Cellular Energy Sensors
One of the things I personally find fascinating about all life forms is the universal ability to sense cellular energy status. All biological systems have multiple ways of detecting low levels of cellular energy-containing molecules (e.g. ATP, NADH, etc.) and downstream feedback mechanisms to increase the production of energy-producing molecules and restore cellular energy balance. More intriguing is the role of these energy sensors in health and disease, and when these sensory pathways are beneficial or harmful.
Required biology review: Adenosine triphosphate (ATP), the cell’s main energy source, produces energy when one of the phosphate ions is cleaved from the molecule, thus creating adenosine diphosphate (ADP), inorganic phosphate, and energy. Under high energy demand, a second phosphate ion can be cleaved from ADP, thus producing adenosine monophosphate (AMP), inorganic phosphate, and energy. These basics are important for the discussion below.
The first-known and most-studied energy sensing pathway is the AMPK signaling pathway. Relatively low cellular levels of ATP and high levels of AMP activate AMP kinase (AMPK), an enzyme that controls a myriad of downstream signaling molecules and DNA transcriptors. Activation of AMPK is a potent driver of many, many important cellular pathways (see diagram below), but for the purpose of this article I will focus on the roles of mitochondria and glucose homeostasis.
Cellular activation of AMPK is an activator of glucose-transporter 4 (GLUT4) translocation to the cellular membrane, thus increasing glucose entry into the cell and activity of glycolysis-related enzymes. It also stimulates autophagy, lipolysis, and mitochondrial biogenesis through other mechanisms, with the ultimate end goal of producing more energy more efficiently.
A second important pathway is the NAD-sirtuin pathway. NAD is a universal metabolite that, in humans, is derived from vitamin B3. NAD is important because several cellular processes reduce NAD to NADH, which can then be oxidized by the mitochondria back to NAD. The oxidation of NADH allows electron transfer in the mitochondrial inner membrane to facilitate the electrical gradient needed to produce ATP.
When energy supply is low (caloric restriction, fasting, or even ketogenic diets), there is an increased amount of NAD relative to NADH. The increase in NAD:NADH ratio is an important activator of NAD-dependent transcriptors, sirtuins. Sirtuins are a very important and neat class of proteins that are involved in the regulation of “master regulators” of mitochondrial biogenesis, glycolysis, lipolysis, and many other important processes. Essentially, sirtuins are sort of like the directors of a show, where the director controls the tempo and pace of the show, and controls the que for all of the performers.
So, what does this mean for health and disease?
With the vast amount of cellular processes that are effected by the two mechanisms I’ve talked about, it makes a very strong case to understand how these are involved in diseases, and the development of drugs to activate these pathways to treat diseases. Sure enough, the AMPK pathway is a major target in several metabolic conditions, most notably type 2 diabetes. Moreso, activation of the AMPK pathway is thought to be one of the main targets of many anti-diabetic drugs, including metformin and berberine (which I talked about last week). In addition, ways to activate the NAD-sirtuin pathway is becoming a novel target for the development of drugs, and I imagine that we will see a lot more drugs that target this pathway entering the market in the next few decades.
Activating these pathways seems to be a very good way to prevent a large number of chronic diseases: diabetes, cardiovascular disease, Alzheimer’s, so on and so on. While I don’t think there is a need to activate these pathways constantly, there’s definitely a need to achieve some depletion of ATP and NADH in order to spark beneficial physiological adaptations to biological stressors.
But, as always, there are ways to activate these pathways without pharmaceutical intervention:
Good ol’ diet and exercise.
