Mitochondrial reactive oxygen species regulate hypoxic signaling

Abstract

Physiological hypoxia results in a host of responses that include increased ventilation, constriction of the pulmonary artery, and a cellular transcriptional program that promotes glycolysis, angiogenesis, and erythropoiesis. Mitochondria are the primary consumers of cellular oxygen and have thus been speculated for years to be the site of cellular oxygen sensing. Many of the cellular responses to hypoxia are now known to be mediated by the production of reactive oxygen species at mitochondrial complex III. While the mechanism by which cytosolic oxidant concentration is increased during hypoxia is unknown, the importance of the maintenance of cellular oxygen supply requires further investigation into the role of ROS as hypoxia signaling molecules. The following is a brief overview of the current understanding of the role of mitochondrial-produced ROS in cellular oxygen signaling.

Figure 1. Mitochondrial generation of reactive oxygen species

Mitochondrial complexes I, II, and III produce superoxide. While complexes I and II only produce superoxide into the mitochondrial matrix, complex III can produce superoxide on both sides of the mitochondrial inner membrane in a process termed the Q-cycle. Complexes I and II donate two electrons to coenzyme Q, forming ubiquinol. At complex III, the first of these electrons is transferred by the Rieske iron-sulfur protein (RISP) to cytochrome c1, leaving the radical ubisemiquinone. Subsequently, ubisemiquinone transfers the second electron to cytochrome b. Ubisemiquinone formed at the Q_o site can donate its electron directly to oxygen, producing superoxide.

Figure 2. Hypoxia-induced mitochondrial ROS inhibit HIFα subunit turnover

Under normoxic conditions, HIFα subunits are hydroxylated on prolines by prolyl hydroxylases (PHDs). Hydroxylation tags HIFα for recognition by the von Hippel Lindau (VHL) tumor suppressor leading to ubiquitination and degradation of HIFα. During hypoxia, mitochondrial production of ROS inhibits the activity of PHDs allowing for stabilization of HIFα subunits and HIF-mediated transcription.

Figure 3. Hypoxia-induced mitochondrial ROS are required for elevation of cytosolic calcium and contraction of PASMCs

During hypoxia, mitochondrial production of ROS leads to activation of NADPH oxidases, further amplifying the ROS signal. The combined production of ROS at mitochondria and NADPH oxidase allows for elevation of cytosolic calcium and contraction of PASMCs.