The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.
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We apologize to the many authors whose work we were unable to cite because of space limitations. The authors thank current and past members of their groups, collaborators and colleagues who have contributed to discoveries discussed in this Review and for critical advice on this manuscript. A.F. and O.R. are supported by fellowships and grants from the National Health and Medical Research Council, the Australian Research Council, the Cancer Council of Western Australia and Telethon Kids Institute.
The authors declare no competing interests.
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A complex composed of mitochondrial DNA and its associated proteins that regulate the organization and expression of the mitochondrial genome.
Secondary structures formed between guanine residues within nucleic acids, which are important for gene organization and expression. Sets of four guanine bases bound via Hoogsteen hydrogen bonds stack on top of each other to form stable structures.
- Mitochondrial RNA granule
(MRGs) A heterogeneous complex composed of mitochondrial RNA and proteins involved in RNA regulation.
- Mitochondrial diseases
A group of multi-systemic diseases that are primarily caused by defects in nuclear or mitochondrial DNA genes, causing mitochondrial dysfunction and resulting in a range of symptoms that predominantly affect organs with high energy demands and aerobic metabolism.
The co-existence of mutant and wild-type mitochondrial DNA molecules within the same mitochondrion or within a cell.
A cell devoid of a nucleus that contains mitochondria and can be fused with a nucleus from a donor cell.
Created by introducing a donor nucleus introduced into a cytoplast. Because cybrids contain the nuclear genes from one cell and the mitochondrial genes from another, they can be used to assess the contributions of mitochondrial genes and nuclear genes independently.
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Rackham, O., Filipovska, A. Organization and expression of the mammalian mitochondrial genome. Nat Rev Genet 23, 606–623 (2022). https://doi.org/10.1038/s41576-022-00480-x
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