While the elevation of H2S production in Down syndrome has subsequently been repeatedly confirmed [90,282], the actual functional role of CBS-derived H2S in the pathogenesis of mitochondrial dysfunction remained untested until 2019, when our group has directly tested the hypothesis by evaluating the effect of CBS silencing (as well as the effect of AOAA, a PLP-dependent enzyme inhibitor with limited selectivity for CBS, see below) on the proliferation, mitochondrial oxygen consumption and Complex IV activity in Down syndrome fibroblasts. The gene discussed is CBS; the disease is Down syndrome.