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

FEBS Letters

article

Mara Mennuni¹  David Alsina¹  Nils-Göran Larsson¹  Roberta Filograna¹ 

[1] Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet;Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet

关键词: ageing;    Alzheimer’s disease;    cancer;    mitochondria;    mitochondrial diseases;    mtDNA;    mtDNA copy number;    neurodegenerative disorders;    Parkinson’s disease;    TFAM;   

DOI  :  10.1002/1873-3468.14021

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown