Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Nat Commun. 2022 Jul 7;13(1):3775. doi: 10.1038/s41467-022-31324-1.
Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
线粒体融合蛋白位于线粒体的外膜上，调节线粒体融合，这一生理过程影响着多种细胞过程。线粒体融合蛋白通过构象变化被激活，随后寡聚化以实现线粒体融合。在这里，我们鉴定了一些小分子，这些小分子通过调节线粒体融合蛋白的构象和寡聚化，直接增加或抑制线粒体融合蛋白的活性。我们利用这些小分子来更好地理解线粒体融合、功能和信号中，线粒体融合蛋白活性的作用。我们发现，线粒体融合蛋白的激活增加，而线粒体融合蛋白的抑制减少线粒体融合和功能。值得注意的是，线粒体融合蛋白的抑制也会诱导少数线粒体的外膜通透性增加，随后引发亚致死的 caspase-3/7 激活，进而诱导 DNA 损伤并上调 DNA 损伤反应基因。在这种情况下，第二种线粒体衍生的半胱天冬酶激活剂（SMAC）模拟物诱导的细胞凋亡死亡会被线粒体融合蛋白的抑制所增强。这些数据为线粒体融合蛋白的功能和调节提供了机制上的见解，以及用于药理学靶向线粒体融合蛋白的小分子。
