Thursday, 6 November 2014

A Mitochondrial ATP Synthase Subunit Interacts with TOR Signaling to Modulate Protein Homeostasis and Lifespan in Drosophila

http://www.cell.com/cell-reports/abstract/S2211-1247(14)00685-8

Xiaoping Sun, Charles T Wheeler, Jason Yolitz, Mara Laslo, Thomas Alberico, Yaning Sun, Qisheng Song, Sige Zou

The authors studied a Drosophila model in which ATP synthase d (ATPsyn-d) was knocked down after reaching adulthood using a drug-inducible gene switch system (simply knocking down ATPsyn-d led to lethality before pupation). ATPsyn-d knockdown after reaching adulthood increased lifespan in female but not male Drosophila with no alteration to food intake, however overexpression did not have any effect. The lifespan extension was diet-dependent, and enhanced lifespan in high protein, low sugar diets but decreased them when the proportions were reversed.

ATPsyn-d knockdown paradoxically led to increased ATP levels through a decrease in UCP expression, but only on a protein-rich diet. It also caused significant transcriptional changes, including proteins involved in a range of protective, proteostatic and energy-generating roles.

The authors also explored the effects of ATPsyn-d knockdown on TOR and MAPK pathways, and found that overexpression of the TOR signalling suppressor Tsc2 cancelled out the longevity-promoting effects of ATPsyn-d knockdown. Feeding with rapamycin had a similar but less pronounced effect, reducing the lifespan extension due to ATPsyn-d knockdown. This is attributed to overlapping pathways of lifespan extension between ATPsyn-d and rapamycin, which are likely to include TOR signalling.

Finally, a decrease in protein polyubiquitination and polyubiquitinated protein aggregates was observed. These are biomarkers for proteostasis, leading the authors to conclude that the lifespan extension due to ATPsyn-d knockdown is at least partially accomplished through improved proteostasis. The authors suggest that ATPsyn-d and other mitochondrial proteins regulate TOR signalling, and that perhaps the beneficial effects exist in high protein, low carbohydrate diets because there TOR levels are high, whereas in low protein, high carbohydrate diets TOR levels are low so there is nothing to knock down.

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