Sphingosine Kinase Activates the Mitochondrial Unfolded Protein Response and Is Targeted to Mitochondria by Stress

The mitochondrial unfolded protein response (UPR(mt)) is critical for maintaining mitochondrial protein homeostasis in response to mitochondrial stress, but early steps in UPR(mt) activation are not well understood. Here, we report a function for SPHK-1 sphingosine kinase in activating the UPR(mt) in C. elegans. Genetic deficiency of sphk-1 in the intestine inhibits UPR(mt) activation, whereas selective SPHK-1 intestinal overexpression is sufficient to activate the UPR(mt). Acute mitochondrial stress leads to rapid, reversible localization of SPHK-1::GFP fusion proteins with mitochondrial membranes before UPR(mt) activation. SPHK-1 variants lacking kinase activity or mitochondrial targeting fail to rescue the stress-induced UPR(mt) activation defects of sphk-1 mutants. Activation of the UPR(mt) by the nervous system requires sphk-1 and elicits SPHK-1 mitochondrial association in the intestine. We propose that stress-regulated mitochondrial recruitment of SPHK-1 and subsequent S1P production are critical early events for both cell autonomous and cell non-autonomous UPR(mt) activation.