Damage to mtDNA in aging age-related diseases

Author: M. N. Gadaleta
Submitted: Thursday 10th of February 2011 09:02:16 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: expert, qc3

Abstract

The mitochondria as “the aging clock” were proposed in 1972 by Harman. The theory was based on the fact that ROS (Reactive Oxygen Species) are, in physiological conditions, by-products of the OXPHOS (oxidative phosporylation) process which occurs in mitochondria. There is good agreement, today, that mitochondria are the most important cellular source of ROS as well as the most important target. ROS produced during lifespan by complex I and IV of respiratory chain (RC) in mitochondria might induce, “in primis”, damage to mtDNA, which is located nearby RC. MtDNA mutations, point mutations and/or large deletions, might be due to errors made during the repair or replication of damaged DNA. One of the most obvious adverse effect of mtDNA mutations is the malfunctioning of RC. The effects of loss-of-function mtDNA mutations depend, however, on the percent of mutated mtDNA (heteroplasmy) in a given cell. MtDNA mutations, in fact, expand clonally in a tissue, driven by random genetic drift within intracellular population or because of a selective advantage. Clonal expansion of deleterious mtDNA mutations exceeding the tissue specific physiological threshold results in focal RC defects. The most exposed tissues to mtDNA damages accumulation during lifespan are terminally differentiated highly oxidative tissues such as muscle and brain. However, although several lines of evidence support a role for accumulating somatic mtDNA mutations in the etiology of aging, the roles for the mtDNA damage and the replications errors in aging need to be further experimentally addressed. Advancing age is the most important risk factor for neurodegenerative diseases such as Alzheimer‟s disease (AD) and Parkinson‟s disease (PD) as well as for other age-related metabolic and degenerative diseases like diabetes or for cancer. All these pathologies are characterized by delayed onset and progressive course of the disease, characteristics that make them suspected to result from the accumulation of somatic mutations in the mtDNA of tissues. However, this is still matter of debate. The variation in the individual and regional predisposition to degenerative diseases and cancer may result, according to Wallace, from the interaction of modern dietary caloric intake and ancient 23 mitochondrial genetic polymorphisms so that mitochondria might provide the direct link between environment and genes.

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abstract Mitochondria_and_aging_Gadaleta_5116.ppt

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M. N. Gadaleta. Damage to mtDNA in aging age-related diseases. EUROGENE portal. February 2011. online: http://eurogene.open.ac.uk/content/damage-mtdna-aging-age-related-diseases

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