Hydrogen sulfide perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cells

Abstract

Unlike most other tissues, the colon epithelium is exposed to high levels of H 2 S derived from gut microbial metabolism. H 2 S is a signaling molecule that modulates various physiological effects. It is also a respiratory toxin that inhibits complex IV in the electron transfer chain (ETC). Colon epithelial cells are adapted to high environmental H 2 S exposure as they harbor an efficient mitochondrial H 2 S oxidation pathway, which is dedicated to its disposal. Herein, we report that the sulfide oxidation pathway enzymes are apically localized in human colonic crypts at the host-microbiome interface, but that the normal apical-to-crypt gradient is lost in colorectal cancer epithelium. We found that sulfide quinone oxidoreductase (SQR), which catalyzes the committing step in the mitochondrial sulfide oxidation pathway and couples to complex III, is a critical respiratory shield against H 2 S poisoning. H 2 S at concentrations <20 M stimulated the oxygen consumption rate in colon epithelial cells, but, when SQR expression was ablated, H 2 S concentrations as low as 5 M poisoned cells. Mitochondrial H 2 S oxidation altered cellular bioenergetics, inducing a reductive shift in the NAD ؉ /NADH redox couple. The consequent electron acceptor insufficiency caused uridine and aspartate deficiency and enhanced glutamine-dependent reductive carboxylation. The metabolomic signature of this H 2 S-induced stress response mapped, in part, to redox-sensitive nodes in central carbon metabolism. Colorectal cancer tissues and cell lines appeared to counter the growth-restricting effects of H 2 S by overexpressing sulfide oxidation pathway enzymes. Our findings reveal an alternative mechanism for H 2 S signaling, arising from alterations in mitochondrial bioenergetics that drive metabolic reprogramming

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

“…This niche is also home to sulfate-reducing bacteria that are responsible for significant production of H 2 S (73,74), in addition to the reduction of tetrathionate and thiosulfate to H 2 S that also occurs in the gut (75). H 2 S produced by the gut microbiota is oxidized by gastrointestinal epithelial cells to thiosulfate and tetrathionate (76,77); these molecules in turn are utilized by the microbiota as electron acceptors, resulting in a symbiotic relationship derived from interconversion of sulfur species (Fig. 3A) (72).…”

“…Of these tools, the WSP and SSP series of fluorescent molecules that detect H 2 S and sulfane sulfur, respectively, are most commonly used in both mammalian and bacterial cells (Fig. 6C) (24,77). When used by themselves, these probes cannot be used to perform absolute quantitation of H 2 S/RSS; however, one group recently coupled SSP4 cell labeling with MS to quantitate sulfane sulfur, thus establishing the possibility of making these optical methods quantitative (171).…”

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

“…In red blood cells (and other tissues, such as spleen, heart, lung, muscle, bone marrow) it is likely most often produced nonenzymatically, utilizing cysteine [43]. H 2 S can signal through four mechanisms [44]: (1) reduction and/or direct binding of metalloprotein heme centers; (2) antioxidant action through reactive oxygen species (ROS)/reactive nitrogen species scavenging; (3) post-translational modification of proteins by addition of a thiol (-SH) group onto reactive cysteine residues, so-called persulfidation (or S-sulfhydration), and formation of polysulfides [45,46]; (4) a postulated redox-linked metabolic reprogramming mechanism through sulfide quinone oxidoreductase in mitochondria [47].…”

The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis

“…Pharmacological inhibition of CBS in these colon cancer cell lines reduced cell proliferation, invasion, and migration along with suppressed glycolysis and mitochondrial function, suggesting that H 2 S can facilitate tumor growth ( Szabo et al., 2013 ). In another study, increased levels of H 2 S in colonocytes activated the sulfide oxidation pathway and inhibited the ETC resulting in reductive stress as indicated by a reduced NAD + /NADH redox ratio ( Libiad et al., 2019 ).…”