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 (H₂S). When H₂S 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 H₂S are well documented in individuals with DS. Two decades ago, it has been proposed that a toxic overproduction of H₂S 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 H₂S, 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. H₂S 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 H₂S neutralization) and future experimental studies in this re‐emerging field of pathobiochemistry.

中文翻译：

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半胱氨酸-β-合酶-硫化氢系统在唐氏综合症中的重新出现的病理生理作用。

唐氏综合症（DS）与许多形态和生化特征的明显扰动有关。胱硫醚-β-合酶（CBS）是重要的哺乳动物酶之一，负责生物产生气态递质硫化氢（H ₂ S）。当H ₂ S过量产生时，它可能发挥有害的细胞作用，部分原因是抑制了线粒体复合物IV的活性。在患有DS的个体中，CBS的表达增加以及随之而来的H ₂ S的过量生产被充分证明。二十年前，有人提出H ₂的有毒过量生产S重要地促进了与DS相关的代谢和神经功能缺陷。但是，直到最近，这一假设还没有通过实验得到检验。人类皮肤成纤维细胞中产生的最新数据表明，DS细胞过量产生H ₂ S，从而抑制线粒体复合物IV活性并削弱线粒体耗氧量和ATP生成。CBS的治疗性抑制作用可解除复合物IV的强直性（和可逆性）抑制作用：这导致DS细胞中线粒体功能正常化。高₂S还可能通过其他几种分子机制，通过与各种线粒体和线粒体分子靶标的相互作用，促进细胞功能障碍。本文提供了该领域的历史背景，总结了最近发表的数据及其潜在影响，并概述了在病理生物化学这个新兴领域的潜在翻译方法（例如CBS抑制和H ₂ S中和）和未来的实验研究。