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大学・研究所にある論文を検索できる 「Glyoxalase Iの欠損とカルボニルストレスの外的な負荷はヒトiPS細胞とヒトiPS細胞由来神経細胞でミトコンドリア機能障害を起こす」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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Glyoxalase Iの欠損とカルボニルストレスの外的な負荷はヒトiPS細胞とヒトiPS細胞由来神経細胞でミトコンドリア機能障害を起こす

原 伯徳 東北大学

2022.03.25

概要

酸化ストレスの一種であるカルボニルストレスは統合失調症の病態生理に関与することが臨床的に示唆されている。しかし、そのメカニズムの多くは未だ知られていない。そのため、カルボニルストレスに対する主要な代謝酵素である Glyoxalase I(GLO1)に着目し、human induced pluripotent stem cells(hiPSCs)において GLO1 遺伝子を欠損させてその影響を調べた。その結果、GLO1 の欠損はカルボニルストレスの負荷に対する脆弱性を増大させ、細胞に異常な表現型をもたらすことが明らかになった。具体的には、反応性が高いカルボニル化合物である methylglyoxal(MGO)の負荷に対し、GLO1-knock out(KO) hiPSCs は野生型細胞に比べ caspase-3 の活性増加と細胞生存率の低下を呈した。GLO1-KO hiPSCs 由来神経細胞では MGO の負荷により神経突起の伸長と細胞遊走が低下した。細胞障害の原因を検索するために MGO の誘導体である methylglyoxal-derived hydroimidazolone(MG-H1)に対する抗体を用いて検討したところ、ミトコンドリアに MG-H1 の集積を認めた。機能レベルの評価では、MGO の負荷により GLO1- KO hiPSCs 及び GLO1-KO hiPSCs 由来神経細胞でミトコンドリアの膜電位低下とミトコンドリア呼吸の低下がみられた。上記より、カルボニルストレスによる細胞障害にはミトコンドリア機能不全が介在していることが示唆された。また、カルボニル化合物の捕捉剤である pyridoxamine を用いることにより MGO への脆弱性を一部軽減させることが可能であった。これらの知見は、カルボニルストレスないし酸化ストレスの関与する統合失調症を含む諸病態への治療的介入の開発に向けた重要な所見であると思われる。

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