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

Abstract

The dual role 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) is a mitochondrial inner membrane flavoprotein that catalyzes the first step in the H2S oxidation pathway and uses coenzyme Q (CoQ) as an electron acceptor. However, complex IV poisoning by H2S inhibits complex III-dependent recycling of CoQH2, which is needed to sustain H2S oxidation. We have discovered that under these conditions, reversal of complex II activity using fumarate as an electron acceptor, establishes a new redox cycle with SQOR. The purine nucleotide cycle and the malate aspartate shuttle are sources of fumarate in H2S treated cells, which accumulate succinate. Complex II knockdown decreases the efficiency of H2S clearance and increases recovery time to the basal respiration rate in H2S treated cells. In contrast, attenuation of complex I, which is a major competitor for the mitochondrial CoQ pool, has the opposite effects. Targeted knockout of complex II in murine intestinal epithelial cells that are routinely exposed to microbiota derived H2S, decreases serum, urine, and fecal thiosulfate, a product of H2S oxidation. Our study identifies a metabolic reprogramming response to H2S that furnishes fumarate as an alternate electron acceptor and supports H2S oxidation independent of complex IV activity. Complex II-linked redox cycling of SQOR has important implications for gut H2S metabolism as colonocytes are routinely exposed to high concentrations of this gas derived from the microbiota.

From Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology

“…However, at physiologic levels, H 2 S elevates oxygen consumption rates and electron flow through ETC via SQR [ 16 ]. Recent evidence challenges the conventional view that H 2 S only exerts toxic effects in cells; in these conditions where the electron transport chain is obstructed, high levels of H 2 S can continue to undergo oxidation by SQR, leading to a redox cycle with fumarate as the terminal electron acceptor at complex II [ 78 ].…”

“…H 2 S attacks the disulfide bond in SQR, generating a persulfide charge transfer complex. This outer sulfane sulfur is moved to a thiophilic acceptor, such as GSH, safeguarding ETC function from H 2 S [ 75 , 78 , 103 ]. H 2 S orchestrates regulatory pathways in cellular bioenergetics, modulating mitochondrial energy production and promoting glycolysis.…”