Fight Aging!

A herd of bacteria-like mitochondria exist in every cell in the body, constantly dividing, fusing, and swapping component parts among one another, as well as being destroyed when damaged by cellular quality control mechanisms. Mitochondria are responsible for a range of tasks vital to the cell, but the best known involves the creation of ATP chemical energy stores used to power cell operations. Each mitochondrion has at least one copy of the small set of mitochondrial DNA, separate from the DNA in the cell nucleus. As long term readers know damage to this mitochondrial DNA is implicated as one of the primary causes of degenerative aging, leading to a Rube Goldberg chain of consequences that in the end produces a small population of very dysfunctional cells that export damaging reactive molecules to harm tissues both near and far in the body.

Mitochondrial DNA doesn't just become more damaged with age, the number of distinct mitochondrial genomes in a cell - called the copy number - falls dramatically in all cells in many tissues. This has no straightforward or well-understood relationship with mitochondrial damage: it isn't just the dysfunctional cells that have lower copy numbers, and higher copy numbers may be a response to damaged DNA. Falling copy number doesn't linearly correlate with number of mitochondria or the mitochondrial output in term of necessary energy stores for cellular processes, but it does seem to have a significant impact. As an example, researchers here suggest that reduced mitochondrial copy number and its effects on function are a proximate cause for lost insulin production in type 2 diabetes:

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide.

This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

Link: http://dx.doi.org/10.1371/journal.pone.0115433