Damage to MtDNA

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 3 Three ways that ROS generated hy the mitochondrial respiratory chain may be involved in hypoxic gene induction in yeast. In the first, ROS oxidize a mitochondrial protein, which initiates a signaling pathway to the nucleus. In the second, free ROS are released from mitochondria and initiate a signaling pathway to the nucleus. In the third, ROS modify mitochondrial gene expression via oxidative damage to MtDNA, which initiates a signaling pathway to the nucleus.

Peroxynitrite, the hydroxyl radical, and lipid peroxidation products damage DNA. Mitochondrial DNA (mtDNA) is particularly sensitive to ROS-induced damage due to its proximity to the inner membrane (the main cellular source of ROS), the absence of protective histones, and the nonrepair of bulky DNA lesions (LeDoux et al. 1999) such as those induced by reactive lipid peroxidation products. Oxidative lesions of mtDNA bases can cause errors during mtDNA replication (Kuchino et al. 1987) or repair (Pinz et al. 1995) and result in point mutations. Furthermore, ROS-mediated mtDNA strand breaks can occasionally lead to mtDNA deletions (Bemeburg et al. 1999). 

The use of quantitative PCR (QPCR), based in the blockage of amplification caused by some DNA insults, is being assayed for a more precise identification of damage to nuclear (nDNA) and mitochondrial (mtDNA) mammalian spermatozoa genomes (Rennets and Aitken, 2005).This is particularly interesting in species whose genome is sequenced (such as zebra-fish and rainbow trout and sea bass, very soon), as results can be analysed on ships themselves. 

Cardiac function deteriorates with age, and endogenous damage to mitochondrial DNA is believed to be a major contributory factor to ageing. The 7 kb deletion of mtDNA was commonly detected in elderly subjects, and the proportion of deleted mtDNA to normal mtDNA increased with age (Hattori etal. 1991). A chronic ischaemia-like state is induced in the myocardium, which might contribute to the genesis of ageing heart (presbycar-dia). 

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]. 

As aptly put by Wallace in a comprehensive review of mitochondria in aging, degenerative diseases, and cancer [1], "ROS damage to the mitochondria, mtDNA, and host cells must be one of the most important entropic factors in determining age-related cellular decline."... 

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. 

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.

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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