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

Abstract

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.

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

“…Much of their genetic content is included in the nuclear genome, but a significant part remains in mitochondria. The mitochondrial genome, mtDNA, is a doublestranded molecule, 16 kbp in size, containing 37 genes that encode 13 polypeptides that take part in the oxidative phosphorylation chain, 2 rRNAs and 22 tRNAs, all exclusive to the mitochondria [8]. Mutations in mtDNA have been associated with multiple metabolic and neuromuscular degenerative syndromes, and connected with Parkinson's and Alzheimer's diseases, diabetes and several types of cancer [9][10][11][12][13][14][15][16][17].…”

Mitochondrial dysfunction as part of an inflammatory intermediate phenotype that drives premature ageing

“…There are nine accepted hallmarks of ageing, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, altered intracellular communication and mitochondrial dysfunction [1]. The mitochondrial theory of ageing is established on the basic fact that mitochondria during evolution have retained their own genome and the observation that mitochondrial DNA function copy number (mtDNA-CN) has an excessive rate of mutations and less efficient repair machinery compared to nuclear DNA [2]. Evidence suggests that mtDNA mutations in humans and mammals promote a prematurely aged phenotype with reduced life span [2].…”

“…The mitochondrial theory of ageing is established on the basic fact that mitochondria during evolution have retained their own genome and the observation that mitochondrial DNA function copy number (mtDNA-CN) has an excessive rate of mutations and less efficient repair machinery compared to nuclear DNA [2]. Evidence suggests that mtDNA mutations in humans and mammals promote a prematurely aged phenotype with reduced life span [2]. Since the mitochondrial genome is thoroughly conserved in mammals, studies of long-lived animals may lead to better understanding of ageing processes in humans.…”

“…Amongst a number of methods to assess mitochondrial function, mtDNA-CN has received much attention [2]. In correlative studies, lower mtDNA-CN associates with overall mortality and/or a number of age-related diseases [2].…”

“…Amongst a number of methods to assess mitochondrial function, mtDNA-CN has received much attention [2]. In correlative studies, lower mtDNA-CN associates with overall mortality and/or a number of age-related diseases [2]. A study performed in subjects with a wide range of age reported that the abundance of mtDNA and mRNA and mitochondrial ATP production declined with advancing age [4].…”