Abstract
The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in chordates, whose function we investigated in mice carrying a homozygous mutation in the nuclear gene encoding this protein. The Mrps34 mutation causes a significant decrease of this protein, which we show is required for the stability of the 12S rRNA, the small ribosomal subunit and actively translating ribosomes. The synthesis of all 13 mitochondrially-encoded polypeptides is compromised in the mutant mice, resulting in reduced levels of mitochondrial proteins and complexes, which leads to decreased oxygen consumption and respiratory complex activity. The Mrps34 mutation causes tissue-specific molecular changes that result in heterogeneous pathology involving alterations in fractional shortening of the heart and pronounced liver dysfunction that is exacerbated with age. The defects in mitochondrial protein synthesis in the mutant mice are caused by destabilization of the small ribosomal subunit that affects the stability of the mitochondrial ribosome with age.
Highlights
Mitochondria are composed of proteins encoded by the nuclear and mitochondrial genomes
The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in chordates, whose function we investigated in mice carrying a homozygous mutation in the nuclear gene encoding this protein
The Mrps34 mutation causes a significant decrease of this protein, which we show is required for the stability of the 12S rRNA, the small ribosomal subunit and actively translating ribosomes
Summary
Mitochondria are composed of proteins encoded by the nuclear and mitochondrial genomes. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs that are translated on mitochondrial ribosomes (mitoribosomes) into 13 polypeptides, all members of the oxidative phosphorylation complexes [1]. Recent cryo-electron microscopy (cryo-EM) reconstructions indicate that the additional protein elements may fulfil roles necessitated by the unique features of the mitochondrial leaderless mRNAs, likely in their recognition, as well as facilitating the translation of the hydrophobic proteins they encode and making the contacts between the small and large ribosomal subunits [6,7,9,10,12]. The mitoribosomes are located inside the matrix, the site of the transcriptome, and associate closely with the mitochondrial inner membrane through MRPL45 [7] This positioning allows for co-translational insertion of the hydrophobic proteins, which are translated by the mitoribosome, into the inner membrane and their assembly into oxidative phosphorylation (OXPHOS) complexes [13]
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