The re-emerging pathophysiological role of the cystathionine-β-synthase - hydrogen sulfide system in Down syndrome.

Down syndrome (DS) is associated with significant perturbances in many morphological and biochemical features. Cystathionine-β-synthase (CBS) is one of the key mammalian enzymes that is responsible for the biological production of the gaseous transmitter hydrogen sulfide (H S). When H S is overproduced, it can exert detrimental cellular effects, in part due to inhibition of mitochondrial Complex IV activity. An increased expression of CBS and the consequent overproduction of H S are well documented in individuals with DS. Two decades ago, it has been proposed that a toxic overproduction of H S importantly contributes to the metabolic and neurological deficits associated with DS. However, until recently, this hypothesis has not yet been tested experimentally. Recent data generated in human dermal fibroblasts show that DS cells overproduce H S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: This results in the normalization of mitochondrial function in DS cells. H S may also contribute to the cellular dysfunction via several other molecular mechanisms through interactions with various mitochondrial and extramitochondrial molecular targets. The current article provides a historical background of the field, summarizes the recently published data and their potential implications, and outlines potential translational approaches (such as CBS inhibition and H S neutralization) and future experimental studies in this re-emerging field of pathobiochemistry.