Journal article
A neuroglobin-based high-affinity ligand trap reverses carbon monoxide–induced mitochondrial poisoning
The Journal of biological chemistry, Vol.295(19), pp.6357-6371
05/08/2020
DOI: 10.1074/jbc.RA119.010593
PMCID: PMC7212636
PMID: 32205448
Abstract
Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.
Details
- Title: Subtitle
- A neuroglobin-based high-affinity ligand trap reverses carbon monoxide–induced mitochondrial poisoning
- Creators
- Jason J. Rose - University of PittsburghKaitlin A. Bocian - University of PittsburghQinzi Xu - University of PittsburghLing Wang - University of PittsburghAnthony W. DeMartino - University of PittsburghXiukai Chen - University of PittsburghCatherine G. Corey - University of PittsburghDanielle A. Guimarães - University of PittsburghIvan Azarov - University of PittsburghXueyin N. Huang - University of PittsburghQin Tong - University of PittsburghLanping Guo - University of PittsburghMehdi Nouraie - University of PittsburghCharles F. McTiernan - University of PittsburghChristopher P. O'Donnell - University of PittsburghJesús Tejero - University of PittsburghSruti Shiva - University of PittsburghMark T. Gladwin - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.295(19), pp.6357-6371
- DOI
- 10.1074/jbc.RA119.010593
- PMID
- 32205448
- PMCID
- PMC7212636
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000050, name: HHS | NIH | National Heart, Lung, and Blood Institute, award: F32 HL132418, K08 HL136857, R01 HL111706, R01 HL125886, R01 HL098032, P01 HL103455, T32 HL110849, T32 HL007563, SMARTT Program; DOI: 10.13039/100000057, name: HHS | NIH | National Institute of General Medical Sciences, award: R01 GM113816; DOI: 10.13039/100000066, name: HHS | NIH | National Institute of Environmental Health Sciences, award: R21 ES027390; name: Institute for Transfusion Medicine, award: n/a; name: Hemophilia Center of Western Pennsylvania, award: n/a; name: Parker B. Francis Foundation, award: n/a
- Language
- English
- Date published
- 05/08/2020
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984304718202771
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