Seminar in Biological Mechanisms of Aging and Cancer/Genomic Instability (mitochondrial DNA)
Genomic instability of mitochondrial DNA has been described as a cause of the process of aging[1]. This refers to the possibility of mutations and deletions of genetic material within the DNA of a mitochondrion, ultimately leading to premature aging of an organism. A mitochondrion is considered the "powerhouse" of a cell since they are responsible for the vast majority of ATP (adenosine triphosphate) synthesis, the molecule used as the energy source to drive anabolic reactions. The synthesis of ATP is primarily done by the production of a proton gradient produced in the intermembrane space of the mitochondrion, which provides the energy for intermembrane ATPsynthase proteins to convert ADP + Pi (adenosine diphosphate) to ATP. Many of the proteins responsible for the production of this proton gradient are coded for in the the DNA of the mitochondria themselves. Mutations in mitochondrial DNA would therefore be expected to affect the function of mitochondria, leading to another Hallmark of Aging, mitochondrial dysfunction[1]. An investigation into mutations of mitochondrial DNA (mtDNA) by Edgar, et al. in 2009 suggests that they cause a decrease in the efficiency of the electron transport system (ETS) by a reduced number of functional proteins required to provide the proton gradient[2].
Experiments done by Edgar, et al. with mice containing a mutation in the gene for mitochondrial DNA polymerase that results in a a lack of proofreading ability, show a decrease in the subunits of ETS complexes I, III, and IV and corresponding fully assembled complexes, which aid in the proton gradient formation[2]. It is also demonstrated that the resulting aged phenotype of these mutated mice is a direct result of point mutations in the mtDNA, rather than a result of large deletions of portions of the mtDNA[2].
==Notes==
- ↑ 1.0 1.1 Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. "Cell 153," 1194-1217.
- ↑ 2.0 2.1 2.2 Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M.A., Nijtamns, L., Nedergaard, J., Cannon, B., Larsson, N., Trifunovic, A. (2009). Random Point Mutations with Major Effects on Protein-Coding Genes Are the Driving Force behind Premature Aging in mtDNA Mutator Mice. Cell Metabolism 10, 11-138. Retrieved 13 Feb, 2017.