A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus

Abstract

The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMC) in pulmonary arteries (PA), ductus arteriosus (DA) and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimises ventilation-perfusion matching. In utero, HPV diverts placentally-oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilate the pulmonary vasculature and, constrict the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2-sensing is intrinsic to PA- and DASMCs. Within the SMC’s dynamic mitochondrial network, changes in PO2 alter the reduction-oxidation state of redox couples (NAD+/NADH, NADP+/NADPH) and the production of reactive oxygen species, ROS (e.g. H2O2) by Complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca2+]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMC, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca2+]i and causing vasoconstriction. In DASMC, elevated PO2 causes mitochondrial fission, increasing ETC Complex I activity and ROS production. The DASMC’s downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca2+]i and rho kinase activation) is similar to the PASMC’s hypoxic response. Impaired O2-sensing contributes to human diseases, including pulmonary arterial hypertension and patent DA.

O 2 sensing, mitochondria and ROS signaling: The fog is lifting

“…Hence, Kv channel sensitivity to ROS would be similar in PASMC and SASMC but opposite to that in DA, whereas mitochondria in PASMC and DA decrease ROS in response to hypoxia whereas those in SASMC increase ROS generation. This complex set of proposed mechanisms has been the topic of previous reviews 33, 35–38 , and is summarized in Table 1.…”

RETRACTED ARTICLE: The quantum physiology of oxygen; from electrons to the evolution of redox signaling in the human brain

“…4b). However, this theory is not without its critics and remains a source of ongoing debate (Ward 2006;Weir and Archer 2006), considered by some as controversial if not indeed counterintuitive (↓O 2 → ↓ electron flux/uncoupled leakage) with evidence supporting a more direct link between molecular O 2 and PHD inhibition/HIF activation (Dunham-Snary et al 2016).…”

Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension

“…Our studies demonstrate that the reduction in CES1 expression and activity increases PMVEC apoptosis alone and in response to METH, but several questions remain concerning the mechanism behind METH-induced ROS generation, initiation of ER stress, and possible impairment of mitochondrial bioenergetics, a well-established feature of other forms of PAH (14,37,46). It is worth pointing out that mitochondrial toxicity is also a consequence of METH exposure and could be linked to the autophagy response, as these pathways can also interact with the mitochondria to trigger release of cytochrome c and other proapoptotic factors (52,59).…”