Modulating mitofusins to control mitochondrial function and signaling

Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins' activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage. 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.

Automated summary

Mitofusins are proteins that regulate mitochondrial fusion, a process with significant impact on cellular processes. This study identifies small molecules that can activate or inhibit Mitofusins' activity, thereby modulating mitochondrial fusion and functionality. Inhibition of mitochondrial fusion leads to certain physiological changes such as caspase-3/7 activation and DNA damage. The findings highlight the importance of Mitofusins' conformational changes and oligomerization in enabling mitochondrial fusion. The study provides insights into the function and regulation of Mitofusins and offers potential small molecules for pharmacological targeting.