Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

Abstract

Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes

“…Thus, the unfoldase activity of CLPB and CLPX seem to influence prominently the translation initiation and elongation steps, e.g., in mitochondria. In this process, MTIF2 protects formylmethionyl-tRNA and promotes its binding to the 30S mitoribosomal subunit, and TSFM then hydrolyzes GTP to trigger TUFM-dependent binding of any aminoacyl-tRNA to the A-site, before GFM1-dependent translocation to the P-site occurs [ 126 ]. If CLPB- or CLPX-mediated unfolding cannot repair the inappropriate conformation of any nascent incomplete RNA–protein complex or of any damaged RNP, the CLPXP degradation machine would assemble to linearize and degrade the RNP substrate.…”

The Bacterial ClpXP-ClpB Family is Enriched with RNA-Binding Protein Complexes

“…Thus, the unfoldase activity of ClpB and ClpX seem to influence prominently the translation initiation and elongation steps e.g. in mitochondria, when MTIF2 protects formylmethionyl-tRNA and promotes its binding to the 30S mitoribosomal subunit, and TSFM then hydrolyzes GTP to trigger TUFM-dependent binding of any aminoacyl-tRNA to the A-site, before GFM1-dependent translocation to the P-site occurs [124]. If ClpB or ClpX-mediated unfolding cannot repair the inappropriate conformation of any nascent incomplete RNA-protein complex or of any damaged RNP, the ClpXP degradation machine would assemble to linearize and degrade the RNP substrate.…”

Role of Mitochondrial Stress Response in Cancer Progression

“…Just like mitochondrial RNA transcription, abnormal translation of mitochondrial encoded proteins, which are part of the OXPHOS system, are strongly associated with cancer progression. Mitochondrial translation consists of initiation, elongation, termination, and ribosome recycling stages, during which dysfunction of protein translation factors and translation activators due to mutation or deletion cause various mitochondrial diseases, including cancer [ 182 ]. Targeting mitochondrial DNA polymerase or mitochondrial ribosomes is an off-target effect of antibiotics, such as tigecycline, because mitochondria originated from an endosymbiotic bacterium [ 183 ].…”