The Diseased Mitoribosome

Abstract

Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a specialized and evolutionary divergent protein synthesis machinery, the mitoribosome. Mitoribosome biogenesis depends on elements encoded in both the mitochondrial genome (the RNA components) and the nuclear genome (all ribosomal proteins and assembly factors). Recent cryo-EM structures of mammalian mitoribosomes have illuminated their composition and provided hints regarding their assembly and elusive mitochondrial translation mechanisms. A growing body of literature involves the mitoribosome in inherited primary mitochondrial disorders. Mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors impede mitoribosome biogenesis, causing protein synthesis defects that lead to respiratory chain failure and mitochondrial disorders such as encephalo-and cardiomyopathy, deafness, neuropathy, and developmental delays. In this article, we review the current fundamental understanding of mitoribosome assembly and function, and the clinical landscape of mitochondrial disorders driven by mutations in mitoribosome components and assembly factors, to portray how basic and clinical studies combined help us better understand both mitochondrial biology and medicine.

Stepwise maturation of the peptidyl transferase region of human mitoribosomes

“…The obtained model was then used as an input in homogenous refinement with all 1,064,609 selected particles from the 2D classification. The resulting refined map was used to create a mask covering the intersubunit side of the large subunit in UCSF Chimera 6 . Aligned particles, together with the mask, were used in a 3D Variability analysis 7 with 8 modes to solve and the resolution filtered to 6 Å.…”

“…All particles were used for ab-initio reconstruction, and the resulting cryo-EM map was used as an input model in homogenous refinement. The previously created intersubunit mask was resampled onto the new map using UCSF Chimera 6 and together with the aligned particles was used for 3D Variability analysis 7 with 5 modes to solve and the resolution filtered to 10 Å. The particles were then divided into 25 clusters using 3D Variability Display.…”

“…Published structures of the mature human mitoribosome 10 (PDB 6ZM6) and of a late assembly intermediate containing the ACP module 11 (PDB 5OOL) were used as initial models and docked into the cryo-EM maps using UCSF Chimera 6 . Composite models were assembled in PyMOL Molecular Graphics System, Version 2.1.5 (Schrödinger, LLC), followed by manual rebuilding of the proteins and nucleic acids using Coot 12 .…”

“…Molecular graphics and analyses were performed with UCSF Chimera 6 and UCSF ChimeraX 18 , developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health P41-GM103311 and R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. Detailed views of cryo-EM map densities were created using The PyMOL Molecular Graphics System, Version 2.1.5 Schrödinger, LLC.…”

“…Many factors, including conserved and essential GTPases and methyltransferases participate in human mitoribosome assembly 1 . They ensure production of translationally competent ribosomes and defects in the mitochondrial translation machinery lead to a range of severe human pathologies 6 . Although human mitoribosome assembly has been extensively investigated using a combination of biochemical and high-throughput approaches 1,7–9 , structural understanding of this process is currently limited to a late assembly intermediate with a bound MALSU1–L0R8F8–mt-ACP module 10 .…”