Reprogramming of Colonic Cell Metabolism by H₂S

Abstract

Synthesis of H2S by gut microbiota leads to routine colonic cells exposure to this respiratory toxin. Herein we studied the effect of H2S on metabolism and proliferation in human colonic cells in culture at sulfide concentrations up to 300 μM, which represents a physiologically relevant exposure for these cells. H2S caused a marked activation of glycolysis and inhibition of proliferation. Between 5–20 μM H2S the oxygen consumption rate (OCR) was activated, while OCR was inhibited at higher concentrations. A high‐capacity mitochondrial sulfide oxidation pathway housed in colonocytes supports O2‐dependent H2S clearance and the absence of the committing enzyme (sulfide quinone reductase) in the pathway leads to inhibition of OCR even at the lowest H2S concentration that was tested. H2S triggers persulfidation of numerous protein targets that are enriched in energy metabolism pathways. The antiproliferative effect of H2S exposure results from electron acceptor insufficiency that ensues from H2S oxidation activity and inhibition of respiration. Under these conditions, reductive carboxylation of a‐ketoglutarate is enhanced and exogenous uridine and aspartate alleviated H2S‐imposed growth restriction. Overexpression of the sulfide oxidation enzymes in colon cancer tissue and cells confers a growth advantage during H2S exposure compared to non‐malignant cells. These results predict that the stress response in colonocytes triggered by microbial H2S exposure involves metabolic reprogramming to recycle electron acceptors.Support or Funding InformationNIH (GM112455 to R.B.), AACR NextGen Grant for Transformative Cancer Research (17‐20‐01‐LYSS) to C.A.L., UMCCC Core Grant (P30 CA046592) to R.B. and C.A.L.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.