Abstract
Mitochondria are cellular organelles responsible for generation of chemical energy in the process called oxidative phosphorylation. They originate from a bacterial ancestor and maintain their own genome, which is expressed by designated, mitochondrial transcription and translation machineries that differ from those operating for nuclear gene expression. In particular, the mitochondrial protein synthesis machinery is structurally and functionally very different from that governing eukaryotic, cytosolic translation. Despite harbouring their own genetic information, mitochondria are far from being independent of the rest of the cell and, conversely, cellular fitness is closely linked to mitochondrial function. Mitochondria depend heavily on the import of nuclear-encoded proteins for gene expression and function, and hence engage in extensive inter-compartmental crosstalk to regulate their proteome. This connectivity allows mitochondria to adapt to changes in cellular conditions and also mediates responses to stress and mitochondrial dysfunction. With a focus on mammals and yeast, we review fundamental insights that have been made into the biogenesis, architecture and mechanisms of the mitochondrial translation apparatus in the past years owing to the emergence of numerous near-atomic structures and a considerable amount of biochemical work. Moreover, we discuss how cellular mitochondrial protein expression is regulated, including aspects of mRNA and tRNA maturation and stability, roles of auxiliary factors, such as translation regulators, that adapt mitochondrial translation rates, and the importance of inter-compartmental crosstalk with nuclear gene expression and cytosolic translation and how it enables integration of mitochondrial translation into the cellular context.
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Acknowledgements
The authors thank A. Filipovska, T. Lenarcic, M.Saurer and M. Jaskolowski for critical reading of the manuscript and helpful comments. They also thank all referees for helpful comments. The authors apologize to everyone whose work unfortunately could not be included in this review due to space restrictions. E.K. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (1196-2014). This work was supported by a Swiss National Science Foundation grant (310030B_163478) and via the National Centre of Excellence in RNA and Disease and project funding 138262 to N.B.
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E.K. conceptualized and wrote the manuscript and prepared the figures. N.B. edited the manuscript.
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Glossary
- Pseudouridylation
-
RNA modification whereby the nucleoside uridine is converted into an isomer, in which the nucleobase uracil is attached to the ribose via a carbon–carbon instead of a nitrogen–carbon bond.
- Small nucleolar RNAs
-
Short RNA molecules that are usually found in complex with proteins and that target specific sites of ribosomal RNA (rRNA) to trigger modification of these rRNA sites by the associated protein component.
- Peptidyl transferase centre
-
An active site of the large ribosomal subunit that catalyses peptide bond formation during protein synthesis.
- Ribosomal P site
-
The peptidyl (P) site is one of three ribosomal tRNA binding sites and contains the tRNA carrying the nascent polypeptide chain.
- Formylated methionine
-
(fMet-tRNAMet). A derivative of the amino acid methionine (Met-tRNAMet) that carries an additional formyl modification at its amino group.
- Ribosomal A site
-
The aminoacyl (A) site is one of three ribosomal tRNA binding sites and contains the newly delivered, aminoacylated tRNA.
- Ribosomal decoding centre
-
A site on the small ribosomal subunit at which the correct base pairing of the mRNA codon and the aminoacylated tRNA is probed.
- Shine–Dalgarno sequence
-
A ribosomal binding site in bacterial mRNAs with the consensus sequence AGGAGG that is located upstream of the start codon and helps to align the ribosome with the start of the open reading frame.
- Kozak sequence
-
A consensus sequence of the most frequent nucleobases surrounding the mRNA start codon in eukaryotes, which aids start codon recognition by the ribosome during translation initiation.
- Pentatricopeptide repeat
-
(PPR). A conserved protein fold that usually occurs in tandem to mediate binding to RNAs or proteins.
- Ribosomal GTPase-associated centre
-
A site on the large ribosomal subunit that contains multiple protein and RNA elements involved in binding and activation of translational GTPases.
- Back-translocation
-
Backward movement of the tRNA–mRNA complex on the ribosome that may help to overcome ribosome stalling or that may reduce translation speed to facilitate co-translational protein folding.
- –1 frameshifting
-
Movement of the ribosome on the mRNA in the 5′ direction by one nucleotide.
- G-quadruplex structures
-
Guanosine-rich RNA or DNA sequences that fold into a stable secondary structure, in which four guanine nucleobases self-assemble via Hoogsteen hydrogen base pairing into a planar array.
- Poly(A)-assisted RNA degradation
-
A 3′–5′ RNA decay pathway, in which a short poly(A) tail serves as a degron to initiate exonucleolytic RNA cleavage, for example in order to remove aberrant RNA fragments generated by endoribonucleases, and to control the abundance of regulatory non-coding RNAs.
- Leigh syndrome
-
A severe neurological disorder driven by the degeneration of the central nervous system, which results, among others, in cognitive and movement disabilities.
- OXPHOS assembly factors
-
Protein factors that aid the assembly but are not part of the oxidative phosphorylation (OXPHOS) complex. Assembly factors may, for example, stabilize assembly intermediates, modify OXPHOS subunits or mediate delivery of cofactors.
- Mitochondrial membrane potential
-
The potential across the inner mitochondrial membrane due to an electrochemical proton gradient that is generated by oxidative phosphorylation.
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Kummer, E., Ban, N. Mechanisms and regulation of protein synthesis in mitochondria. Nat Rev Mol Cell Biol 22, 307–325 (2021). https://doi.org/10.1038/s41580-021-00332-2
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DOI: https://doi.org/10.1038/s41580-021-00332-2
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