GSE106105
PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila
The mitochondrial unfolded protein response (UPRmt) has been associated with long  lifespan across metazoans. In Caenorhabditis elegans, mild developmental mitochondrial stress  activates UPRmt reporters and extends lifespan. We show that similar developmental stress is  necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5  (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of  FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This  activation persists into adulthood and induces a select set of chaperones, many of which have been  implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high-  protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan  extension is prevented on a high-protein diet and in FoxO-null flies. The diet-sensitivity of this  pathway has important implications for interventions that seek to engage the UPRmt to improve  metabolic health and longevity. Overall design: Three thoracic samples, including one genetic control and two experimental conditions. Also eight fat body samples, four each from adults and larvae, from wild type and PGAM5 mutant flies, with and without RU486 treatment to induce genetic phenotype.