The Biological Consequences of the Knockout of Genes Involved in the Synthesis and Metabolism of HS in .

Here, we describe the effects of double knockout (KO) of the and genes, which are responsible for HS synthesis through the transsulfuration pathway, and KO of the sulfurtransferase gene () in females. The analysis of HS production in flies showed minimal levels in the double- and triple-knockout strains. The double- (; ) and triple- (; ; ) KO flies exhibited a shortened lifespan and reduced fecundity, and showed dramatic changes in Malpighian tubule morphology. The transcriptomic analysis revealed a profound increase in the expression levels of several genes involved in excretory system function in the double-KO and especially the triple-KO flies. Importantly, major groups of differentially expressed genes (DEGs) in the whole bodies of females and ovaries of KO strains included genes responsible for detoxification, reproduction, mitochondrial activity, excretion, cell migration, and muscle system function. The reduced fecundity observed in the double- and triple-KO flies correlated with pronounced changes in the ovarian transcriptome. At the same time, the single knockout of increased the flies' fecundity and lifespan. Our experiments exploring unique strains with KO of major HS-related genes revealed several new pathways controlled by this ancient adaptogenic system that is involved in various human diseases and aging.