Mitochondrial ribosome biogenesis and redox sensing

Abstract

Mitoribosome biogenesis is a complex process involving RNA elements encoded in the mitochondrial genome and mitoribosomal proteins typically encoded in the nuclear genome. This process is orchestrated by extra-ribosomal proteins, nucleus-encoded assembly factors, which play roles across all assembly stages to coordinate ribosomal RNA processing and maturation with the sequential association of ribosomal proteins. Both biochemical studies and recent cryo-EM structures of mammalian mitoribosomes have provided insights into their assembly process. In this article, we will briefly outline the current understanding of mammalian mitoribosome biogenesis pathways and the factors involved. Special attention is devoted to the recent identification of iron-sulfur clusters as structural components of the mitoribosome and a small subunit assembly factor, the existence of redox-sensitive cysteines in mitoribosome proteins and assembly factors, and the role they may play as redox sensor units to regulate mitochondrial translation under stress.

Keywords: iron–sulfur cluster; mitochondrial disease; mitochondrial ribosome; mitochondrial translation; mitoribosome assembly; redox sensing.

Fig. 1

Redox sensing in the human mitochondrial ribosome. (A) High‐resolution 2.2 Å cryo‐EM structure of the human mitoribosome LSU (top left) and SSU (bottom left) and the monosome (right) (PDB ID: 7QI4). Protein components are displayed as density maps, and RNA components (12S rRNA, 16S rRNA, and the central protuberance CP‐tRNA) are displayed as ribbons and labeled in italics. The main structural features of the mtSSU (head, body, foot, mRNA entry channel) and the mtLSU (polypeptide exit tunnel, L1 stalk, and L7/L12 stalk) are labeled in bold. (B) Cryo‐EM structure of the mitochondrial ribosome highlighting subunits that have redox‐responsive elements, namely mS25/bS16m and bL32m. Cysteine residues in the small subunits mS25 and bS16m coordinate an iron–sulfur cluster (2Fe–2S). Cysteine residues in the large subunit bL32m coordinate a Zinc (Zn) atom.

Fig. 2

Mitoribosome SSU assembly. Model for the assembly pathway for the human 28S mt‐SSU. delineating the recruitment of proteins and the incorporation and release of known assembly factors in their respective stages of assembly. Individual proteins and protein clusters are depicted using distinct boxes. Proteins involved in [Fe–S] cluster coordination are marked in red. The rectangular boxes highlight assembly factors essential for mitoribosome biogenesis. The figures were prepared using biorender and chimerax [126]. The maturation of the 12S rRNA is not depicted. ? indicates proposed but not experimentally proven steps during the assembly process.

Fig. 3

Mitoribosome LSU assembly. Model for the assembly pathway for the human 39S mt‐LSU, delineating the recruitment of proteins and the incorporation and release of known assembly factors in their respective stages of assembly. Individual proteins and protein clusters are depicted using distinct boxes. Proteins critical to iron–sulfur (Fe–S) cluster coordination are marked in red. The rectangular boxes highlight assembly factors essential for mitoribosome biogenesis. The figures were prepared using biorender and chimerax [126]. The maturation of the 16S rRNA is not depicted. ? indicates proposed but not experimentally proven steps during the assembly process.