Mitochondrial ribosome assembly in health and disease

Abstract

The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells, mitochondria contain their own ribosomes (mitoribosomes), which synthesize a handful of proteins, all essential for the biogenesis of the oxidative phosphorylation system. High-resolution cryo-EM structures of the yeast, porcine and human mitoribosomal subunits and of the entire human mitoribosome have uncovered a wealth of new information to illustrate their evolutionary divergence from their bacterial ancestors and their adaptation to synthesis of highly hydrophobic membrane proteins. With such structural data becoming available, one of the most important remaining questions is that of the mitoribosome assembly pathway and factors involved. The regulation of mitoribosome biogenesis is paramount to mitochondrial respiration, and thus to cell viability, growth and differentiation. Moreover, mutations affecting the rRNA and protein components produce severe human mitochondrial disorders. Despite its biological and biomedical significance, knowledge on mitoribosome biogenesis and its deviations from the much-studied bacterial ribosome assembly processes is scarce, especially the order of rRNA processing and assembly events and the regulatory factors required to achieve fully functional particles. This article focuses on summarizing the current available information on mitoribosome assembly pathway, factors that form the mitoribosome assembly machinery, and the effect of defective mitoribosome assembly on human health.

Keywords: mitochondrial disease; mitochondrial ribosome; mitochondrial translation; mitochondriolus; mitoribosome assembly; mitoribosome assembly factor; mitoribosome biogenesis.

Figure 1.

Structure of mitochondrial ribosomes. Top panel, human 55S; bottom panel, yeast LSU. LSU rRNA is shown in blue, SSU rRNA is yellow, tRNA-Val is red. Individual proteins are depicted in different colors, and those mentioned in the text are labeled.

Figure 2.

Mitoribosome assembly lines. Assembly pathway of the (A) mitochondrial large subunit (SSU) and (B) mitochondrial small subunit (SSU). The assembly pathways for the bacterial subunits are presented as a reference. Only some ribosome biogenetic factors are included. The assembly stage at which they act is depicted only approximately.

Figure 3.

Compartmentalization of mitoribosome biogenesis. The processes of mtDNA replication and expression occur in submitochondrial matrix compartments. The mtDNA and proteins involved in mtDNA metabolism form a nucleoprotein complex called the mitochondrial nucleoid. Upon transcription, RNAs are sorted at the mitochondriolus (RNA granule), where ribosome assembly largely occurs.