Implication of Homocysteine in protein quality control processes

Abstract Homocysteine (Hcy) is a key metabolite generated during methionine metabolism. The elevated levels of Hcy in the blood is reffered as hyperhomocystenimeia (HHcy). The HHcy is caused by imapired metabolism/deficiency of either folate, or B12 or defects in Hcy metabolism. Accumulating evidence suggests that HHcy is associated with cardiovascular and brain diseases including atherosclerosis, endothelial injury, and stroke etc. Vitamin B12 (cobalamin; B12) is a water-soluble vitamin essential for two metabolic reactions. It acts as a co-factor for methionine synthase and L-methylmalonyl-CoA mutase. Besides, it is also vital for DNA synthesis and maturation of RBC. Deficiency of B12 is associated with haematological and neurological disorders. Hyperhomocysteinemia (HHcy)-induced toxicity is thought to be mediated by accumulation of Hcy and its metabolites, homocysteinylated proteins. Cellular protein quality control (PQC) is essential for the maintenance of proteome integrity, and cell viability and its failure contributes to the development of multiple diseases. Chaperones, unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy are analogous strategies of PQC that maintain cellular proteome integrity. Recently, multiple studies reported that HHcy responsible for perturbation of PQC by reducing chaperone levels, activating UPR, and impairing autophagy. Besides, HHcy also induce cytotoxicity, inflammation, protein aggregation and apoptosis. It has been shown that some of the factors including altered SIRT1-HSF1 axis and irreversible homocysteinylation of proteins responsible for folate and/or B12 deficiency or HHcy-induced impairment of PQC. Therefore, this review highlights the current understanding of HHcy in the impairment of cellular PQC and their pathophysiological and clinical consequences, epigenomic changes, therapeutic implications of B12, and chemical chaperones based on cell culture and experimental animal models.