Does AMP-activated Protein Kinase Couple Inhibition of Mitochondrial Oxidative Phosphorylation by Hypoxia to Pulmonary Artery Constriction?

Abstract

Pulmonary arteries constricts in response to hypoxia and thereby aid ventilation-perfusion matching in the lung. Although O2-sensitive mechanisms independent of mitochondria may also play a role, it is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation and that this underpins, at least in part, cell activation. Despite this consensus, the mechanism by which inhibition of mitochondrial oxidative phosphorylation couples to Ca-dependent vasoconstriction has remained elusive. To date, the field has focussed on the role of the cellular energy status (ATP), reduced redox couples and reactive oxygen species, respectively, but investigation of these hypotheses has delivered conflicting data and failed to unite the field. Recently, the AMPK cascade has come to prominence as a sensor of metabolic stress that appears to be ubiquitous throughout eukaryotes. AMPK complexes are heterotrimers comprising a catalytic subunit and regulatory and subunits, which monitor the cellular AMP/ATP ratio as an index of metabolic stress. Binding of AMP to two sites in the subunits triggers activation of the kinase via phosphorylation of the subunit at Thr-172, an effect antagonized by high concentrations of ATP. This phosphorylation is catalyzed by upstream kinases (AMPK kinases) the major form of which is a complex between the tumour suppressor kinase, LKB1, and two accessory subunits, STRAD and MO25. Given that inhibition of mitochondrial oxidative phosphorylation by hypoxia would be expected to promote a rise in the AMP/ATP ratio we considered the proposal that AMPK activation may mediate, in part, pulmonary artery constriction by hypoxia.