MtDNA damage

SWNTs (10 or 40pg/mouse) Male C57BL/6 mice Single intrapharyngeal instillation 7 days, 28 days, mtDNA damage was accompanied by changes in and 60 days aortic mitochondrial glutathione and protein carbonyl levels Li et al. (2007)... 

Cao J, Liu Y, Jia L, Zhou HM, Kong Y, Yang G. Jiang LP, Li QJ, Zhong LF. 2007a. Curcumin induces apoptosis through mitochondrial hypcrpolarization and mtDNA damage in human hepatoma G2 cells. Free Radic Biol Med 43 968-975. 

APOE-related pathogenic mechanisms are also associated with brain aging and with the neuropathological hallmarks of AD [17, 28], mtDNA damage may also contribute to increase brain vulnerability and neurodegeneration [29, 30],... 

Cellular oxygen utilization decreases as a function of age and the ATP generating capacity of the cell is a function of age. The attenuation of ATP synthesis is associated with an age-related increase in somatic mtDNA damage in postmitotic tissue. The normal decline in ATP generating capability may facilitate disease occurrence when it is associated with an inherited oxidative phosphorylation mutation. 

Fig. 5 Vicious cycle of oxidative damage in mitochondria. After an initial ROS generation due to an environmental noxa mtDNA damage occurs. This results in damage compounds of the mitochondrial respiratory chain (OxPhos), leading to the generation of additional ROS...

Alterations in DNA are particularly important in the mitochondrial DNA (mtDNA) and nuclear DNA, which play important roles in the pathogenesis of the respiratory chain complex activities and oxidative stress in HD (Banoei et al., 2007). Determination of mtDNA damage in 60 HD patients and 70 healthy controls indicate that HD patients have higher frequencies of mtDNA deletions in lymphocytes than control subjects. Although the molecular mechanism associated with mtDNA damage is not known, it is proposed that CAG repeats instability and mutant huntingtin may be causative factors in mtDNA damage (Banoei et al., 2007). 

Using concentrations of menadione (100 pM for 1 h) that resulted in comparable initial mtDNA damage, more efficient repair was observed in rat astrocytes compared to either oUgodendrocytes or microglia (Hollensworth etal. 2000). The differ-... 

Ischaemic hearts of 7 patients aged 48 to 63 years had increased mtDNA damage and OXPHOS gene expression, suggesting that mtDNA damage is associated with OXPHOS deficiency (Corral-Debrinski et al. 1991). Oxidative phosphorylation defects may also play a role in some other forms of cardiac disease as idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, brown atrophy and coronary aAerosclerosis. 

Lee CH, Wu SB, Hong CH, Chen GS, Wei YH, Yu HS. Involvement of mtDNA damage elicited by oxidative stress in the arsenical skin cancers. J Invest Dermatol 2013 133(7) 1890-900. 

Initial studies used a specific deletion of 4977 bp (the "common deletion" [15]) as a marker of mtDNA damage, which increased as much as 10,000-fold in the course of the normal lifespan [12] and reached an overall abundance of 0.1% of total muscle mtDNA [12,13,16], A major criticism leveled at the pathogenic role of mtDNA deletions in aging is that these cumulative levels of rearrangements are a world apart from those found in muscle from patients with primary mitochondrial diseases due to mtDNA deletions, such as Keams-Sayre syndrome (KSS), in whom mutation loads hover around 80% [17]. 

The crucial notion here is that, as ROS accumulate, the propensity to apoptosis increases, thus coimecting mtDNA damage, ETC dysfunction, ROS accumnlation, and cell death, or sarcopenia [47]. 

Nucleoside analogues are drugs used to treat HIV and hepatitis. One such drug fialuridine and other drugs of this type have caused severe hepatic dysfunction. This dysfunction was characterized by fatty liver and fatal liver failure. Fialuridine caused fatal damage in 5 of 12 patients in early clinical trials. Fialuridine inhibits DNA polymerases. However, there is also DNA in the mitochondria [mitochondrial DNA (mtDNA)]. 

The structure of doxorubicin includes a quinone moiety therefore, it can easily accept an electron and undergo redox cycling (Fig. 7.47). Because it accumulates in the mitochondria, it can accept electrons from the electron transport chain and divert them away from complex I. It becomes reduced to the semiquinone radical in the process. This will then reduce oxygen to superoxide and return to the quinone form (Fig. 7.47). This could lead to oxidation of GSH and mtDNA. The subsequent damage may lead to the opening of the mitochondrial permeability transition pore. Consequently, mitochondrial ATP production will be compromised, and ATP levels will decline. 

The damage to mtDNA may persist in cardiac tissue and thereby compromise the ability of the cardiac mitchondria to function as efficient energy-producing units. This could cause the cardiac damage to persist. The mtDNA codes for mitochondrial enzymes, and therefore damage to it, will impact on the synthesis of new mitochondrial components. mtDNA is especially susceptible to damage. The mechanism is summarized in Figure 7.47. 

Figure 7.47 The mechanism of cardiotoxicity of doxorubicin. The drug can acquire electrons from mitochondrial complex I. The quinone thus produced can donate the electron to oxygen, and the superoxide produced damages heart tissues and mtDNA. Abbreviation mtDNA, mitochondrial DNA.

Oxidative Stress and Oxidative Damage Elicited by mtDNA Mutations. 102... 

On the other hand, defective respiratory function elicited by the mtDNA mutation contributes to an increase in the production of ROS and free radicals, thereby causing higher oxidative stress and severe oxidative damage in affected cells (P2, W6). Because either enhanced oxidative stress or disruption of calcium homeostasis is an important factor in the triggering of cell death, mitochondrial dysfunction in tissue cells from MELAS and MERRF patients may contribute significantly to the pathogenesis of these diseases. 

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