AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

Abstract

AMP-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy homeostasis. It arose very early during eukaryotic evolution, and its ancestral role may have been in the response to starvation. Recent work shows that the kinase is activated by increases not only in AMP, but also in ADP. Although best known for its effects on metabolism, AMPK has many other functions, including regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation. Both tumor cells and viruses establish mechanisms to down-regulate AMPK, allowing them to escape its restraining influences on growth.Living cells use ATP and ADP in a manner similar to the chemicals in a rechargeable battery. Most cellular processes require energy and are driven (directly or indirectly) by the hydrolysis of ATP to ADP and phosphate (or, less frequently, to AMP and pyrophosphate), thus ''flattening the battery.'' In heterotrophic organisms, the battery is recharged by catabolism; i.e., the oxidation of reduced carbon compounds of organic origin, such as glucose. In most cells (especially quiescent cells), oxidation of glucose usually proceeds completely to carbon dioxide via the process of oxidative phosphorylation. Under these conditions, most ATP synthesis occurs at the inner mitochondrial membrane, ATP being generated when protons pumped out via the respiratory chain flow back across the membrane via channels in complex V (the ATP synthase). It has been argued that the endosymbiotic acquisition of aerobic bacteria to form mitochondria was the crucial event in the development of the eukaryotes (Lane and Martin 2010). The large increase in surface area of membrane available for proton transfer (in the form of the inner mitochondrial membrane) allowed a large increase in capacity to generate ATP, which may in turn have allowed the dramatic increase in complexity displayed by eukaryotic cells and organisms. When mitochondria became the main cellular power source, one additional event required was the development of systems that sense energy status in the cytoplasm and then signal this information back to modulate mitochondrial function. Interestingly, AMP-activated protein kinase (AMPK, the subject of this review) fulfills this role and appears to be almost universal in eukaryotes. One interesting exception is Encephalitozoon cuniculi, a eukaryote with a strippeddown genome that appears to have lost not only its mitochondria, but also AMPK (Miranda-Saavedra et al. 2007). However, as it is an obligate intracellular parasite, the host cell would provide both of these missing functions.The obvious way to achieve energy sensing would be to have proteins that monitor the cellular ratio of ATP:ADP. However, because of the very active adenylate kinases in all eukaryotic cells, which catalyze the interconversion of adenine nucleotides (2ADP 4 ATP + AMP), the AMP:ATP ratio tends to change in concert with, and to an even greater extent than, the ADP:ATP ratio (Hardie and Hawley 2001). Thus,...

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