Mitochondrial proteostasis mediated by CRL5Ozzand Alix maintains skeletal muscle function

Author:

Campos YvanORCID,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 AlessandraORCID

Abstract

SUMMARYHigh 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 CRL5Ozz, 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 inOzz−/−orAlix−/−skeletal muscle share overt morphologic alterations (they are supernumerary, swollen, and dysmorphic) and have abnormal metabolomic profiles. We found that CRL5Ozzubiquitinates 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.

Publisher

Cold Spring Harbor Laboratory

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