Neuroglobin protects nerve cells from apoptosis by inhibiting the intrinsic pathway of cell death.
In the past few years, overwhelming evidence has accrued that a high level of expression of the protein neuroglobin protects neurons in vitro, in animal models, and in humans, against cell death associated with hypoxic and amyloid insult. However, until now, the exact mechanism of neuroglobin's protective action has not been determined. Using cell biology and biochemical approaches we demonstrate that neuroglobin inhibits the intrinsic pathway of apoptosis in vitro and intervenes in activation of pro-caspase 9 by interaction with cytochrome c. Using systems level information of the apoptotic signalling reactions we have developed a quantitative model of neuroglobin inhibition of apoptosis, which simulates neuroglobin blocking of apoptosome formation at a single cell level. Furthermore, this model allows us to explore the effect of neuroglobin in conditions not easily accessible to experimental study. We found that the protection of neurons by neuroglobin is very concentration sensitive. The impact of neuroglobin may arise from both its binding to cytochrome c and its subsequent redox reaction, although the binding alone is sufficient to block pro-caspase 9 activation. These data provides an explanation the action of neuroglobin in the protection of nerve cells from unwanted apoptosis.
Raychaudhuri
Subhadip
S
Department of Biomedical Engineering, University of California, Davis, 95616-5294, USA. raychaudhuri@ucdavis.edu
Skommer
Joanna
J
Henty
Kristen
K
Birch
Nigel
N
Brittain
Thomas
T
D017209:Apoptosis / Q000187:drug effects; D053478:Apoptosomes / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005914:Globins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000078787:Neuroglobin; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000187:drug effects
D053478:Apoptosomes; D001578:Benzopyrans; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D018696:Neuroprotective Agents; D009570:Nitriles; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D005914:Globins; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9