Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Abstract

AMP-activated protein kinase (AMPK) is known as a pivotal cellular energy sensor, mediating the adaptation to low energy levels by deactivating anabolic processes and activating catabolic processes in order to restore the cellular ATP supply when the cellular AMP/ATP ratio is increased. Besides this well-known role, it has also been shown to exert protective effects under hypoxia. While an insufficient supply with oxygen might easily deplete cellular energy levels, i.e., ATP concentration, manifold other mechanisms have been suggested and are heavily disputed regarding the activation of AMPK under hypoxia independently from cellular AMP concentrations. However, an activation of AMPK preceding energy depletion could induce a timely adaptation reaction preventing more serious damage. A connection between AMPK and the master regulator of hypoxic adaptation via gene transcription, hypoxia-inducible factor (HIF), has also been taken into account, orchestrating their concerted protective action. This review will summarize the current knowledge on mechanisms of AMPK activation under hypoxia and its interrelationship with HIF.

Keywords: AMPK; CaMKK; FIH1; HIF; HIF-P4H; LKB1; [Ca2+i]; hypoxia; reactive oxygen species (ROS).

Figure 1

Graphical summary illustrating possible mechanisms regulating AMP-activated protein kinase (AMPK) activity under hypoxia. A decreased oxygen supply impairs oxidative phosphorylation (oxphos) in mitochondria and thus leads to increased AMP/ATP ratios, which will activate the canonical pathway of AMPK activation by LKB1. Besides LKB1, AMPK can also be phosphorylated by CaMKK2 subsequently to an increase of [Ca²⁺_i] under hypoxia. Impaired mitochondrial oxphos also causes formation of reactive oxygen species (ROS), which might not only induce these pathways but also activate AMPK directly. ROS are also supposed to inhibit hypoxia-inducible factor (HIF)-hydroxylase enzymes, which work oxygen-dependently and have been suggested to regulate AMPK in concert with HIF. Crosstalk between AMPK and HIF might help to orchestrate the adaptation to low oxygen levels as well. More details are given in the text.