Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Acute HPV (occurring within seconds to minutes) diverts blood from poorly to well oxygenated alveoli of the lung and thereby prevents shunt flow and arterial hypoxemia on a breath-to-breath basis. Decreased HPV, e.g., during anesthesia, pneumonia, the adult respiratory distress syndrome, septic events or liver failure can result in shunting and life threatening hypoxemia, whereas exaggerated HPV in chronic lung disease or at high altitude contributes to pulmonary hypertension, which can culminate in right ventricular failure. Since the systemic vasculature dilates in response to hypoxia, a unique oxygen sensing mechanism has been suggested for the pulmonary vasculature. Acute and chronic oxygen sensing mechanisms of HPV and pulmonary hypertension have been shown to be located in pulmonary arterial smooth muscle cells (PASMCs), but the exact acute oxygen sensor in the lung remains unknown. For acute HPV both increased or decreased release of reactive oxygen species (ROS) originating from mitochondrial electron transport chain (ETC) complexes I and/or III have been suggested to initiate the oxygen sensing pathway. However, the mechanism remains unclear. Although ROS are preferentially released from mitochondrial respiratory chain complexes I and III, mitochondrial complex IV (or cytochrome c oxidase, COX) catalyzes the final step of the ETC and should be particularly susceptible to hypoxia since it converts oxygen to water. The isoform 2 of COX subunit 4 (Cox4i2) was suggested to increase COX activity, thereby promoting ETC activity, mitochondrial membrane potential (ΔΨm), and ROS production. Cox4i2 is preferentially expressed in the adult mammalian lung, specifically in smooth muscle cells and to a lesser degree also in the fetal lung. In this work, the authors show that Cox4i2 is an essential component in the acute oxygen sensing process of the pulmonary vasculature by promoting ΔΨm hyperpolarization and ROS production during hypoxia. Interestingly, development of chronic hypoxia-induced pulmonary hypertension was only slightly effect by Cox4i2 deficiency. These findings provide a new model for oxygen sensing processes in the lung and possibly also in other organs.