Speaker: Shimin Zhao
Title: Metabolites Deregulation and Human Diseases
Besides being energetic and biosynthetic cues, metabolites are signaling molecules that regulate cell signaling through non-covalent binding or covalent post translational modification to proteins that are functioning in diverse range of signaling pathways. Inhibition of a-ketoglutarate (a-KG) – dependent dioxygenases through decreasing cellular a-KG levels or accumulating a-KG structural analogous metabolites, such as 2-hydroxyglutarate, sucinate and fumarate, by metabolic enzymes mutations alters cancer-associated signaling pathways such as HIF1a pathway and epigenetic functions such as histones and DNA methylation. Moreover, metabolic enzymes mutations that accumulate a-KG analogous that induce hypersuccinylation, which preferentially impairs mitochondria respiration and induces the Warburg effect-like metabolism in cells. This, together with that hypersuccinylation induces apoptosis resistance by overexpressing BCL-2, accounts for the tumorigenicities of a-KG analogous metabolites. Our results highlight role of altered metabolites sensing and provides possibilities of novel cancer treatment approaches through intervening metabolites-protein interactions.