PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila

The mitochondrial unfolded protein response (UPR^mt) has been associated with long lifespan across metazoans. In <i>Caenorhabditis elegans</i>, mild developmental mitochondrial stress activates UPR^mt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend <i>Drosophila</i> 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 UPR^mt to improve metabolic health and longevity.