Examining Mitochondrial DNA Damage With Aging in Human Tissues
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We age in part because mitochondrial DNA accumulates mutations, probably via oxidative damage. Mitochondria exist as bacteria-like self-replicating herds within our cells, and mitochondrial function is essential to cellular processes. Mitochondria have their own DNA, distinct from that in the cell nucleus. This DNA is the blueprint for a number of essential portions of protein machinery used within mitochondria: severe mutations such as deletions can remove the ability of a particular mitochondrion to maintain itself and continue to operate correctly. Cellular quality control should destroy all such damaged mitochondria, but unfortunately some damage can cause forms of dysfunction that evade these quality control processes. This ultimately leads to cells overtaken by clones of a dysfunctional mitochondria, and which themselves become dysfunctional as a result, harming surrounding tissues.

Possible approaches to remove this contribution to degenerative aging include periodic mitochondrial DNA repair or replacement, and the SENS method of adding backup copies of the relevant genes to the cell nucleus.

Here is an example of research that supports this view, in which researchers examine the prevalence of mitochondrial DNA mutations with advancing age in human brain tissue, showing that deletion mutations increase significantly with age:

Mitochondria are unique among animal organelles in that they contain their own multi-copy genome (mtDNA). For the past 20 years it has been known that tissues like brain and muscle accumulate somatic mtDNA mutations with age. Because individual mtDNA mutations are present at very low levels, few details are known about the spectrum of mutations associated with aging.

Advances in sequencing technology now permit the examination of mtDNA mutations at high resolution. We have examined the spectrum of mtDNA mutations present in putamen, a brain region prone to the accumulation of somatic mtDNA mutations. We were able to quantify the accumulation of clonal and non-clonal deletions in the mtDNA coding region which are known to have a strong association with aging. Partial deletions and novel duplications of the mtDNA control region were also identified, and appear to be more prevalent than previously recognized, but levels showed weaker associations with age than coding region deletions. Single nucleotide variants accumulate fastest in the control region, with a skew towards the accumulation of pathogenic mutations in the coding region.

Understanding how the mitochondrial genome alters with age provides a benchmark for studies of somatic mtDNA mutations and dissection of the role they play in normal aging and degenerative diseases.

Link: http://dx.doi.org/10.1371/journal.pgen.1003990

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