Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and schizophrenia-like behavioral deficits
Kazuya Toriumi; Stefano Berto; Shin Koike; Noriyoshi Usui; Takashi Dan; Kazuhiro Suzuki; Mitsuhiro Miyashita; Yasue Horiuchi; Akane Yoshikawa; Yuki Sugaya; Takaki Watanabe; Mai Asakura; Masanobu Kano; Yuki Ogasawara; Toshio Miyata; Masanari Itokawa; Genevieve Konopka; Makoto Arai
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Methylglyoxal (MG) is a cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and a scavenge system by vitamin B6 (VB6). We know a population of patients with schizophrenia impaired MG detoxification systems. However, the molecular mechanism connecting them remains poorly understood. We created a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice VB6-lacking diets (KO/VB6(-)) and evaluated the effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice accumulated MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice. We 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.Competing Interest StatementThe authors have declared no competing interest.View Full Text
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