Mitochondrial DNA copy number in human disease: the more the better?

• Published in: FEBS letters Vol. 595; no. 8; pp. 976 - 1002
• Main Authors: Filograna, Roberta, Mennuni, Mara, Alsina, David, Larsson, Nils‐Göran
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.04.2021
• Subjects: ageing; Alzheimer’s disease; cancer; evolution; genome; human diseases; humans; mitochondria; mitochondrial diseases; mitochondrial DNA; mtDNA; mtDNA copy number; neurodegenerative disorders; oxidative phosphorylation; Parkinson’s disease; proteome; Review; TFAM; therapeutics; ageing; mitochondrial diseases; Alzheimer’s disease; mtDNA; mitochondria; TFAM; cancer; neurodegenerative disorders; mtDNA copy number; Parkinson’s disease
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14021

Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.