Biomedical research institute
    You are here: Home / PhD program / Thesis defense / Importance of mitochondrial hydrogen sulfide oxidation in liver pathophysiology

    Importance of mitochondrial hydrogen sulfide oxidation in liver pathophysiology

    Inês Mateus


    Monday 3th of May 2021 at 2 pm

    Institut Cochin
    Rosalind Franklin room 
    Videoconference for the public

    Hydrogen sulfide (H2S) is the third gasotransmitter described in mammals. Colourless and water-soluble, H2S is a highly effective inhibitor of mitochondrial cytochrome c oxidase when present at high concentrations. However, when present at low concentrations, H2S can act as an inorganic energetic substrate for mammalian mitochondria. To oxidize H2S, mitochondria need the sulfide oxidizing unit (SOU), a set of three specific enzymes: sulfide quinone reductase (SQR), dioxygenase (ETHE1) and thiosulfate sulfurtransferase (TST). Liver metabolism, finely regulated by hormones and nutrients, is central to energy homeostasis, and liver metabolic inflexibility is known to be associated with several metabolic diseases, such as Non-Alcoholic Fatty Liver Disease (NAFLD). The unique position of this organ makes it likely to be exposed to high levels of H2S coming from both exogenous (gastrointestinal tract) and endogenous (metabolism of sulfur-containing amino acids) sources. Recently, impaired liver H2S biosynthesis has been reported in animal models of NAFLD, and in vivo supplementation of H2S donors prevented the further escalation of the illness into steatohepatitis (NASH). Almost all studies exploring the hepatic pathological relevance of H2S are usually focused on H2S biosynthesis pathway and/or using exogenous donors. As intrahepatic H2S levels can also be controlled by its mitochondrial oxidation, the objectives of my PhD were to investigate the pathophysiological importance of this pathway in liver metabolism and in the development of NAFLD.

    First, we showed that, physiologically, the liver nutritional status regulates hepatic mitochondrial H2S oxidation capacity and SQR protein expression, both being downregulated by fasting while overnight refeeding abolished the fasting inhibitory effect. Adenovirus-mediated overexpression of human SQR in mouse liver clearly demonstrated that SQR is the key regulatory enzyme of mitochondrial H2S oxidation. Enhancing this pathway i) increased in vivo glucose tolerance and liver insulin signalling, ii) stimulated glucose metabolism in primary cultures of mouse hepatocytes (13C-glucose fluoxomics), and iii) decreased liver fatty acid oxidation capacity. Second, when exploring the context of NAFLD, we observed that liver mitochondrial H2S oxidation capacity was downregulated in mice fed high fat/high sucrose (HF/HS) diet (NAFL model) and surprisingly was upregulated in mice fed methionine-choline deficient (MCD) diet (NASH model). In vivo supplementation with sodium thiosulfate (STS), an H2S donor, abrogated the inhibitory effect of HF/HS diet while it had no impact in the NASH model. Additionally, STS supplementation had no effect on body weight, glucose tolerance and insulin sensitivity in the NAFL model, and on liver steatosis in both NAFL and NASH models. However, STS supplementation did have an impact in the composition of gut microbiota. Similarly to the NAFLD mouse models, in morbid obese patients with simple steatosis (NAFL), liver SQR protein expression was found decreased, while in individuals with NASH SQR expression was found increased. Altogether, these studies, which confirmed that SQR is the key rate-limiting enzyme for liver mitochondrial H2S oxidation, clearly demonstrated for the first time that this pathway is finely regulated by the nutritional status of the liver and is altered in animal models of NAFLD and obese NAFLD patients. The novel observation that increasing hepatic mitochondrial H2S oxidation capacity increases hepatic glucose metabolism opens a new door in the field of liver pathophysiology, with this pathway being a potential protective target against the development of liver insulin resistance.