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Proteomic response to cytotoxicity of methylglyoxall

ABSTRACT: Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. MG is increased to cytotoxic levels by clinical anticancer drugs, contributing to their mechanism of action. We investigated the role of the proteomic response to MG in mediating cytotoxicity. The proteomic response to MG-induced cytotoxicity was explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. MG induced decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. We conclude that MG-mediated cytotoxicity targets the spliceosome.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Kidney Cancer

SUBMITTER: Paul Thornalley

LAB HEAD: Paul J Thornalley

PROVIDER: PXD029315 | Pride | 2021-11-02

REPOSITORIES: Pride

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			Action	DRS
	MS18-194_MC1.dat	Other
	MS18-194_MC2.dat	Other
	MS18-194_MC3.dat	Other
	MS18-194_MIMC1.dat	Other
	MS18-194_MIMC2.dat	Other

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Project description:Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

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