The role of redox changes in oxygen sensing

Abstract

The specialized oxygen-sensing tissues include the carotid body and arterial smooth muscle cells in the pulmonary artery (PA) and ductus arteriosus (DA). We discuss the evidence that changes in oxygen tension are sensed through changes in redox status. "Redox" changes imply the giving or accepting of electrons. This might occur through the direct tunneling of electrons from mitochondria or redox couples to an effector protein (e.g. ion channel). Alternatively, the electron might be transferred through reactive oxygen species from mitochondria or an NADPH oxidase isoform. The PA's response to hypoxia and DA's response to normoxia result from reduction or oxidation, respectively. These opposing redox stimuli lead to K+ channel inhibition, membrane depolarization and an increase in cytosolic calcium and/or calcium sensitization that causes contraction. In the neuroendocrine cells (the type 1 cell of the carotid body, neuroepithelial body and adrenomedullary cells), the response is secretion. We examine the roles played by superoxide anion, hydrogen peroxide and the anti-oxidant enzymes in the signaling of oxygen tensions.

Fig 1

The Redox Hypothesis applies to the specialized tissues of the Oxygen Homeostatic System. Changes in ROS or Redox Couples, often mediated by the mitochondria, regulate ion channels, transporters and transcription factors, usually by altering the reduction or oxidation of key sulfhydryl groups that regulate protein function. These changes, are transduced into tissue-specific biologic activities including vasoconstriction, vasodilatation and secretion. In each tissue the net effect of activation is to enhance O₂ uptake and delivery.

Fig 2

Mitochondrial-targeted GFP shows the mitochondrial network in a normal pulmonary artery smooth muscle cell cultured from a rat resistance pulmonary artery.

Fig 3

The ETC is comprised of four mega-complexes that mediate transfer of electrons down a redox potential gradient through series of carriers resulting in final acceptance of the electron by O₂, producing ATP and water. This electron transport leads to extrusion of hydrogen ions which creates the mitochondrial membrane potential (Ψm) and accounts for the negative membrane potential of mitochondria. This potential energy is later used as the driving force to power the F1F0 ATPase. A small percentage (<3%) of total electron flux involves unpaired electrons, resulting in the generation of ROS within the mitochondrion (e.g. superoxide radical). Mitochondrial manganese superoxide dismutase (SOD2) rapidly transforms this superoxide to hydrogen peroxide which is a diffusible signaling mediator (unless over produced in which case it becomes toxic to the cell). P_O2-dependent changes in ETC activity and ROS production, together with the actions of a variety of “anti-oxidant” enzymes, vary levels of hydrogen peroxide and redox couples which alter the function of ion channels, such as Kv1.5 and the large conductance, voltage-gated calcium channel. The resulting changes in intracellular calcium lead to changes in secretion and vascular tone.

Fig 4

SOD plays a key role in determining the predominance of either O₂⁻ or H₂O₂ in the cascade of oxygen signaling. In this figure, the end effector is shown as the oxygen-sensitive potassium channel. The intermediate links that are susceptible to redox changes might include enzymes, such as tyrosine kinases and phosphatases.

Fig 5

The most important concept in the redox hypothesis of oxygen signaling is that it is the control of electron flow which determines the activation or inhibition of the effector mechanisms (including K⁺ channels, Ca²⁺ channels, SR and small G proteins).