Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide

Joseph W Horsman,Dana L Miller

doi:10.1074/jbc.m115.697102

Joseph W Horsman, Dana L Miller

Open Access

https://doi.org/10.1074/jbc.m115.697102

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Abstract

Hydrogen sulfide (H2S) is an endogenously produced gaseous molecule with important roles in cellular signaling. In mammals, exogenous H2S improves survival of ischemia/reperfusion. We have previously shown that exposure to H2S increases the lifespan and thermotolerance in Caenorhabditis elegans, and improves protein homeostasis in low oxygen. The mitochondrial SQRD-1 (sulfide quinone oxidoreductase) protein is a highly conserved enzyme involved in H2S metabolism. SQRD-1 is generally considered important to detoxify H2S. Here, we show that SQRD-1 is also required to maintain protein translation in H2S. In sqrd-1 mutant animals, exposure to H2S leads to phosphorylation of eIF2α and inhibition of protein synthesis. In contrast, global protein translation is not altered in wild-type animals exposed to lethally high H2S or in hif-1(ia04) mutants that die when exposed to low H2S. We demonstrate that both gcn-2 and pek-1 kinases are involved in the H2S-induced phosphorylation of eIF2α. Both ER and mitochondrial stress responses are activated in sqrd-1 mutant animals exposed to H2S, but not in wild-type animals. We speculate that SQRD-1 activity in H2S may coordinate proteostasis responses in multiple cellular compartments.

Highlights

Sulfide-quinone oxidoreductase (SQRD) is a highly conserved mitochondrial protein that oxidizes cellular H2S by transferring electrons to the mitochondrial electron transport chain and adding sulfane sulfur atoms to free sulhydryl moieties (Fig. 1A) [7,8,9]
We found that the translation initiation factor eIF2␣ is phosphorylated by both PEK-1 and GCN-2 kinases in sqrd-1 mutant animals exposed to H2S
C. elegans exposed to low concentration H2S are long-lived and better able to maintain proteostasis in hypoxia [18, 19]

Summary

Introduction

Sulfide-quinone oxidoreductase (SQRD) is a highly conserved mitochondrial protein that oxidizes cellular H2S by transferring electrons to the mitochondrial electron transport chain and adding sulfane sulfur atoms to free sulhydryl moieties (Fig. 1A) [7,8,9]. We found that the translation initiation factor eIF2␣ is phosphorylated by both PEK-1 and GCN-2 kinases in sqrd-1 mutant animals exposed to H2S. We observed less [35S]methionine incorporation in sqrd-1(tm3378) mutant animals exposed to low concentration of H2S, suggesting that translation had arrested in these animals (Fig. 1, C and D).

Results

Conclusion