PMID- 36112670 OWN - NLM STAT- MEDLINE DCOM- 20230321 LR - 20230322 IS - 1557-7716 (Electronic) IS - 1523-0864 (Print) IS - 1523-0864 (Linking) VI - 38 IP - 7-9 DP - 2023 Mar TI - Nitric Oxide Derived from Cytoglobin-Deficient Hepatic Stellate Cells Causes Suppression of Cytochrome c Oxidase Activity in Hepatocytes. PG - 463-479 LID - 10.1089/ars.2021.0279 [doi] AB - Aims: Cell-cell interactions between hepatocytes (Hep) 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 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 nitric oxide (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 the neighboring Hep 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. Its inhibitory action toward 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 the 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 Hep dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO. Antioxid. Redox Signal. 38, 463-479. FAU - Okina, Yoshinori AU - Okina Y AUID- ORCID: 0000-0002-9306-2176 AD - Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Sato-Matsubara, Misako AU - Sato-Matsubara M AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Kido, Yasutoshi AU - Kido Y AD - Department of Virology and Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Urushima, Hayato AU - Urushima H AD - Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Daikoku, Atsuko AU - Daikoku A AD - Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Kadono, Chiho AU - Kadono C AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Nakagama, Yu AU - Nakagama Y AD - Department of Virology and Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Nitahara, Yuko AU - Nitahara Y AD - Department of Virology and Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Hoang, Truong Huu AU - Hoang TH AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Thuy, Le Thi Thanh AU - Thuy LTT AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Matsubara, Tsutomu AU - Matsubara T AD - Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Ohtani, Naoko AU - Ohtani N AD - Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Ikeda, Kazuo AU - Ikeda K AD - Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. FAU - Yoshizato, Katsutoshi AU - Yoshizato K AD - Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. AD - BioIntegrence Co., Ltd., Osaka, Japan. FAU - Kawada, Norifumi AU - Kawada N AD - Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Antioxid Redox Signal JT - Antioxidants & redox signaling JID - 100888899 RN - 0 (Cytoglobin) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.9.3.1 (Electron Transport Complex IV) RN - 9004-22-2 (Globins) SB - IM MH - Mice MH - Animals MH - Cytoglobin/metabolism MH - *Hepatic Stellate Cells/metabolism MH - *Nitric Oxide/metabolism MH - Electron Transport Complex IV/metabolism MH - Globins MH - Hepatocytes/metabolism PMC - PMC10025843 OTO - NOTNLM OT - cell-cell interaction OT - globin OT - liver OT - mitochondrial complex OT - superoxide COIS- All authors declare that they have no financial conflicts of interest to disclose. EDAT- 2022/09/17 06:00 MHDA- 2023/03/22 06:00 PMCR- 2023/03/16 CRDT- 2022/09/16 14:03 PHST- 2022/09/17 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2022/09/16 14:03 [entrez] PHST- 2023/03/16 00:00 [pmc-release] AID - 10.1089/ars.2021.0279 [pii] AID - 10.1089/ars.2021.0279 [doi] PST - ppublish SO - Antioxid Redox Signal. 2023 Mar;38(7-9):463-479. doi: 10.1089/ars.2021.0279.