Ricerc@Sapienza

Hydrogen sulfide (H2S) plays a key signalling role in human physiology. Deregulation of H2S production and/or its downstream actions have been implicated in the pathophysiology of several diseases. Therefore, understanding how the metabolism of this gasotransmitter is altered either under pathological conditions or following pharmacological administrations is crucial to identify novel drug targets for therapeutic interventions and evaluate the efficacy of treatments.

Endogenously synthesized by cytosolic enzymes, H2S is oxidatively catabolized in the mitochondrion, where H2S-derived electrons are transferred by sulfide:quinone oxidoreductase (SQR) to coenzyme Q. Relevant to human pathophysiology, low concentrations of coenzyme Q has been observed in Ataxia oculomotor apraxia- type 1 (AOA1), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding the DNA strand-break repair protein aprataxin (APTX). APTX function has been associated with both mitochondrial DNA repair and the transcriptional regulation of mitochondrial proteins. Hence, defects in APTX expression and/or function results in organelle dysfunction and oxidative stress.
Our working hypothesis is that the sulphide oxidation pathway is impaired in AOA1 due to secondary coenzyme Q deficiency, and its impairment contributes to the pathogenesis of the disease.

The present project aims at studying the metabolism of H2S either in APTX deficient cell models of AOA1 to understand its role in cellular dysfunction, and in colon cancer cells to comprehend the controversial effect of the N-acetylcysteine in cancer therapy, an antioxidant recently suggested to be involved in sulphide metabolism.
Research will focus on the quantification of the expression level and of the activity of enzymes involved in H2S synthesis and degradation as well as on the determination of the redox state and the bioenergetic parameters of the cells.