Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation.
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 Po2 (PmO2). Because PmO2 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.
Center for respiratory diagnoses, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES) and Universitat de Barcelona, Barcelona, Catalonia, Spain.
Isaac
I
Cano
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona and Institute of Biomedicine (IBUB), Barcelona, Catalonia, Spain.
Vitaly
V
Selivanov
Unit of Computational Medicine of the Center for Molecular Medicine, Karolinska Institutet and Karoliska University Hospital - Department of Medicine, Stockholm, Sweden.
David
D
Gomez-Cabrero
Unit of Computational Medicine of the Center for Molecular Medicine, Karolinska Institutet and Karoliska University Hospital - Department of Medicine, Stockholm, Sweden.
Jesper
J
Tegnér
Center for respiratory diagnoses, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES) and Universitat de Barcelona, Barcelona, Catalonia, Spain.
Josep
J
Roca
Division of Physiology, Pulmonary and Critical Care Medicine, University of California San Diego, San Diego, California, United States of America.
Peter D
PD
Wagner
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona and Institute of Biomedicine (IBUB), Barcelona, Catalonia, Spain.
Marta
M
Cascante
D000531:Altitude; D003198:Computer Simulation; D006801:Humans; D008931:Mitochondria, Muscle / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D010100:Oxygen