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MtDNA in Aging, Cancer and Mitochondrial Disease?
Posted on: February 3, 2003

Mitochondria are the main integrated power organelles in the cell. And they are straightly concerned with cell and organism. It is well known that somatic mitochondrial DNA (mtDNA) mutations accumulate with age in healthy individuals. Usually old people typically harbour a wide range of different mtDNA deletions in postmitotic tissues, such as skeletal muscle, myocardium, and brain. Such mutations do not seem to be present in young people. Although the overall amount of mutant mtDNA in old people is usually very low in the tissue as a whole, individual cells can contain high percentage concentrations of a single mutant species, and different cells usually contain different mutations. When the proportion of mutant mtDNA exceeds a critical threshold concentration, a defect of mitochondrial oxidative phosphorylation results. A combination of different respiratory chain complexes (I, III, IV, and V) can be involved, but complex IV (cytochrome c oxidase, COX) is often affected, and this effect is easily shown in single cells by enzyme histochemistry. Although only a few cells develop COX deficiency, the resultant cellular dysfunction might have substantial effects, especially if the cell is part of a complex network; the central nervous system. Clonal expansion of a single somatic mtDNA mutation has substantial implications for a cell, but is not yet known how this process comes about. Polyak and colleagues observed that various tumours contained mtDNA point-mutations that were not present in healthy tissues from the same individuals. This was an exciting observation, in view of the potential role of mitochondria in carcinogenesis, and potential new avenues for detection and treatment. Various explanations to account for these findings were suggested, but there was little evidence to lend support to them. Unlike the mutations that were identified in the COX-deficient cells of old individuals, the mutations in the tumour cells were at non-conserved sites of mtDNA that are regarded as functionally unimportant. Thus the presence of mtDNA mutations within tumours might not always be dependent on mitochondrial dysfunction. mtDNA mutations are also an important cause of disease. At least one in 8000 adults harbours a pathogenic mtDNA mutation. Unlike the range of mtDNA mutations that accumulate with age, patients with mtDNA disease usually have high levels of only one mutant species. This situation often results in a devastating neurological disorder with additional multisystemic features, such as cardiomyopathy and diabetes mellitus. These patients have usually inherited a mixture of mutant and wildtype mtDNA (heteroplasmy) from their mother. Why, therefore, do they fail to develop symptoms until late childhood or early adult life? mtDNA disorders are progressive, and clinical progression is accompanied by the accumulation of COX-deficient cells, which is similar to that seen in normal ageing. Understanding precisely how this accumulation takes place could provide the key to our understanding of mtDNA diseases and the development of novel treatments that act at the genetic level.

To simulate linear fate of mitochondria in organism, scientists have used mathematical models to predict it. In process of mathematical and biophysical manipulations they have raised mathematically based hypothesis of COX negative cells accumulation with age. This hypothesis states that the accumulation of COX-negative cells with age, homoplasmic mtDNA mutations in tumours, and mtDNA disease progression arise because of three basic properties of mtDNA: polyploidy (multiple copies of the same genome within each cell), relaxed replication, and a mechanism that regulates the normal intracellular mtDNA copy number. These properties are responsible for the common basic mechanism of random genetic drift, and different time scales account for the accumulation of mutant mtDNA in ageing, cancer, and mitochondrial disease. The accumulation of COX-negative cells with age takes the longest time: a long time is required for clonal expansion through random drift from a single mutated mtDNA molecule to very high amounts of mutated mtDNA in large cells containing many mtDNA molecules. Disease progression might take place through the same mechanism of random drift, but the effects are seen more quickly than in ageing because the initial numbers of mutated mtDNA are much higher than a single molecule. Finally, homoplasmic mtDNA mutations in tumours might develop quickly because random drift of mtDNA is accelerated by the higher replication rate of mtDNA in rapidly dividing cells. To test the hypothesis, it is needed to directly measure the accumulation of mutant mtDNA within individual cells in each of the three situations; ageing, cancer, and disease. At this moment such tests are technically impossible to proceed. Although in ageing and cancer, large numbers of normal cells that would never undergo a substantial change in mtDNA content would need to be studied too.

Picture: Mitochondrial hyperplasia can be encountered in tumors from different organs, so-called oncocytomas, and it has been suggested to be related to defective mitochondrial function. The finding of true lipidic inclusions in mitochodria, however, is a strong suggestion that a given lesion has originated in an upper abdominal organ. This electron micrograph shows intramitochodrial lipidic inclusions in a renal oncocytoma. (By Bruce Mackay, MD Anderson Cancer Center, Houston, Texas); web: http://sup.ultrakohl.com/uscap/loreta.htm
Source: www.thelancet.com; Patrick F Chinnery, David C Samuels, Joanna Elson, Douglass M Turnbull; Lancet 2002; 360: 1323-25; Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?
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