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

SUMMARY

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.

In Brief

The mitochondrial unfolded protein response (UPR ^mt) maintains mitochondrial protein homeostasis in response to stress. Kim and Sieburth identify SPHK-1/sphingosine kinase as a positive regulator of the UPR ^mt that promotes UPR ^mt activation in response to a variety of mitochondrial stressors. SPHK-1 associates with mitochondria and SPHK-1 mitochondrial association is stress dependent, reversible, and necessary for the UPR ^mt, indicating that SPHK-1 mitochondrial targeting is an early step in UPR ^mt activation.

Graphical Abstract