論文

国際誌
2022年9月16日

Nitric oxide derived from cytoglobin-deficient hepatic stellate cells causes suppression of cytochrome c oxidase activity in hepatocytes.

Antioxidants & redox signaling
  • Yoshinori Okina
  • Misako Sato-Matsubara
  • Yasutoshi Kido
  • Hayato Urushima
  • Atsuko Daikoku
  • Chiho Kadono
  • Yu Nakagama
  • Yuko Nitahara
  • Truong Huu Hoang
  • Le Thi Thanh Thuy
  • Tsutomu Matsubara
  • Naoko Ohtani
  • Kazuo Ikeda
  • Katsutoshi Yoshizato
  • Norifumi Kawada
  • 全て表示

38
7-9
開始ページ
463
終了ページ
479
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1089/ars.2021.0279

AIMS: Cell-cell interactions between hepatocytes and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes hepatocyte (Hep) dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of NO. Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. RESULTS: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into neighboring hepatocytes to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. It's inhibitory action towards CcO specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo. INNOVATION AND CONCLUSION: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring hepatocyte dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO.

リンク情報
DOI
https://doi.org/10.1089/ars.2021.0279
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/36112670
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025843
ID情報
  • DOI : 10.1089/ars.2021.0279
  • PubMed ID : 36112670
  • PubMed Central 記事ID : PMC10025843

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