Sorbonne Universités, UPMC University of Paris 06, CNRS, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France.
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
Nat Commun. 2017 Jun 13;8:15832. doi: 10.1038/ncomms15832.
Mitochondrial integrity relies on homotypic fusion between adjacent outer membranes, which is mediated by large GTPases called mitofusins. The regulation of this process remains nonetheless elusive. Here, we report a crosstalk between the ubiquitin protease Ubp2 and the ubiquitin ligases Mdm30 and Rsp5 that modulates mitochondrial fusion. Ubp2 is an antagonist of Rsp5, which promotes synthesis of the fatty acids desaturase Ole1. We show that Ubp2 also counteracts Mdm30-mediated turnover of the yeast mitofusin Fzo1 and that Mdm30 targets Ubp2 for degradation thereby inducing Rsp5-mediated desaturation of fatty acids. Exogenous desaturated fatty acids inhibit Ubp2 degradation resulting in higher levels of Fzo1 and maintenance of efficient mitochondrial fusion. Our results demonstrate that the Mdm30-Ubp2-Rsp5 crosstalk regulates mitochondrial fusion by coordinating an intricate balance between Fzo1 turnover and the status of fatty acids saturation. This pathway may link outer membrane fusion to lipids homeostasis.
线粒体的完整性依赖于相邻外膜之间的同源融合，这由称为线粒体融合蛋白的大型 GTP 酶介导。然而，这个过程的调节仍然难以捉摸。在这里，我们报告了泛素蛋白酶 Ubp2 与泛素连接酶 Mdm30 和 Rsp5 之间的串扰，它们调节线粒体融合。Ubp2 是 Rsp5 的拮抗剂，促进脂肪酸去饱和酶 Ole1 的合成。我们表明，Ubp2 还拮抗 Mdm30 介导的酵母线粒体融合蛋白 Fzo1 的周转，并且 Mdm30 将 Ubp2 靶向降解，从而诱导 Rsp5 介导的脂肪酸去饱和。外源性去饱和脂肪酸抑制 Ubp2 的降解，导致 Fzo1 水平升高，并维持有效的线粒体融合。我们的结果表明，Mdm30-Ubp2-Rsp5 串扰通过协调 Fzo1 周转和脂肪酸饱和度之间的复杂平衡来调节线粒体融合。该途径可能将外膜融合与脂质动态平衡联系起来。
