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

Abstract

Hydrogen sulfide (H 2 S) is an endogenously produced gaseous molecule with important roles in cellular signaling. In mammals, exogenous H 2 S improves survival of ischemia/reperfusion. We have previously shown that exposure to H 2 S 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 H 2 S metabolism. SQRD-1 is generally considered important to detoxify H 2 S. Here, we show that SQRD-1 is also required to maintain protein translation in H 2 S. In sqrd-1 mutant animals, exposure to H 2 S leads to phosphorylation of eIF2␣ and inhibition of protein synthesis. In contrast, global protein translation is not altered in wild-type animals exposed to lethally high H 2 S or in hif-1(ia04) mutants that die when exposed to low H 2 S. We demonstrate that both gcn-2 and pek-1 kinases are involved in the H 2 S-induced phosphorylation of eIF2␣. Both ER and mitochondrial stress responses are activated in sqrd-1 mutant animals exposed to H 2 S, but not in wild-type animals. We speculate that SQRD-1 activity in H 2 S may coordinate proteostasis responses in multiple cellular compartments. Hydrogen sulfide (H 2 S)3 is an endogenously produced gas molecule with roles in signaling, neuromodulation, and vasodilation (reviewed in Ref. [1][2][3][4]. Treatment with exogenous H 2 S improves outcome in multiple mammalian models of ischemia/ reperfusion injury (5). However, H 2 S is also toxic at high concentrations, provoking immediate apnea and loss of consciousness that can result in death (6). Industrial exposure to H 2 S is the second-leading cause of death by inhalation, behind only carbon monoxide. The mechanistic differences between beneficial and toxic effects of H 2 S are poorly understood.Sulfide-quinone oxidoreductase (SQRD) is a highly conserved mitochondrial protein that oxidizes cellular H 2 S by transferring electrons to the mitochondrial electron transport chain and adding sulfane sulfur atoms to free sulhydryl moieties (Fig. 1A) (7-9). Isolated mitochondria from chicken liver and human cells can generate ATP when exposed to H 2 S as a result of SQRD activity, which is considered an important aspect of cellular sulfide detoxification (10 -12). However, it is now clear that protein activity can be regulated by post-translational modification by sulfide, and this may be an important aspect of the cellular signaling roles of H 2 S (2, 4). SQRD is therefore positioned to modulate both signaling and toxicity of H 2 S in animals.The nematode Caenorhabditis elegans has a single orthologue of SQRD, sqrd-1. SQRD-1 localizes to mitochondria and is essential for animals to survive exposure to even low concentrations of H 2 S (13). Here, we show SQRD-1 activity is required to prevent activation of the integrated stress response upon exposure to H 2 S. We found that the translation initiation factor eIF2␣ is phosphorylated by both PEK-1 and GCN-2 kinases in sqrd-1 mu...

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

“…This was primarily due to the lack of detectable DR-enhanced H2S production ( Figure 1H) along with the purported sensitivity to H2S-induced toxicity in the central nervous system (CNS) owning to its low or non-existent sulfide quinone oxidoreductase (SQR) expression (Supplemental Figure 1H) (Lagoutte et al, 2010;Linden et al, 2012). SQR is a key mitochondrial enzyme catalyzing the initial steps of H2S oxidation, detoxification, and removal (Horsman and Miller, 2016;Libiad et al, 2014). However, H2S does serve beneficial roles in the brain, as decreased H2S or disruption of H2S producing enzymes in the brain or neuronal cells are associated with aging-related Parkinson's, Huntington's, and Alzheimer's disease-like phenotypes (Paul and Snyder, 2018), while controlled H2S exposure serves to protect against cerebral ischemia-reperfusion injury (Yin et al, 2013) and slow the progression of neurodegeneration (Kamat et al, 2013).…”

H2S biosynthesis and catabolism: new insights from molecular studies

“…In SQR mutant worms, exposure to H 2 S leads to phosphorylation of eIF2α and the inhibition of protein synthesis. The authors speculating that SQR may be involved in H 2 S signalling relating to proteostasis [ 241 ]. Of relevance, here is the potential link with H 2 S, proteostasis and the anti-ageing effects of this gas.…”

Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway

“…We propose that although a transient increase in H 2 S production induces an acute response, which is consistent with its cytoprotective effects, continuous exposure results in a persistent increase in eIF2␣-P levels but is tolerated in cells due to the presence of an efficient H 2 S oxidation pathway present in mitochondria. Consistent with this model, disruption of the first sulfide oxidation pathway enzyme in Caenorhabditis elegans leads to death upon H 2 S exposure resulting from both ER and mitochondrial stress (54).…”