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First published online June 13, 2008
Journal of Experimental Biology 211, vii-a (2008)
Copyright © 2008 The Company of Biologists Limited
doi: 10.1242/jeb.010975
Outside JEB |
REPROGRAMMING BASAL METABOLISM PROTECTS CELLS FROM HYPOXIA AND ISCHEMIA
Portland State University
jpod{at}pdx.edu
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As a rule, animal cells require molecular oxygen to support mitochondrial
energy production, and have thus evolved elaborate mechanisms to sense and
respond to changes in ambient oxygen concentrations. The HIF prolyl
hydroxylases (PHD1–3) are enzymes that use molecular oxygen as a
substrate, and thus their activity is dependent on the availability of oxygen,
which makes them highly sensitive oxygen sensors. When oxygen is high, these
enzymes hydroxylate proline residues on the Hif-1
and Hif-2
proteins, which marks these proteins for degradation and thus keeps their
activity low. When oxygen becomes limiting, hydroxylation is inhibited, which
leads to Hif protein stabilization and the subsequent activation of the HIF-1
transcription factor. HIF-1 activates the transcription of a number of genes
that collectively initiate a cellular response to hypoxia. Julián
Aragonés and colleagues investigated the role of Phd1 in regulating
metabolism and the cellular response to hypoxia in their 2008 Nature
Genetics paper.
To investigate the function of Phd1, the group created a Phd1 knockout (Phd1–/–) line of mice. They then characterized a battery of physiological, metabolic and biochemical parameters in skeletal muscle tissue and isolated myofibers from these mice including oxygen consumption, glucose utilization, levels of oxidative stress and hypoxia tolerance. The team hoped to find a link between oxygen sensing and the changes in metabolism that are associated with survival of hypoxia.
They found that loss of Phd1 function caused a reduction in oxygen consumption in cells exposed to normal levels of oxygen. This decreased oxygen consumption was associated with decreased oxidation of glucose, while oxidation of lipids was not affected. In addition, anaerobic utilization of glucose increased in Phd1–/– mice, indicating a shift towards increased anaerobic capacity even under aerobic conditions. Taken together, these findings suggest a reorganization of basal metabolism in mice lacking the Phd1 gene.
The group also discovered that isolated myofibers from
Phd1–/– mice were protected from damage
normally associated with a lack of blood flow (ischemia) and exhibited an
increased tolerance of hypoxia. These traits are probably due to changes in
basal metabolism that are mediated by activation of two potent transcription
factors Ppar and Hif-2 due to the loss of Phd1. Increased
tolerance of hypoxia in Phd1–/– mice was
associated with decreased oxygen consumption, reduced oxidative stress and
reduced mitochondrial damage compared with hypoxic wild-type myofibers.
Importantly, the muscle fibres of mice lacking the Phd1 gene were
able to continue producing ATP at low oxygen levels when ATP production failed
in normal mice. Interestingly, Phd1-deficient mice showed a reduced
exercise endurance compared with wild-type mice when forced to run uphill on a
treadmill, indicating that increased hypoxia tolerance may come at the cost of
decreased exercise performance.
Loss of Phd1 activity appears to pre-adapt myofibers for increased tolerance of hypoxia. These findings are the first report of a mechanistic link between cellular oxygen sensing and the rate of oxygen consumption in cells. This reprogramming of metabolism and the associated increase in hypoxia tolerance may help to explain changes in metabolism associated with metabolic dormancy in a variety of animals, and the baseline differences in the metabolism of hypoxia-tolerant and -intolerant species. In addition, this study establishes the possibility that inhibition of Phd1 may be one avenue for reducing damage during ischemic events in mammalian tissues.
References
Aragonés, J., Schneider, M., Van Geyte, K., Fraisl, P., Dresselaers, T., Mazzone, M., Dirkx, R., Zacchigna, S., Lemieux, H., Jeoung, N. H. et al. (2008). Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genetics 40,170 -180.[CrossRef][Medline]
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