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Roles of AMPK in energy homeostasis and nutrient sensing

Published on November 28, 2021   40 min

A selection of talks on Oncology

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0:00
Hello, my name is Grahame Hardie from the School of Life Sciences at the University of Dundee, in Scotland. I'm going to be talking to you today about the AMP-activated protein kinase, and its rôles in energy homeostasis and in nutrient sensing.
0:16
Throughout the talk, I'm going to be using the acronym AMPK to signify AMP-activated protein kinase. I'll divide the talk into five sections. Firstly, I'll introduce you to the AMPK system, and explain the concept that it acts as a sensor of cellular energy status. Next, I'll talk about its classical, or canonical, activation by changes in adenine nucleotide ratios, and I'll also discuss its structure. Next, I'll discuss various non-canonical activation mechanisms that have been discovered more recently, including the manner in which it can sense availability of glucose and fatty acids. Next, I'll discuss why it's a target for drugs used to treat type 2 diabetes, and I'll summarise what progress has been made in that direction. Finally, I'll talk about a topic in which there is much current interest, which is the potential rôle of AMPK as a target for drugs used to treat cancer. Let's start by introducing the AMPK system.
1:13
I like to keep things as simple as possible, so this is my view of the eukaryotic cell, which is an oval with AMPK at the centre. There are, of course, one or two other things in the cell, and two of these are ATP and ADP. I like to draw the analogy between ATP and ADP, and the chemicals in a rechargeable electrical battery. Using this analogy, catabolism charges up the battery by converting ADP to ATP. Practically everything else that the cell does - whether it's growing, dividing, moving, or secreting things into the medium - requires energy, and tends to flatten the battery by converting ATP back to ADP. It's obviously very important that these two processes are kept in balance, and the fact that ATP and ADP levels are usually pretty constant indicates that there are systems within the cell that regulate this balance. Although there are others, I would argue that AMPK is the most important of these. In a normal healthy cell that has plenty of glucose and oxygen, and when the environmental conditions are ideal, catabolism maintains the ATP to ADP ratio at around 10:1. Under these conditions, ATP is in the low millimolar range, and it binds to AMPK and keeps it in its largely inactive state. Now imagine that the cell experiences some kind of stress. It could be a stress that interferes with the production of ATP by catabolism, such as interruption of the blood supply, also known as ischaemia. Alternatively, it could be a stress that accelerates ATP consumption, such as contraction in a muscle cell. Either way, there'd be a tendency for the ADP to ATP ratio to increase, which I've indicated here by changing the font size. Any increase in ADP to ATP is immediately amplified by the enzyme adenylate kinase, into an even larger rise in the AMP to ADP ratio. In fact, if the adenylate kinase reaction is at equilibrium (which appears to be the case in most cells), it's easy to show that the AMP to ADP ratio will vary as the square of the ADP to ATP ratio. Thus, if the ADP to ATP ratio rises by three-fold, the AMP to ATP ratio will rise nine-fold, making the latter a much more sensitive indicator of cellular energy status. It's therefore a rise in AMP, coupled with a fall in ATP, that are the key signals activating AMPK, although increases in ADP may play a secondary rôle. Thus, AMPK is switched on by cellular energy stress, signified here by red turning to green. An obvious analogy is that the AMPK system is the cellular equivalent of the system in your mobile phone (or cell phone) that monitors the state of the battery charge. However, it's much more than that, because it doesn't just monitor a falling energy state in the cell, but it also does something about it. In short, what it does is to switch on catabolic pathways that generate more ATP, while at the same time switching off energy-consuming processes that are not essential to short-term survival of the cell.
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Roles of AMPK in energy homeostasis and nutrient sensing

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