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SummaryThe large majority of mitochondrial proteins is synthesized in the cytosol and then imported to the organelle. To ensure proper mitochondrial functions, the quality of these proteins needs to be guaranteed. Here, we show that the E3 ubiquitin ligase F-box/LRR-repeat protein 6 (FBXL6) participates to the quality of these mitochondrial proteins at the level of the cytosolic translation. We found that lack of FBXL6 has severe effects including mitochondrial ribosomal protein aggregations, altered mitochondrial metabolism and inhibited cell cycle progression in oxidative conditions. FBXL6 was found to interact specifically with ribosomal-associated quality control proteins and chaperones involved in the regulation of newly synthesized proteins and also it preferentially binds newly synthesized mitochondrial ribosomal proteins. Consistently, deletion of the RQC protein, NEMF or HSP70-family chaperone HSPA1A impedes FBXL6 interaction with its substrate. In addition, cells lacking FBXL6 display altered degradation of defective mitochondrial ribosomal protein containing C-terminal alanyl-threonyl extension.