Work

A redox cycle with complex II promotes sulfide quinone oxidoreductase dependent H 2 S oxidation

Year: 2021

Type: preprint

Abstract: The dueling roles of H 2 S 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 H 2 S oxidation pathway and uses coenzyme Q (CoQ) as an electron acceptor. However, complex IV poisoning by H 2 S inhibits complex III-dependent recycling of CoQH 2 , which is needed to sustain H 2 S 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 H 2 S treated cells, which accumulate succinate. Complex II knockdown decreases the efficiency of H 2 S clearance and increases recovery time to the basal respiration rate in H 2 S 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 H 2 S, decreases serum, urine, and fecal thiosulfate, a product of H 2 S oxidation. Our study identifies a metabolic reprogramming response to H 2 S that furnishes fumarate as an alternate electron acceptor and supports H 2 S oxidation independent of complex IV activity. Complex II-linked redox cycling of SQOR has important implications for gut H 2 S metabolism as colonocytes are routinely exposed to high concentrations of this gas derived from the microbiota. One Sentence Summary Reversal of complex II sustains and prioritizes H 2 S oxidation when respiration is poisoned.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2021.09.08.459449