**1.3. High mutation speed**

The mtDNA has a spontaneous mutation rate 10 times higher than that of nuclear DNA. Continuous mitochondrial production of oxygen radicals by the final oxidation of carbon compounds probably damages the unprotected mtDNA (e.g., mtDNA reminds bacterial genomes as it lacks histones). Therefore, the within-species individual sequence variation is large, up to about 70 nucleotides. Within single individuals, low heterogeneity levels in the mtDNA will be generated throughout life. It has been proposed that the decrease in respiratory capacity of the tissues, which takes place during aging, may be due to an accumulation of such mitochondrial damages. This theory was first evidenced in a study by the Attardi Group, who documented that the mitochondria deteriorate with age as a result of the accumulation of mutations [13]. Mitochondrial dysfunction is characterized by a deficient production of energy, a failure in calcium homeostasis, an activation of proteases and phospholipases, activation of nitric oxide synthase, and an abundant generation of free radicals [14–16]. Mitochondria, besides being the main source of free radicals, are also very susceptible to oxidative stress, which is made evident by a massive induction of lipid peroxidation, protein oxidation, and mutations in mtDNA. Oxidative stress also induces apoptotic death, and the mitochondria play a central role in this phenomenon since there is cytochrome c release to the cytoplasm and opening of the permeability transition pore [16].
