Campos Yvan, Rodriguez-Enriquez Ricardo, Palacios Gustavo, Van de Vlekkert Diantha, Qiu Xiaohui, Weesner Jayce, Gomero Elida, Demmers Jeroen, Bertorini Tulio, Opferman Joseph T, Grosveld Gerard C, d'Azzo Alessandra
bioRxiv. 2023 Jul 11:2023.07.11.548601. doi: 10.1101/2023.07.11.548601.
High energy-demanding tissues, such as skeletal muscle, require mitochondrial proteostasis to function properly. Two quality-control mechanisms, the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles, safeguard mitochondrial proteostasis. However, whether these processes interact is unknown. Here we show that the E3 ligase CRL5 , a member of the UPS, and its substrate Alix control the mitochondrial concentration of Slc25A4, a solute carrier that is essential for ATP production. The mitochondria in or skeletal muscle share overt morphologic alterations (they are supernumerary, swollen, and dysmorphic) and have abnormal metabolomic profiles. We found that CRL5 ubiquitinates Slc25A4 and promotes its proteasomal degradation, while Alix facilitates SLC25A4 loading into exosomes destined for lysosomal destruction. The loss of Ozz or Alix offsets steady-state levels of Slc25A4, which disturbs mitochondrial metabolism and alters muscle fiber composition. These findings reveal hitherto unknown regulatory functions of Ozz and Alix in mitochondrial proteostasis.
高能量需求组织，如骨骼肌，需要线粒体蛋白质稳态才能正常运作。两种质量控制机制，即泛素蛋白酶体系统（UPS）和线粒体衍生囊泡的释放，保障线粒体蛋白质稳态。然而，这些过程是否相互作用尚不清楚。在这里，我们表明E3连接酶CRL5（UPS的成员之一）及其底物Alix控制着Slc25A4的线粒体浓度，Slc25A4是一种对ATP产生至关重要的溶质载体。Ozz或骨骼肌中的线粒体具有明显的形态改变（数量过多、肿胀且形态异常），并且具有异常的代谢组学特征。我们发现CRL5使Slc25A4泛素化并促进其蛋白酶体降解，而Alix则促进SLC25A4加载到注定要被溶酶体破坏的外泌体中。Ozz或Alix的缺失会抵消Slc25A4的稳态水平，这会扰乱线粒体代谢并改变肌纤维组成。这些发现揭示了Ozz和Alix在线粒体蛋白质稳态中迄今未知的调节功能。
