Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons

Tomonori Hara, Manabu Toyoshima, Yasuko Hisano, Shabeesh Balan, Yoshimi Iwayama, Harumi Aono, Yushi Futamura, Hiroyuki Osada, Yuji Owada, Takeo Yoshikawa*

*この研究の対応する著者

研究成果: Article査読

8 被引用数 (Scopus)

抄録

Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.

本文言語English
論文番号275
ジャーナルTranslational Psychiatry
11
1
DOI
出版ステータスPublished - 2021 6月
外部発表はい

ASJC Scopus subject areas

  • 精神医学および精神衛生
  • 細胞および分子神経科学
  • 生物学的精神医学

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