Abstract
Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
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Acknowledgements
The authors thank V. Singh and D. Shriaev for help with preparation of the original figures, and A. Khawaja for critical reading of the manuscript and helpful comments. The work was funded by Karolinska Institute, the Knut and Alice Wallenberg Foundation (WAF2017, KAW 2018.0080 to J.R.), Swedish Research Council (VR2022-02179, to J.R.), the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Germany’s Excellence Strategy EXC 2067/1-390729940, a DFG Emmy-Noether grant (RI 2715/1-1 to R.R.-D.) and SFB1565 (project number 469281184, P19 to R.R.-D), and the Volkswagen Foundation (to R.R.-D).
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Glossary
- Chimeric antigen receptor (CAR) T cells
-
Genetically engineered T cells commonly used in cancer immunotherapy that express synthetic receptors comprising antigen-binding and T cell signalling domains, which enable MHC-independent recognition and killing of target cells.
- Degenerated mt-tRNAs
-
Mitochondrial transfer RNAs that have unusual, truncated, or non-canonical secondary structures compared with standard cloverleaf tRNAs. They often lack entire arms (such as the D- or T-arm) and rely on specialized mitochondrial proteins and RNA modifications to remain functional.
- MALSU1 module
-
A protein complex comprising MALSU1, L0R8F8 and mtACP that forms an anti-association module on mtLSU during its biogenesis and mitoribosome rescue.
- Mitohormesis
-
A process in which mild or transient mitochondrial stress triggers adaptive cellular responses that improve mitochondrial function.
- Morpholino hybrids
-
Synthetic antisense oligonucleotides that contain morpholine ring backbones, used to bind complementary RNA sequences and modulate gene expression by blocking translation or RNA processing.
- Pentatricopeptide repeat
-
(PPR). A structural motif consisting of a tandem of 35 amino acid repeats found in proteins primarily involved in RNA binding and regulation of gene expression in organelles such as mitochondria and chloroplasts.
- Peptidyl transferase centre
-
(PTC). The ribosome catalytic site, found within the large ribosomal subunit, which facilitates the formation of peptide bonds between amino acids during protein synthesis.
- Polypeptide exit tunnel
-
A narrow channel within the large subunit of the ribosome through which the newly synthesized polypeptide exits during translation.
- Programmed ribosome frameshifting
-
A regulated change of the reading frame by the ribosome, usually by moving one nucleotide backwards or forwards, resulting in the production of an alternative protein from the same mRNA.
- Shine–Dalgarno sequence
-
A short conserved sequence in bacterial mRNA, located upstream of the start codon, that aligns the mRNA on the ribosome through base pairing with the 16S rRNA, thereby facilitating translation initiation.
- TOM–TIM machinery
-
The protein translocation system that imports nuclear-encoded proteins into mitochondria through the TOM (translocase of the outer membrane) and TIM (translocase of the inner membrane) complexes.
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Richter-Dennerlein, R., Dopico, X.C. & Rorbach, J. Mechanisms and disease relevance of mitochondrial translation in humans. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-026-00948-2
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DOI: https://doi.org/10.1038/s41580-026-00948-2
