MARCH5调控线粒体自噬受体蛋白FUNDC1选择性降解的机制研究

Mitochondria are essential organelles for many fundamental cellular processes, including energy production, free radical generation and programmed cell death. It is therefore of pivotal importance to monitor the functional status of mitochondria and to remove damaged or unwanted mitochondrial by mitophagy FUNDC1 is a new mitophagy receptor which can interact with LC3 to mediate mitophagy in response to hypoxia. In an effort to understand the molecular regulation of FUNDC1 mediated mitophagy, we found that FUNDC1 became degraded prior to other mitochondrial proteins. Subsequently, we identified that MARCH5, a mitochondrial localized E3 ubiquitin ligase, is related to FUNDC1 ubiquitination and degradation. We will investigate the molecular mechanism of FUNDC1 degradation by MARCH5 and its biological significance for mitochondrial quality control. Our research will offer new understanding of how functional status of mitochondria is monitored to determined mitophagy activities.

做为一个重要的细胞器，线粒体与能量生产、自由基产生以及细胞死亡都密切相关。因此，线粒体的质量的监控对于细胞的功能维持十分重要，损伤的线粒体主要通过自噬的机制被清除掉。FUNDC1是我们鉴定的一个线粒体自噬受体，其通过和自噬关键蛋白LC3的相互作用调控缺氧等诱导的线粒体自噬。我们发现在线粒体自噬诱导的早期，FUNDC1会早于其他线粒体蛋白发生降解，而这种降解与线粒体定位的E3泛素酶MARCH5有关。我们计划研究MARCH5参与FUNDC1降解的具体分子机制，明确MARCH5在FUNDC1蛋白降解中的关键作用，进一步阐明在线粒体自噬诱导早期FUNDC1的降解对于线粒体功能维持的意义。我们的研究将有助于了解细胞通过调控线粒体自噬活性从而监控线粒体功能的具体机制。

线粒体在细胞的很多生理活动中起着关键作用，线粒体自噬在线粒体的稳态的调控中起着关键作用。线粒体自噬通路主要分为两大类，一种是Parkin/PINK1介导的泛素依赖的线粒体清除途径，一种是线粒体自噬受体介导的线粒体自噬途径，这些自噬受体与自噬的关键蛋白LC3有直接的相互作用。关于这两条途径是否能协同介导应激情况下的线粒体自噬以及线粒体自噬受体如何感知应激信号引发自噬的机制仍不清楚。我们的研究发现线粒体定位的E3泛素连接酶MARCH5通过控制线粒体自噬受体FUNDC1的泛素化和降解参与缺氧介导的线粒体自噬的调控。MARCH5与FUNDC1有直接的相互作用，并介导FUNDC1的119位的赖氨酸的泛素化以及其随后的降解。过表达MARHC5通过降解FUNDC1抵抗缺氧引起的线粒体自噬，而敲除MARCH5能抑制FUNDC1的降解并进一步增强缺氧引起的线粒体自噬。我们的发现揭示了线粒体自噬受体的泛素化降解在线粒体质量和稳态调控中的关键作用，有助于我们深入理解应激情况下线粒体质量控制的分子机制。