Mitochondria's own DNA (mtDNA), consisting of 16.6 kb of double strands of DNA organized in a circle, is located in the matrix compartment of the mitochondria. The mtDNA codes for 37 proteins—13 of the oxidative phosphorylation (OXPHOS) system, 22 tRNAs, and 2 rRNAs. Besides the regions coding the proteins of the OXPHOS system, the mtDNA also consists of a "noncoding region" (also called the hypervariable region, control region, or the D-loop), which is responsible for mitochondr-ial maintenance and mitochondrial replication. The nucleotide sequence in this control region also controls RNA and DNA synthesis. The nuclear DNA (nDNA) is also responsible for the synthesis of several other proteins that contribute to normal functions of the OXPHOS system. These polypeptides are synthesized in the cytoplasm and tagged to be transported specifically into the mitochondria, and the proteins are subsequently reassembled to form the OXPHOS system (42). Mutations of both mtDNA and nDNA, encoding for the proteins of the mitochondria, have been reported to cause neurological disorders (33,43,44).
Since mtDNA is recycled more than the nDNA, mtDNA mutations are about 10 times higher than the nDNA. The mtDNA mutations appear to start at the age of 45 to 55 years and gradually increase in frequency (45). The high level of mtDNA mutations associated with aging has been proposed to be due to damage to mtDNA caused by life-long production of free radicals in the mitochondria (46).
The role of mtDNA mutations in aging and neurodegenerative disorders was brought to attention by the study of the distribution of pattern I of mtDNA in different parts of the brain. These studies showed that the most common mutation of mtDNA, deletion of 4977 bp, was found in several nuclei of the brain and was higher with aging. A higher level of this mutation was found in the neurons of the cerebral cortex and putamen, but not in the cerebellum in aging brains (47). This mutation is noted in PD brains (48-50) and platelets (51) and does not appear to cause the disease but may be responsible for susceptibility to PD (52) and may be age-related (53).
In PD, mtDNA mutations are higher than age-matched controls in the dopamine neurons of the SN (54). The mtDNA mutations are significantly higher in the substantia nigra than any other regions of the brain and are more common in PD than in the brains of persons with Alzheimer's disease, multiple system atrophy, and diffuse Lewy body disease, as well as age-matched controls (55). The increased level of mtDNA mutations has been proposed to be due to an increased level of oxidative stress in the SNpc neurons. With aging, immunostaining for COX (cytochrome c or complex IV), an enzyme that has a significant role in cellular respiration, decreases significantly in the melanin positive neurons of the SN (56). The level of mtDNA mutations are higher in the COX-negative dopamine neurons of the SN than in the COX-positive neurons, raising the possibility that mtDNA mutations might contribute to the decrease in COX activity (45).
The precise role played by these mtDNA mutations in the degenerative process of SN cells remains to be established. It is unclear whether they cause death directly or play a role in the aging process of the SN, increasing vulnerability to other factors that cause SN apoptosis.
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