Suggesting Impaired Quality Control as the Cause of Greater Mitochondrial DNA Damage in Aging

Thousands of mitochondria swarm within each of our cells, working to produce energy store molecules that power cellular processes. Mitochondria multiply by division, contain remnant DNA from their origin as symbiotic bacteria, and are culled when dysfunctional by cellular quality control mechanisms. Despite the destruction of faulty mitochondria, damage to their DNA nonetheless accumulates. More serious forms of this mutational damage can block the production of proteins necessary for mitochondrial function, leading to dysfunctional cells and contributing to a range of ultimately fatal age-related conditions.

There is a fair degree of debate over just how this damage originates, spreads, and increases with age, however. Whatever the process by which a single damaged mitochondrion can replicate its damage throughout all of the mitochondria in a cell in some circumstances, this transformation happens rapidly: researchers don't have intermediate states to study. The causes of increasing damage might include mitochondrial division, or the reactive oxygen species produced by the normal operation of mitochondrial processes, or some other process, such as a progressive failure of quality control as suggested here:

We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities.

Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.



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