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

The mitochondrial unfolded protein response (UPRmt) is critical for maintaining mitochondrial protein homeostasis in response to mitochondrial stress, but early steps in UPRmt activation are not well understood. Here, we report a function for SPHK-1 sphingosine kinase in activating the UPRmt in C. elegans. Genetic deficiency of sphk-1 in the intestine inhibits UPRmt activation, whereas selective SPHK-1 intestinal overexpression is sufficient to activate the UPRmt. Acute mitochondrial stress leads to rapid, reversible localization of SPHK-1::GFP fusion proteins with mitochondrial membranes before UPRmt activation. SPHK-1 variants lacking kinase activity or mitochondrial targeting fail to rescue the stress-induced UPRmt activation defects of sphk-1 mutants. Activation of the UPRmt 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 UPRmt activation.