balance between mitochondrial fusion and fission, the mitochondrial derived vesicles and the mitochondrial autophagy (mitophagy), are the very players that are indispensable for mitochondrial quality control. However, their mechanistic relationship in terms of mitochondrial quality control is largely yet to elucidate. Our previous work on Drosophila dYME1L mutant discovered that the deficient mitochondria caused by mitochondrial i-AAA protease loss of function could not be efficiently cleared by autophagy. Instead, the loss of this protease actually led to the severe blockage of autophagic influx with an age-dependent manner. Based on these findings, we propose that mitochondrial i-AAA protease mediates the organelle-organelle interactions between mitochondria and autophagosomes for the sake of mitochondrial quality control. In this proposal, we will further elucidate their interactions and pathophysiological consequences from molecular, cellular and tissue levels. The outcomes of this project will improve the understanding of the biology of the organelle-organelle interactions underlying the mitochondrial quality control, providing new insights into the medical treatment of the related human diseases.