A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation

Roshan Kumar,Aaron P Landry,Arkajit Guha,Victor Vitvitsky,Ho Joon Lee,Keisuke Seike,Pavan Reddy,Costas A Lyssiotis,Ruma Banerjee

doi:10.1016/j.jbc.2021.101435

Roshan Kumar, Aaron P Landry + Show 7 more

Open Access

https://doi.org/10.1016/j.jbc.2021.101435

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Abstract

The dual roles of H2S as an endogenously synthesized respiratory substrate and as a toxin raise questions as to how it is cleared when the electron transport chain is inhibited. Sulfide quinone oxidoreductase (SQOR) catalyzes the first step in the mitochondrial H2S oxidation pathway, using CoQ as an electron acceptor, and connects to the electron transport chain at the level of complex III. We have discovered that at high H2S concentrations, which are known to inhibit complex IV, a new redox cycle is established between SQOR and complex II, operating in reverse. Under these conditions, the purine nucleotide cycle and the malate aspartate shuttle furnish fumarate, which supports complex II reversal and leads to succinate accumulation. Complex II knockdown in colonocytes decreases the efficiency of H2S clearance while targeted knockout of complex II in intestinal epithelial cells significantly decreases the levels of thiosulfate, a biomarker of H2S oxidation, to approximately one-third of the values seen in serum and urine samples from control mice. These data establish the physiological relevance of this newly discovered redox circuitry between SQOR and complex II for prioritizing H2S oxidation and reveal the quantitatively significant contribution of intestinal epithelial cells to systemic H2S metabolism.

Highlights

The dual roles of H2S as an endogenously synthesized respiratory substrate and as a toxin raise questions as to how it is cleared when the electron transport chain is inhibited
We examined whether O2 can serve an alternate electron acceptor for Sulfide quinone oxidoreductase (SQOR) since complex IV poisoning by H2S should not restrict O2 availability (Fig. S1A)
We found that when nanodisc-embedded SQOR [27] was reduced in the presence of sulfide and sulfite but in the absence of coenzyme Q (CoQ), O2 consumption was stimulated (Fig. S1B)

Summary

Introduction

The dual roles of H2S as an endogenously synthesized respiratory substrate and as a toxin raise questions as to how it is cleared when the electron transport chain is inhibited. Sulfide quinone oxidoreductase (SQOR) catalyzes the first step in the mitochondrial H2S oxidation pathway, using CoQ as an electron acceptor, and connects to the electron transport chain at the level of complex III. Complex II knockdown in colonocytes decreases the efficiency of H2S clearance while targeted knockout of complex II in intestinal epithelial cells significantly decreases the levels of thiosulfate, a biomarker of H2S oxidation, to approximately one-third of the values seen in serum and urine samples from control mice These data establish the physiological relevance of this newly discovered redox circuitry between SQOR and complex II for prioritizing H2S oxidation and reveal the quantitatively significant contribution of intestinal epithelial cells to systemic H2S metabolism. The best characterized cellular effects of H2S are its oxidation via a dedicated mitochondrial pathway [7] or by globins [8–10] and its inhibition of complex IV [11] in the electron transport chain (ETC), leading to respiratory poisoning (Fig. 1A). The observed increase in succinate and decrease in malate at H2S concentrations that inhibit

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Discussion

Conclusion