Abstract
The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po 2 (). Because depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the “death zone” in mountaineering.
Highlights
It is well accepted that cellular hypoxia [1,2,3,4] triggers a constellation of biological responses involving transcriptional and post-transcriptional events [5,6] through activation of cellular oxygen sensors
In addition to describing the integrated modeling system, we present estimates of reactive oxygen species (ROS) generation in exercising muscle of healthy subjects at different altitudes at and above sea level using O2 transport data from Operation Everest II [22] and published mitochondrial kinetic data in normal human muscle
We found that at sea level, O2 transport at maximal exercise is sufficient to keep PmO2 high enough that mitochondrial ROS generation is not significantly increased
Summary
It is well accepted that cellular hypoxia [1,2,3,4] triggers a constellation of biological responses involving transcriptional and post-transcriptional events [5,6] through activation of cellular oxygen sensors. This includes generation of reactive oxygen species (ROS). Current knowledge on the quantitative relationships between mitochondrial Po2 (PmO2 ), hypoxia-induced cellular events, and on the release of ROS from the inner mitochondrial membrane, is minimal. How low PmO2 must be to trigger abnormally high ROS generation has not yet been identified. There are promising new approaches being developed to in vivo assessment of PmO2 [9]
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