At birth, the mtDNA genomes appear to be relatively homogeneous throughout the body. Multiple investigations have demonstrated that mtDNA rearrangement mutations, generally assessed using the common 5 kflobase (kb) [ 4977 nucleotide pair (np)] deletion, are rare or absent in the newborn. This low level of somatic mtDNA mutations appear to be sustained in rapidly dividing tissues such as white blood cells (Cortopassi et al., 1992a, Monnat and Ray, 1986). However, post-mitotic tissues of individuals over 30 years have been found to accumulate a wide variety of deleterious mtDNA mutations including both rearrangement and nucleotide substitution mutations. Studies on the accumulation of the common 5 kb deletion have revealed that the highest levels of somatic mtDNA rearrangements occur in brain, followed by muscle, heart, and kidney, with deletion levels increasing more that 10,000 fold from young to old age (Cortopassi and Arnheim, 1990; Cortopassi et al., 1992b: Corral-Debrinski et al., 1991, 1992a and b; Soong et al., 1992).

In the brain, the 5 kb deletion can increase to 10% of the total mtDNAs in the basal ganglia, by age 80, 0.1 to 2% in the cerebral cortex, by age 75. By contrast, the level of this deletion remains low, about 0.001%, in the cerebellum throughout life (Corral-Debrinski et al., 1992; Soong et al., 1992). Significant levels of mtDNA deletions have also been observed in extraocular muscle (Munscher et al., 1993a and b; Munscher, et al., 1993a and b;) skeletal muscle (Simonetti et al., 1992); heart (Corral-Debrinski et al., 1991 and 1992); and other tissues (Cortopassi et al., 1992; Zhang et al., 1992), though at lower levels then found in the basal ganglia and cortex.

A number of nucleotide substitution mutations have also been found to accumulate with age. All three pathogenic tRNA mutations examined were found to accumulate with age. These included the np 8344 (MERRF) mutation in tRNA LYS, the np 3243 MELAS) mutation in tRNA leu(uur) , and the NP 10006 tRNA Gly mutation. By contrast, the neutral polymorphism at np 12308 in tRNA did not increase (Munscher et al, 1993 a and b; Reigers et al., 1993; Zhange et al., 1993). The reason for this selective increase in deleterious mtDNA mutations in postmitotic cells is unknown. One possibility, however, is that cell nuclei in the presence of defective mitochondria sense the localized bioenergetic defect through the concentration of some mitochondrial metabolite. This signal then stimulates the nuclei to increase the synthesis of the surrounding mitochondria in an effort to compensate for the defect. However, this creates a distinctive cycle, for instead of increasing the levels of normal mitochondria, the nucleus stimulates the replication of the adjacent defective mtDNAS.

New mtDNA mutations have also been shown to arise in the female germline. A portion of the oocytes from normal female donors have recently been to harbor the 5 kb deletion (Suganima et al., 1993); a neutral, heterplasmic mutation has been reported in the ND6 gene at np 14560, in a family for three generations (Howell et al., 1992); and the AFDIL has observed two

cases of the fixation of mtDNA sequence differences between a mother and child. The most dramatic demonstration of the frequent appearance of mutations has come from the rapid identification of new mtDNA mutations in human degenerative diseases (Wallace, 1992a and b; Wallace et al., 1994).

All of these data demonstrate that post-mitotic tissues such as bone may harbor heteroplasmic, mutations, of both somatic and germline origin. Hence, caution should be exercised when drawing conclusions based on a single genetic characteristic state.

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