MAM蛋白FUNDC2调控线粒体自噬和动态的研究

Mitochondria play an important role in cell energy metabolism, cell proliferation, differentiation and death, calcium homeostasis, and innate immunity. Mitochondria are closely connected to endoplasmic reticulum and form a special subdomain，which is termed as Mitochondria-associated ER membrane (MAM). MAM plays a significant role in lipid transport and calcium signaling transduction between endoplasmic reticulum and mitochondria. Recent studies also show that endoplasmic reticulum plays a key role in determining mitochondrial division sites. We have previously identified a new mitochondrial protein FUNDC2，which is located in MAM. Our study revealed that FUNDC2 may be involved in calcium transport between mitochondria and endoplasmic reticulum, and FUNDC2 is also related to the regulation of mitochondrial dynamics. We plan to study the mechanism of FUNDC2 in the maintenance of MAM, and analyze the molecular details of FUNDC2 interactome. We wiil also reveal the role of FUNDC2 in the regulation of mitochondrial dynamics, mitophay and calcium homeostasis. Finally, we will screen the small molecular compounds targeting FUNDC2 and MAM, and explore the new approach for regulation of cell function.

线粒体在细胞能量代谢、细胞增殖分化和死亡、钙稳态维持、天然免疫等方面都起着重要作用。线粒体能和内质网紧密靠近，形成线粒体-内质网膜偶联（Mitochondria-associated ER membrane, MAM）这一特殊结构。MAM在脂类分子转运和钙信号在内质网与线粒体之间转导中发挥重要作用。最新的研究还显示，内质网通过与线粒体互作，在决定线粒体分裂发生的位置中起着关键作用。我们前期鉴定了一个新的定位于MAM的线粒体蛋白FUNDC2,发现这个蛋白可能参与线粒体和内质网的钙转运，同时FUNDC2也与线粒体的动态调控密切相关。本申请计划深入研究FUNDC2在MAM的维持中的作用和机制，解析FUNDC2相互作用组学及其参与线粒体动态、线粒体自噬调控和钙稳态调控的分子细节，同时进一步通过筛选靶向FUNDC2的小分子化合物，探索通过干预MAM调控细胞功能的新手段。

线粒体在细胞能量代谢、细胞死亡、钙稳态维持、天然免疫等方面都发挥着重要作用。线粒体-内质网膜偶联（Mitochondria-associated ER membrane, MAM）在脂类分子转运和钙信号转导和线粒体分裂中发挥重要作用。我们研究表明位于线粒体蛋白FUNDC2定位于MAM，通过与线粒体分裂关键蛋白Drp1的互作，介导线粒体的分裂。通过TAP技术，我们鉴定了FUNDC2互作的蛋白。通过RNAi对这些蛋白进行了敲减，未能发现能够抑制FUNDC2介导的线粒体分裂的蛋白。FUNDC2敲除的细胞中MAM的数目显著减少，证明了FUNDC2在MAM的维持中起着重要作用。进一步研究表明FUNDC2在细胞死亡调控中发挥重要作用，并且与相关疾病等发生密切相关。我们的研究揭示了FUNDC2蛋白在线粒体动态和MAM维持中的重要作用，并阐明了其在疾病发生中的作用，对于相关疾病的预防和治疗提供了理论依据。