Figure 17-9 Schematic model of the mitochondrial O₂ -sensing and effector mechanism probably responsible for hypoxic pulmonary vasoconstriction (HPV). In this model, reactive O₂ species (ROS) are released from electron transport chain complex III and act as second messengers in the hypoxia-induced calcium (Ca²⁺ ) increase and resultant HPV. The solid arrows represent electron transfer steps; solid bars show sites of electron chain inhibition. Normal mitochondrial electron transport involves the movement of reducing equivalents generated in the Krebs cycle through complex I or II and then through complex III (ubiquinone) and IV (cytochrome oxidase). The Q cycle converts the dual electron transfer in complex I and II into a single electron transfer step used in complex IV. The ubisemiquinone (a free radical) created in this process can generate superoxide, which in the presence of superoxide dismutase (SOD) produces H₂ O₂ , the probable mediator of the hypoxia-induced increased Ca²⁺ and HPV. This process is amplified during hypoxia. (DPI, diphenyleneiodonium. DPI, rotenone, and myxothiazol [not shown in figure] are inhibitors of the proximal portion of the electron transport chain.) (From Waypa GB, Marks JD, Mack MM, et al: Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary artery myocytes. Circ Res 91:719–726, 2002.)