The E3 ubiquitin ligase FBXL6 controls the quality of newly synthesized mitochondrial ribosomal proteins.

In mammals, about 99% of mitochondrial proteins are synthesized in the cytosol as precursors that are subsequently imported into the organelle. The mitochondrial health and functions rely on an accurate quality control of these imported proteins. Here, we show that the E3 ubiquitin ligase F box/leucine-rich-repeat protein 6 (FBXL6) regulates the quality of cytosolically translated mitochondrial proteins. Indeed, we found that FBXL6 substrates are newly synthesized mitochondrial ribosomal proteins. This E3 binds to chaperones involved in the folding and trafficking of newly synthesized peptide and to ribosomal-associated quality control proteins. Deletion of these interacting partners is sufficient to hamper interactions between FBXL6 and its substrate. Furthermore, we show that cells lacking FBXL6 fail to degrade specifically mistranslated mitochondrial ribosomal proteins. Finally, showing the role of FBXL6-dependent mechanism, FBXL6-knockout (KO) cells display mitochondrial ribosomal protein aggregations, altered mitochondrial metabolism, and inhibited cell cycle in oxidative conditions. [Display omitted] • FBXL6 is a cytosolic E3 ubiquitin ligase contributing to mitochondrial functions • FBXL6 ensures the quality of newly synthesized mitochondrial ribosomal proteins • FBXL6 contributes to the translational-associated quality control Lavie et al. find that FBXL6 contributes to mitochondrial health by controlling the quality of mitochondrial ribosome proteins prior to their import into the organelle. Moreover, they show that this mechanism is connected to the cytosolic translation-associated quality control and to the folding of newly synthesized proteins. [ABSTRACT FROM AUTHOR]