Hydrogen sulfide stimulates lipid biogenesis from glutamine that is dependent on the mitochondrial NAD(P)H pool

Sebastian Carballal,Victor Vitvitsky,Roshan Kumar,David A Hanna,Marouane Libiad,Aditi Gupta,Jace W Jones,Ruma Banerjee

doi:10.1016/j.jbc.2021.100950

Sebastian Carballal, Victor Vitvitsky + Show 6 more

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https://doi.org/10.1016/j.jbc.2021.100950

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Mammalian cells synthesize H2S from sulfur-containing amino acids and are also exposed to exogenous sources of this signaling molecule, notably from gut microbes. As an inhibitor of complex IV in the electron transport chain, H2S can have a profound impact on metabolism, suggesting the hypothesis that metabolic reprogramming is a primary mechanism by which H2S signals. In this study, we report that H2S increases lipogenesis in many cell types, using carbon derived from glutamine rather than from glucose. H2S-stimulated lipid synthesis is sensitive to the mitochondrial NAD(P)H pools and is enabled by reductive carboxylation of α-ketoglutarate. Lipidomics analysis revealed that H2S elicits time-dependent changes across several lipid classes, e.g., upregulating triglycerides while downregulating phosphatidylcholine. Direct analysis of triglyceride concentration revealed that H2S induces a net increase in the size of this lipid pool. These results provide a mechanistic framework for understanding the effects of H2S on increasing lipid droplets in adipocytes and population studies that have pointed to a positive correlation between cysteine (a substrate for H2S synthesis) and fat mass.

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Complex IV is a bona fide cellular target of H2S, explaining its long-known toxicity as an environmental poison [5]
We report that H2S stimulates lipid synthesis from glutamine but not glucose, and that this response is seen across various malignant and nonmalignant cell lines
We examined the effect of sulfide on lipid biogenesis from [U-14C]-glucose or [U-14C]-glutamine in nonmalignant human colonic epithelial cell (HCEC) and malignant HT29 colorectal carcinoma cells (Fig. 1)

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Introduction

Complex IV is a bona fide cellular target of H2S, explaining its long-known toxicity as an environmental poison [5]. Metabolic flux from glutamine to lipids is sensitive to mitochondrial but not cytoplasmic NAD(P)H and is correlated with this pool affecting sulfide-stimulated oxygen consumption kinetics. Sulfide elicited a significant increase in radiolabel incorporation from glutamine into lipids in control HT29scr cells (transfected with a scrambled sequence), which was dependent on the concentration of sulfide added (Fig. 1D).

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