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

Abstract

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.

Keywords: ATFS-1; cell non-autonomous; mitochondria; mitochondrial unfolded protein response; nervous system; neuropeptide; sphingosine kinase.