Thursday, 7 January 2016

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

http://www.sciencedirect.com/science/article/pii/S1550413115005781

Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J

Cellular senescence is the process by which dividing cells permanently lose their ability to replicate. This phenotype can inhibit the growth of cancerous cells, but it is also thought to occur in normal tissues during aging. It is known that mitochondrial dysfunction can induce senescence, however the mechanisms of this are unclear.

The authors show that several different kinds of mitochondrial dysfunction can induce senescence in the IMR-90 cell line: mtDNA depletion; drugs which inhibit the electron transport chain (rotenone and antimycin A); and inhibition of a particular mitochondrial chaperone (HSPA9) which aids in import of proteins into mitochondria.

Mitochondria oxidise NADH to NAD+ in a number of metabolic reactions involved in generating energy. NAD+ is a substrate of glycolysis, whereas NADH is a product, which can inhibit the pathway if it is not removed. As glycolysis provides pyruvate, the substrate of oxidative phosphorylation, a reduced NAD+/NADH ratio may be expected to slow down glycolysis and therefore oxidative phosphorylation.

The authors provide evidence that the mechanism of mitochondrially-induced senescence is lowered NAD+/NADH ratios, suggesting energetic collapse. This is supported by an increased ADP/ATP ratio in these cells. They find that supplementation of pyruvate to cells can partially rescue the senescent phenotype.

The authors further show the relevance of mitochondrially-induced senescence, by investigating the effect in POLG mutator mice (mice which accumulate mtDNA mutations in time and have a progerioid phenotype). The authors found that the progerioid mice had many more senescent cells in affected tissues, with lowered NAD+/NADH ratios compared to wild-type mice.


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