Mutations in mitochondrial DNA accumulate differentially in three different human tissues during ageing

Abstract

In 60 human tissue samples (encompassing skeletal muscle, heart and kidney) obtained from subjects aged from under 1 to 90 years, we used quantitative PCR procedures to quantify mitochondrial DNA (mtDNA) molecules carrying the 4977 bp deletion (mtDNA4977) and 3243 A-->G base substitution. In addition, the prevalence of multiple mtDNA deletions was assessed in a semi-quantitative manner. For all three tissues, the correlations between the accumulation of the particular mtDNA mutations and age of the subject are highly significant. However, differential extents of accumulation of the two specific mutations in the various tissues were observed. Thus, the mean abundance (percentage of mutant mtDNA out of total mtDNA) of mtDNA4977in a subset of age-matched adults is substantially higher in skeletal muscle than in heart and kidney. However, the mean abundance of the 3243 A-->G mutation in skeletal muscle was found to be lower than that in heart and kidney. Visualisation of arrays of PCR products arising from multiple mtDNA deletions in DNA extracted from adult skeletal muscle, was readily made after 30 cycles of PCR. By contrast, in DNA extracted from adult heart or kidney, amplification for 35 cycles of PCR was required to detect multiple mtDNA deletions. Although such multiple deletions are less abundant in heart and kidney than in skeletal muscle, in all tissue extracts there are unique patterns of bands, even from different tissues of the same subject. The differential accumulation of mtDNA4977, other mtDNA deletions and the 3243 A-->G mutation in the three tissues analysed presumably reflects different metabolic and senescence characteristics of these various tissues.

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

“…All of the nine areas of postmitotic tissues exhibit an increase of the 4977 bp deletion in an age-dependent manner, which is in accordance with other studies (Soong et al, 1992;Corral-Debrinski et al, 1992a;Zhang et al, 1998;Liu et al, 1998). Our data give the best correlation between age and ln mtDNA% for the substantia nigra (Fig.…”

Increased salivary level of 8-hydroxydeoxyguanosine is a marker of premature oxidative mitochondrial DNA damage in gingival tissue of patients with periodontitis

“…Unfortunately, the reasons for the high incidence of the 5-kbp mtDNA deletion are not clear. It is suggested that both the incidence and abundance of the 5-kbp mtDNA deletion tend to be higher in tissues with a high metabolic rate (Liu et al 1998). The very specific metabolic function of inflamed gingival tissue cells may be the reason why the abundance of the 5-kbp mtDNA deletion is higher than that of the 7-kbp mtDNA deletion in periodontitis patients.…”

The mitochondrial theory of aging: dead or alive?

“…Many studies have focused on the levels of specific point mutations found previously in cases of mtDNA disease, such as A3243G (Liu et al ., 1998) or A8344G (Münscher et al ., 1993). Some of these mutations have been previously suggested to lie in mutational hotspot regions.…”

“…Nevertheless, they have been found to accumulate, at least at the whole tissue level, to truly minute levels, never more than a tiny fraction of a per cent of total mtDNA, except in individuals who are members of already recognized families with mtDNA disease. In fact, despite earlier reports which claimed to detect these mutations rather commonly, in various tissues of aged subjects (Münscher et al ., 1993;Liu et al ., 1998), a recent study, using a reliable, sensitive and quantitative method, failed to find the A3243G or A8344G mutations in brain or muscle of aged subjects, above the detection limit of 0.1% (Murdock et al ., 2000).…”