PMID- 32205448
OWN - NLM
STAT- MEDLINE
DCOM- 20201223
LR  - 20240328
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 295
IP  - 19
DP  - 2020 May 8
TI  - A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced 
      mitochondrial poisoning.
PG  - 6357-6371
LID - 10.1074/jbc.RA119.010593 [doi]
AB  - 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 mum) and nitric oxide (100 mum). Both CO and NO 
      inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 mum, 
      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.
CI  - (c) 2020 Rose et al.
FAU - Rose, Jason J
AU  - Rose JJ
AUID- ORCID: 0000-0003-1347-9148
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213 rosejj@upmc.edu.
AD  - Department of Bioengineering, University of Pittsburgh Swanson School of 
      Engineering, Pittsburgh, Pennsylvania 15261.
FAU - Bocian, Kaitlin A
AU  - Bocian KA
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Xu, Qinzi
AU  - Xu Q
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Wang, Ling
AU  - Wang L
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - DeMartino, Anthony W
AU  - DeMartino AW
AUID- ORCID: 0000-0001-5303-5758
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Chen, Xiukai
AU  - Chen X
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Corey, Catherine G
AU  - Corey CG
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania 15213.
FAU - Guimaraes, Danielle A
AU  - Guimaraes DA
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania 15213.
FAU - Azarov, Ivan
AU  - Azarov I
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Huang, Xueyin N
AU  - Huang XN
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Tong, Qin
AU  - Tong Q
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Guo, Lanping
AU  - Guo L
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Nouraie, Mehdi
AU  - Nouraie M
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - McTiernan, Charles F
AU  - McTiernan CF
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - O'Donnell, Christopher P
AU  - O'Donnell CP
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
FAU - Tejero, Jesus
AU  - Tejero J
AUID- ORCID: 0000-0003-3245-9978
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
AD  - Department of Bioengineering, University of Pittsburgh Swanson School of 
      Engineering, Pittsburgh, Pennsylvania 15261.
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania 15213.
FAU - Shiva, Sruti
AU  - Shiva S
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania 15213.
FAU - Gladwin, Mark T
AU  - Gladwin MT
AD  - Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, 
      Pennsylvania 15213.
AD  - Department of Bioengineering, University of Pittsburgh Swanson School of 
      Engineering, Pittsburgh, Pennsylvania 15261.
LA  - eng
GR  - R01 GM113816/GM/NIGMS NIH HHS/United States
GR  - R21 ES027390/ES/NIEHS NIH HHS/United States
GR  - P01 HL103455/HL/NHLBI NIH HHS/United States
GR  - F32 HL132418/HL/NHLBI NIH HHS/United States
GR  - R01 HL098032/HL/NHLBI NIH HHS/United States
GR  - R01 HL125886/HL/NHLBI NIH HHS/United States
GR  - T32 HL007563/HL/NHLBI NIH HHS/United States
GR  - T32 HL110849/HL/NHLBI NIH HHS/United States
GR  - K08 HL136857/HL/NHLBI NIH HHS/United States
GR  - R01 HL111706/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200323
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (NGB protein, human)
RN  - 0 (Neuroglobin)
RN  - 0 (Ngb protein, mouse)
RN  - 0 (Ngb protein, rat)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 7U1EE4V452 (Carbon Monoxide)
RN  - 9061-29-4 (Carboxyhemoglobin)
SB  - IM
MH  - Animals
MH  - Carbon Monoxide/*toxicity
MH  - Carbon Monoxide Poisoning/*metabolism/pathology
MH  - Carboxyhemoglobin/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mitochondria, Heart/*metabolism/pathology
MH  - Mitochondria, Liver/*metabolism/pathology
MH  - Neuroglobin/*metabolism
MH  - Nitric Oxide/metabolism/pharmacology
MH  - Oxygen Consumption/drug effects
MH  - Rats
PMC - PMC7212636
OTO - NOTNLM
OT  - CO poisoning
OT  - antidotes
OT  - carbon monoxide
OT  - hemoglobin
OT  - hypoxia
OT  - hypoxia-inducible factor (HIF)
OT  - medical toxicology
OT  - mitochondria
OT  - mitochondrial disease
OT  - mitochondrial respiratory chain complex
OT  - neuroglobin
OT  - nitric oxide
COIS- J. J. R., L. W., C. F. M., J. T., and M. T. G. are shareholders in Globin 
      Solutions. J. J. R., Q. X., A. W. D., J. T., and M. T. G. are coinventors of 
      provisional, pending, and granted patents for the use of recombinant neuroglobin 
      and other heme-based molecules as antidotes for carbon monoxide poisoning. J. J. 
      R. and J. T. are officers and directors of Globin Solutions, Inc. M. T. G. is a 
      director and advisor of Globin Solutions, Inc., which has licensed this 
      technology and had an option to technology directed at using hydroxycobalamin for 
      carbon monoxide poisoning from Virginia Commonwealth University that has expired. 
      M. T. G. is a coinventor on patents directed to the use of nitrite salts in 
      cardiovascular diseases licensed and exclusively optioned to Globin Solutions, 
      Inc., which has a sponsored research agreement with the University of Pittsburgh 
      aimed at developing carbon monoxide poisoning antidotes into therapeutics that 
      did not support the research contained in this grant that partially supports the 
      efforts of M. T. G., J. T., Q. X., X. C., Q. T., and X. N. H., M. T. G. is a 
      coinvestigator in a research collaboration with Bayer Pharmaceuticals to evaluate 
      riociguate as a treatment for patients with sickle cell disease. The financial 
      conflicts of interest of J. J. R., J. T., Q. X., L. W., A. W. D., C. F. M., and 
      M. T. G. were managed by the University of Pittsburgh Conflict of Interest 
      Committee and a data stewardship committee
EDAT- 2020/03/25 06:00
MHDA- 2020/12/29 06:00
PMCR- 2021/05/08
CRDT- 2020/03/25 06:00
PHST- 2019/08/09 00:00 [received]
PHST- 2020/03/16 00:00 [revised]
PHST- 2020/03/25 06:00 [pubmed]
PHST- 2020/12/29 06:00 [medline]
PHST- 2020/03/25 06:00 [entrez]
PHST- 2021/05/08 00:00 [pmc-release]
AID - S0021-9258(17)48501-2 [pii]
AID - RA119.010593 [pii]
AID - 10.1074/jbc.RA119.010593 [doi]
PST - ppublish
SO  - J Biol Chem. 2020 May 8;295(19):6357-6371. doi: 10.1074/jbc.RA119.010593. Epub 
      2020 Mar 23.