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First published online December 14, 2006
Journal of Experimental Biology 210, vii (2007)
Copyright © 2007 The Company of Biologists Limited
doi: 10.1242/jeb.02639
Outside JEB |
HYPOXIC BRAIN CELLS LOSE THEIR INHIBITIONS
Florida Atlantic University
smilton{at}fau.edu
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The brain is the most energy hungry organ in mammals, and more than 95% of the ATP it consumes is normally derived from aerobic respiration; up to 40-50% of this energy is used by neurons just to drive ion pumps. Thus a fall in oxygen levels (hypoxia) can rapidly deplete ATP levels, with catastrophic consequences. Fortunately, cells can sense and respond to low oxygen levels: originally scientists thought that most cells detect low O2 when cellular ATP levels drop, but it is now apparent that many cells respond to hypoxia before ATP levels reach a critical low, implying that they need a specific sensor. One candidate is the enzyme cytochrome oxidase (COX). COX gives up two electrons to oxygen to create oxygen ions, which combine with hydrogen ions to form water in the final step of aerobic respiration. In this way, COX activity and oxygen levels determine ATP production. A recent Journal of Neurochemistry paper by Susann Horvat and her colleagues at the Max Delbrück Center for Molecular Medicine, Berlin, characterises how COX activity changes with changing oxygen levels in two neural cell types: neuronsupporting astrocytes and granule cells, which are a type of neuron.
First the team exposed the cells to hypoxia, 5% oxygen, and monitored cell death. The cell types responded very differently: cell death did not increase in astrocytes and their ATP levels decreased by only 9%, suggesting that when aerobic respiration is no longer sufficient to meet their energy needs, astrocytes can switch to anaerobic respiration. By contrast, approximately 29% of the granule cells died, and their ATP levels decreased by 31%. These results show that astrocytes change to anaerobic glycolysis in the absence of oxygen, while granule cells die because they are more dependent on O2.
Knowing that COX comprises several different subunits and the enzyme's activity is regulated by expressing different forms (isoforms) of some of these subunits, the team looked at COX subunit transcription patterns and found significant changes in COX transcription and activity. mRNA levels of one of the subunits, the COX IV-1 isoform, did not change with hypoxia in either cell type. In contrast, the COX IV-2 isoform increased in both cell types with hypoxia, showing that changing O2 levels regulate COX by affecting transcription. While astrocytes had no detectable COX IV-2 isoform in normoxia, approximately 10% of total COX transcription in granule cells was the COX IV-2 isoform, which affects overall enzyme kinetics.
COX activity is also regulated by the amount of ATP in a cell, as it binds to the COX IV subunit. When the team measured COX enzyme kinetics under normoxic and hypoxic conditions, they found that ATP inhibition of COX activity changed in the different cell types depending on which COX IV isoform is expressed. In high O2 conditions ATP usually inhibits COX, but in granule cells, which express high levels of COX IV-2, this inhibition didn't occur. In normoxic astrocytes, ATP inhibited COX, but the inhibition disappeared as COX IV-2 mRNA levels increased. COX activity, however, still decreased in hypoxic astrocytes, providing a mechanism for astrocytes to change from aerobic to anaerobic respiration.
The authors propose that even low levels of COX IV-2 prevent inhibition of COX by ATP in granule cells, keeping the enzyme active even at high ATP levels. Since they found COX activity was also high in hypoxic granule cells, the neurons probably continue to meet their high energy demands by maintaining aerobic enzyme activity and ATP levels. However, this continued energy production comes at a price: it may create damaging reactive oxygen species and increase cell death. Apparently then, as in so much in life, losing your inhibitions can be very bad for your health!
References
Horvat, S., Beyer, C. and Arnold, S. (2006). Effect of hypoxia on the transcription pattern of subunit isoforms and the kinetics of cytochrome c oxidase in cortical astrocytes and cerebellar neurons. J. Neurochem. 99,937 -951.[CrossRef][Medline]
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