Nucleic Acids Research, Vol 25, Issue 5 974-982, Copyright © 1997 by Oxford University Press
S Melov, D Hinerfeld, L Esposito and DC Wallace
Mitochondrial DNA (mtDNA) rearrangements have been shown to accumulate with
age in the post-mitotic tissues of a variety of animals and have been
hypothesized to result in the age-related decline of mitochondrial
bioenergetics leading to tissue and organ failure. Caloric restriction in
rodents has been shown to extend life span supporting an association
between bioenergetics and senescence. In the present study, we use full
length mtDNA amplification by long-extension polymerase chain reaction
(LX-PCR) to demonstrate that mice accumulate a wide variety of mtDNA
rearrangements with age in post mitotic tissues. Similarly, using an
alternative PCR strategy, we have found that 2-4 kb minicircles containing
the origin of heavy-strand replication accumulate with age in heart but not
brain. Analysis of mtDNA structure and conformation by Southern blots of
unrestricted DNA resolved by field inversion gel electrophoresis have
revealed that the brain mtDNAs of young animals contain the traditional
linear, nicked, and supercoiled mtDNAs while old animals accumulate
substantial levels of a slower migrating species we designate age-specific
mtDNAs. In old caloric restricted animals, a wide variety of rearranged
mtDNAs can be detected by LX-PCR in post mitotic tissues, but Southern
blots of unrestricted DNA reveals a marked reduction in the levels of the
age- specific mtDNA species. These observations confirm that mtDNA
mutations accumulate with age in mice and suggest that caloric restriction
impedes this progress.
ARTICLES
Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age
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