Biology subjects

Vitvitsky, V.

Publications and source records attributed to Vitvitsky, V..

4 recordsLinked to original sources

bioRxiv2025

Gut sulfide metabolism modulates behavior and brain bioenergetics

The host-microbiome interface is rich in metabolite exchanges and exquisitely sensitive to diet. Hydrogen sulfide (H2S) is present at high concentrations at this interface, and is a product of both microbial and host metabolism. The mitochondrial enzyme, sulfide quinone oxidoreductase (SQOR), couples H2S detoxification to oxidative phosphorylation; its inherited deficiency presents as Leigh disease. Since an estimated two thirds of systemic H2S metabolism originates in gut, it raises questions as to whether impaired sulfide clearance in this compartment contributes to disease, and whether it can be modulated by dietary sulfur content. In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells, perturbs colon bioenergetics that is reversed by antibiotics, establishing a significant local contribution of microbial H2S to host physiology. We also find that a 2.5-fold higher methionine intake, mimicking the difference between animal and plant proteins, synergized with intestinal SQOR deficiency to adversely impact colon architecture and alter microbiome composition. In serum, increased thiosulfate, a biomarker of H2S oxidation, revealed that intestinal SQOR deficiency combined with high dietary methionine, affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies. The mice exhibited lower exploratory locomotor activity while brain MRI revealed an atypical reduction in ventricular volume, which was associated with lower aquaporin 1 that is important for cerebrospinal fluid secretion. Our study reveals the dynamic interaction between dietary sulfur intake and sulfide metabolism at the host-microbe interface, impacting gut health, and the potential for lower dietary methionine intake to modulate pathology. Significance StatementThe host-microbiome interface is rich in metabolite-based communications that are modulated by diet. Hydrogen sulfide (H2S), which is a respiratory poison at high concentrations, is enriched at this interface, and is detoxified by the host enzyme, sulfide quinone oxidoreductase (SQOR). Given the quantitatively significant contribution of gut to systemic H2S metabolism, we examined how SQOR deficiency restricted to murine intestinal epithelial cells, interacts with high dietary methionine, designed to approximate the difference between plant versus animal protein levels, to affect local and global bioenergetics. Our study revealed profound short- and long-range impacts resulting from the synergy between decreased H2S clearance capacity in gut and high dietary methionine on global energy metabolism, brain pathology, and behavior.

biochemistry↗

bioRxiv2023

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Angiogenic programming in the vascular endothelium is a tightly regulated process to maintain tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Herein, we report that hypoxic upregulation of NO synthesis in endothelial cells reprograms the transsulfuration pathway and increases H2S biogenesis. Furthermore, H2S oxidation by mitochondrial sulfide quinone oxidoreductase (SQOR) rather than downstream persulfides, synergizes with hypoxia to induce a reductive shift, limiting endothelial cell proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body WBCreSQORfl/fl knockout mice exhibit lower mass and reduced angiogenesis compared to SQORfl/fl controls. WBCreSQORfl/fl mice also exhibit reduced muscle angiogenesis following femoral artery ligation, compared to controls. Collectively, our data reveal the molecular intersections between H2S, O2 and NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization. HighlightsO_LIHypoxic induction of *NO in endothelial cells inhibits CBS and switches CTH reaction specificity C_LIO_LIHypoxic interruption of the canonical transsulfuration pathway promotes H2S synthesis C_LIO_LISynergizing with hypoxia, SQOR deficiency induces a reductive shift in the ETC and restricts proliferation C_LIO_LISQOR KO mice exhibit lower neovascularization in tumor xenograft and hind limb ischemia models C_LI

biochemistry↗

bioRxiv2021

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

The dueling 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) 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. One Sentence SummaryReversal of complex II sustains and prioritizes H2S oxidation when respiration is poisoned.

biochemistry↗

bioRxiv2020

The hepatic compensatory response to elevated systemic sulfide impairs medium chain fat oxidation and promotes diabetes

Impaired hepatic glucose and lipid metabolism are hallmarks of type-2 diabetes. Increased sulfide production from cysteine, or sulfide-donor compounds, may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver-enriched mitochondrial SOP enzyme thiosulfate sulfur-transferase (Tst-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia and fatty liver, despite whole-body insulin-sensitisation. Unexpectedly, hepatic sulfide levels were normal in Tst-/- mice, a result of homeostatic induction of mitochondrial sulfide disposal and glutathione excretion associated with net suppression of protein persulfidation and nuclear respiratory factor-2 target proteins. Proteomic and persulfidomic profiling converged on gluconeogenesis and hepatic lipid metabolism and revealed a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role for TST in hepatic metabolism that raises implications for sulfide-donor strategies in the context of liver function and metabolic disease.

physiology↗