Abstract
Previous studies identifying the potential anti-apoptotic role of neuroglobin raise the question as to how cells might employ neuroglobin to avoid the apoptotic impact of acute hypoxia whilst also avoiding chronic enhancement of tumour formation. We show that under likely physiological conditions neuroglobin can take part in a futile redox cycle. Determination of the rate constants for each of the steps in the cycle allows us to mathematically model the steady state concentration of the active anti-apoptotic ferrous form of neuroglobin under various conditions. Under likely normal physiological conditions neuroglobin is shown to be present in the ferrous state at approximately 30% of its total cellular concentration. Under hypoxic conditions this rapidly rises to approximately 80%. Temporal analysis of this model indicates that the transition from low concentrations to high concentration of ferrous neuroglobin occurs on the seconds time scale. These findings indicate a potential control model for the anti-apoptotic activity of neuroglobin, under likely physiological conditions, whereby, in normoxic conditions, the anti-apoptotic activity of neuroglobin is maintained at a low level, whilst immediately a transition occurs to a hypoxic situation, as might arise during stroke, the anti-apoptotic activity is drastically increased. In this way the cell avoids unwanted increased oncogenic potential under normal conditions, but the rapid activation of neuroglobin provides anti-apoptotic protection in times of acute hypoxia.
Highlights
Neuroglobin is a small mono-heme protein which has been intensively studied over the past fifteen years [1,2,3,4,5,6]
It has been shown that ferrous-neuroglobin can react with ferric cytochrome c, released from mitochondria during the early stages of apoptosis [25]
Namely chronic promotion of tumour formation, at these sites? In order to go some way towards answering this question we have studied the quantitative reactivity of neuroglobin in vitro, under conditions which match as closely as possible the expected physiological conditions
Summary
Neuroglobin is a small (approx. 17 kDa) mono-heme protein which has been intensively studied over the past fifteen years [1,2,3,4,5,6]. A unique biological role of neuroglobin has not been conclusively identified it has been shown that the presence of neuroglobin, in both cultured neurons and in vivo, in brain tissue, protects cells against apoptosis, in response to hypoxic challenge [15,16,17,18,19,20,21,22,23] Both cellular and computational studies show that the protection provided by neuroglobin is achieved by raising the level of stressor required by the neuroglobin-containing cells necessary to precipitate the apoptotic cascade [24]. We find that this mechanism of control hinges on the differential ligand binding and anti-apoptotic characteristics of the ferrous forms of the neuroglobin protein in equilibrium in solution
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