Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing

Abstract

Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.

Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges

“…Mitochondrial infusion has shown great potential both preclinically and clinically [ 125 ]. An increasing number of studies have attempted to improve mitochondrial function in aging and age-related diseases [ 126 ]. From these attempts, methods involving mitochondrial isolation, blood transfusion and transplantation have become the focus of attention.…”

Causal associations between modifiable risk factors and isolated REM sleep behavior disorder: a mendelian randomization study

“…Secondly, the α-synuclein accumulation in the brainstem is also a mechanism contributing to the pathogenesis of iRBD. Melatonin can reduce the aggregation of α-synuclein and exerts neuroprotective effects by scavenging free radicals ( 84 , 85 ), stimulating glutathione synthesis ( 86 , 87 ), enhancing antioxidant enzyme synthesis, and inhibiting the production of pro-oxidant enzymes ( 88 , 89 ), thus alleviating α-synuclein’s mitochondrial toxicity ( 90 , 91 ). Thirdly, studies have reported that inflammation plays a role in the pathogenesis of iRBD ( 92 , 93 ).…”

Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

“…At the neuronal level, these cytokines cause a drop in serotonin, dopamine and adrenaline neurotransmitters that triggers a neuroinflammatory phenotype. Moreover, oxidative stress and consequent mitophagy sustain the neuroinflammation, accompanied by a leakage of mitochondrial DNA (mtDNA) from damaged mitochondria that physiologically tends to gradually increase with age, contributing to the so-called inflammaging [ 159 , 160 ]. In addition, the similarity between mtDNA and bacterial DNA and its oxidized state stimulates the immune response and promotes inflammation.…”