Structural basis of mitochondrial translation.

Shintaro Aibara,Angelika Modelska,Vivek Singh,Alexey Amunts

doi:10.7554/elife.58362

Shintaro Aibara, Angelika Modelska + Show 2 more

Open Access

https://doi.org/10.7554/elife.58362

Copy DOI

Abstract

Translation of mitochondrial messenger RNA (mt-mRNA) is performed by distinct mitoribosomes comprising at least 36 mitochondria-specific proteins. How these mitoribosomal proteins assist in the binding of mt-mRNA and to what extent they are involved in the translocation of transfer RNA (mt-tRNA) is unclear. To visualize the process of translation in human mitochondria, we report ~3.0 Å resolution structure of the human mitoribosome, including the L7/L12 stalk, and eight structures of its functional complexes with mt-mRNA, mt-tRNAs, recycling factor and additional trans factors. The study reveals a transacting protein module LRPPRC-SLIRP that delivers mt-mRNA to the mitoribosomal small subunit through a dedicated platform formed by the mitochondria-specific protein mS39. Mitoribosomal proteins of the large subunit mL40, mL48, and mL64 coordinate translocation of mt-tRNA. The comparison between those structures shows dynamic interactions between the mitoribosome and its ligands, suggesting a sequential mechanism of conformational changes.

Highlights

Translation in humans takes place in the cytosol and mitochondria
The structural analysis of translating complexes provided an improved model for the human mitoribosome, including the L7/L12 stalk, and revealed new insights into the functionally important regions involved in mt-tRNA translocation and mitochondrial messenger RNA (mt-mRNA) binding
Less stable and short-lived intermediates of partially rotated states that involve minor conformational changes are likely to have escaped detection in our study, we identified populations corresponding to stable classical and hybrid states covering the entire span of mt-tRNA movement on the mitoribosome

Summary

Introduction

Mitochondrial translation is responsible for the maintenance of the cellular energetic balance through synthesis of proteins involved in oxidative phosphorylation. This is required for adenosine triphosphate (ATP) production and the folding of the cristae. Impaired mitochondrial translation results in severe combined respiratory chain dysfunction leading to diminished ATP production and consequent cellular energy deficit. This condition is pathogenic in humans, causing myopathies and neurodegenerative diseases (Boczonadi and Horvath, 2014). A recent study demonstrated that with age, decreased mitochondrial protein synthesis lead to adult-onset obesity that results in liver steatosis and cardiac hypertrophy (Perks et al, 2017). Changes in mitochondrial gene expression have long-term consequences on energy metabolism, and surveys suggest that mitochondrial diseases affect 2–5 in 10,000 individuals, mostly occurring due to disrupted mitochondrial gene expression (Chinnery, 2014)

Methods

Results

Conclusion