Significance of Mitochondria DNA Mutations in Diseases

Abstract

Mitochondria are essential double-membraned cytoplasmic organelles to support aerobic respiration and produce cellular energy by oxidative phosphorylation (OXPHOS). Mitochondrial functions are controlled by mitochondrial (mtDNA) and nuclear genomes (nDNA). Mutations of mtDNA result in mitochondrial dysfunction and multisystem diseases through compromising OXPHOS function directly by a point mutation or a large-scale mtDNA rearrangement. One or more of OXPHOS complexes are impaired and dysfunctional to affect tissues with high energy demands. mtDNA is more susceptible to oxidative damage and has more mutations than nDNA. Unlike diploid nDNA, mtDNA is a multi-copy genome transmitted and maternally inherited through oocyte. The multi-copy nature of mtDNA easily causes the heteroplasmy as a unique aspect of mtDNA, making mitochondrial diseases more complex and heterogeneous. mtDNA-associated mitochondrial dysfunction plays the important role in the development of multisystemic primary mitochondrial disease, neurodegeneration, and cancer. The present article overviews the occurrence of mtDNA mutation, interactions with other factors, and molecular mechanisms of mtDNA-associated diseases.

Changes in Mitochondrial Genome Associated with Predisposition to Atherosclerosis and Related Disease

“…The improvement of molecular biology tools made it possible to study mtDNA genetic variants and mutations and their association with human diseases. To date, numerous such associations have been found, especially connected to neurodegenerative disorders [7]. Mitochondria are now being considered as important players in the disease phenotype formation and possible points of therapeutic intervention.…”

Disentangling the intertwined roles of mutation, selection and drift in the mitochondrial genome

“…Knowing the rate of change in the mtDNA genome is not only a critical component for understanding the function and dysfunction of the mitochondrion [46], it has a wide array of other consequences. In an applied sense, rates of mtDNA change may be correlated with cancer risk and the probability of other mitochondrial diseases [2,47,48]. In terms of basic biology, knowing such rates can inform our understanding of evolution at many levels: the coevolutionary dynamics between proteins encoded in different compartments of the cell [49], the evolution of cell types (including germline and somatic differences; [39]), and the evolution of species differences in life history [50], reproductive mode [51] or patterns of inheritance [52,53].…”

“…calibrating molecular clocks; [1]). On the other end of the spectrum, mtDNA MRs are important for estimating disease risk, rates of ageing and the likelihood of rapid adaptation to a changing climate [2][3][4]. Regardless of the question to which rates are applied, the general idea is that knowing the rate of mutation can provide some insight into the amount of genetic variation being introduced into a population, upon which evolutionary forces might then act.…”

Ginsenosides Rb1 and Rg1 Protect Primary Cultured Astrocytes against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury via Improving Mitochondrial Function

“…Most pathogenic mtDNA mutations induce defects in mitochondrial oxidative phosphorylation [18]. The mitochondrial respiratory chain (MRC) consists of five multimeric protein complexes (I–V) that drive the production of ATP.…”