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Review
. 2024 May 24:12:1410245.
doi: 10.3389/fcell.2024.1410245. eCollection 2024.

Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis

Álvaro Antolínez-Fernández  1   2 , Paula Esteban-Ramos  1   2 , Miguel Ángel Fernández-Moreno  1   2 , Paula Clemente  1   2
Affiliations
Review

Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis

Álvaro Antolínez-Fernández et al. Front Cell Dev Biol. .

Abstract

Mitochondria play a central role in cellular metabolism producing the necessary ATP through oxidative phosphorylation. As a remnant of their prokaryotic past, mitochondria contain their own genome, which encodes 13 subunits of the oxidative phosphorylation system, as well as the tRNAs and rRNAs necessary for their translation in the organelle. Mitochondrial protein synthesis depends on the import of a vast array of nuclear-encoded proteins including the mitochondrial ribosome protein components, translation factors, aminoacyl-tRNA synthetases or assembly factors among others. Cryo-EM studies have improved our understanding of the composition of the mitochondrial ribosome and the factors required for mitochondrial protein synthesis and the advances in next-generation sequencing techniques have allowed for the identification of a growing number of genes involved in mitochondrial pathologies with a defective translation. These disorders are often multisystemic, affecting those tissues with a higher energy demand, and often present with neurodegenerative phenotypes. In this article, we review the known proteins required for mitochondrial translation, the disorders that derive from a defective mitochondrial protein synthesis and the animal models that have been established for their study.

Keywords: OxPhos; mitochondria; mitochondrial disorders; mitoribosome; translation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Processing and maturation of the mitochondrial rRNAs and assembly of the mitorribosome. Mitochondrial transcription generates polycistronic precursors that are processed to release the individual rRNA, tRNA and mRNA molecules. Once the rRNAs are processed, mt-SSU and mt-LSU assembly proceeds aided by methyltransferases, RNA helicases, GTPases and additional assembly factors. The ribosome figure was created with BioRender.
FIGURE 2
FIGURE 2
Schematic representation of the phases in mitochondrial translation and the translation factors that assist in the process. (A) During translation initiation, mitochondrial initiation factors mtIF3 and mtIF2 bind the ribosome and fMet-tRNAfMet is recruited to the P-site. (B) Translation elongation consists on cycles in which mtEF-Tu:GFP delivers an aminoacyl-tRNA to the A-site of the ribosome. mtEF-G1 catalyzes the translocation of the ribosome and contacts the tRNA-mRNA base pairing to maintain the reading frame. (C) mtRF1a recognizes UAA or UAG at the A-site and terminates translation. mtEF-G2 and mtRRF split the mitoribosomal subunits. Figure 2 was created with BioRender.
See this image and copyright information in PMC

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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. PC is funded by grant RYC2022-037640-I funded by MICIU/AEI/10.13039/501100011033 and by “ESF investing in your future”. MF-M is funded by grants PID2019-110320RB-I0 funded by Ministerio de Ciencia e Innovación (MICINN), and IDEAS222917FERN funded by Asociación Española Contra el Cáncer-AECC.