Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex

Kazuya Toriumi, Stefano Berto, Shin Koike, Noriyoshi Usui, Takashi Dan, Kazuhiro Suzuki, Mitsuhiro Miyashita, Yasue Horiuchi, Akane Yoshikawa, Mai Asakura, Kenichiro Nagahama, Hsiao Chun Lin, Yuki Sugaya, Takaki Watanabe, Masanobu Kano, Yuki Ogasawara, Toshio Miyata, Masanari Itokawa, Genevieve Konopka, Makoto Arai

Research output: Contribution to journalArticlepeer-review

Abstract

Methylglyoxal (MG) is a reactive and 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 GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(−)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(−) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and 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-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(−) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.

Original languageEnglish
Article number102057
JournalRedox Biology
Volume45
DOIs
Publication statusPublished - 2021 Sep
Externally publishedYes

Keywords

  • Glyoxalase 1
  • Methylglyoxal
  • Mitochondria
  • Oxidative stress
  • Schizophrenia
  • Vitamin B6

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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