Please use this identifier to cite or link to this item: http://hdl.handle.net/11434/1366
Title: Tissue mitochondrial DNA changes. A stochastic system.
Epworth Authors: Kopsidas, George
Kovalenko, Sergey
Heffernan, Damien
Yarovaya, Natalia
Kramarova, Ludmilla
Stojanovski, Diane
Borg, Judy
Islam, Mohammed
Caragounis, Aphrodite
Linnane, Anthony
Keywords: Bioenergetic Function
DNA, Mitochondrial
Skeletal Muscle
Age-Related Fiber Loss
Aging
Genetics
Glycolysis
DNA Mutation
Nucleic Acid Conformation
Stochastic Processes
mtDNA
DNA Damage
Centre for Molecular Biology and Medicine, Epworth Medical Centre, Richmond, Victoria, Australia.
Issue Date: Jun-2000
Publisher: New York Academy of Sciences
Citation: Ann N Y Acad Sci. 2000 Jun;908:226-43
Abstract: Several lines of evidence support the view that the bioenergetic function of the mitochondria in postmitotic tissue deteriorates during normal aging. Skeletal muscle is one such tissue that undergoes age-related fiber loss and atrophy and an age-associated rise in the number of cytochrome c oxidase (COX) deficient fibers. With such metabolic pressure placed on skeletal muscle it would be an obvious advantage to supplement the cellular requirement for energy by up-regulating glycolysis, and alternative pathway for energy synthesis. Analysis of rat skeletal muscle utilizing antibodies directed against key enzymes involved in glycolysis has provided evidence of an age-associated increase in the enzymes involved in glycolysis. Fructose-6-phosphate kinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase protein levels appeared to increase in the soleus, gracilis, and quadriceps muscle from aged rats. The increase in the level of these proteins appeared to correlate to a corresponding decrease in the amount of cytochrome c oxidase protein measured in the same tissue. Together these results are interpreted to represent a general upregulation of glycolysis that occurs in response to the age-associated decrease in mitochondrial energy capacity. Mitochondrial DNA (mtDNA) damage and mutations may accumulate with advancing age until they reach a threshold level were they impinge on the bioenergy capacity of the cell or tissue. Evidence indicates that mtDNA from the skeletal muscle of both aged rats and humans not only undergoes changes at the nucleotide sequence level (mutations and DNA damage), but also undergoes modifications at the tertiary level to generate unique age-related conformational mtDNA species. One particular age-related conformational form was only detected in aged rat tissues with high demands on respiration, specifically in heart, kidney, soleus muscle, and, to a lesser extent, the quadriceps muscle. The age-related form was not detected in gracilis muscle which is predominantly dependent upon glycolysis with regard to its energy requirements. Finally, a comprehensive hypothesis is presented that features the stochastic nature of the mitochondrial system. The basis of the hypothesis is that a dynamic relationship exists between endogenous mutagen production, DNA repair, mtDNA turnover, and nuclear control of mtDNA copy number and that age-associated changes in the dynamics of this relationship lead to a loss of functional full-length mtDNA that eventually leads to bioenergy decline.
URI: http://hdl.handle.net/11434/1366
DOI: 10.1111/j.1749-6632.2000.tb06650.x
PubMed URL: https://www.ncbi.nlm.nih.gov/pubmed/10911962
ISSN: 1749-6632
Journal Title: Annals of the New York Academy of Sciences
Type: Journal Article
Type of Clinical Study or Trial: Review
Appears in Collections:Pre-Clinical

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