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.

译文

线粒体完整性依赖于相邻外膜之间的同型融合,这是由称为mitofusins的大GTPases介导的。尽管如此,对这一进程的监管仍然难以捉摸。在这里,我们报告了泛素蛋白酶Ubp2与调节线粒体融合的泛素连接酶Mdm30和Rsp5之间的串扰。Ubp2是Rsp5的拮抗剂,可促进脂肪酸去饱和酶ole1的合成。我们表明,Ubp2还抵消了酵母线粒体Fzo1的Mdm30-mediated周转,并且Mdm30靶向Ubp2进行降解,从而诱导了脂肪酸的Rsp5-mediated去饱和。外源性去饱和脂肪酸抑制Ubp2降解,导致更高水平的Fzo1和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转换和脂肪酸饱和状态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稳态联系起来。

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