What is AMPK and Why Should You Care?

There is a constant dance inside our cells, maintaining a balance between processes that build up (anabolic) and break down (catabolic) based on the substrates available to produce the cell’s energy currency, ATP.

Catabolic processes produce ATP.

Anabolic processes consume ATP.

We make ATP mainly by breaking down metabolic fuels like sugar, fat, and ketone bodies. This occurs inside the mitochondria, the cell’s “powerhouse,” where the bulk of ATP production takes place.

To use energy, ATP is broken down into ADP, which can be further broken down to AMP. Ultimately though, using energy means we are decreasing ATP levels.

To ensure that energy consumption and the availability of nutrients remain in balance, the level of ATP serves as a critical marker that indicates whether we break down or store nutrients.

When ATP falls, a cascade of events encourages the restoration of energy balance. We start breaking down stored energy in body fat or liver glycogen (stored glucose); we may even begin to feel hungry as a cue to increase food intake.

Our metabolism is essentially a function of nutrient availability — tightly regulated by AMP-activated Protein Kinase (AMPK).

When energy is used (ATP → ADP → AMP) without being replenished, AMPK turns on. This protein kinase works in opposition to mTOR, the master regulator of growth and, which unsurprisingly is activated by nutrient availability.

The actions of AMPK counter the actions of mTOR.

In response to low ATP levels, AMPK activation:

Triggers catabolic processes (e.g., the breakdown of glycogen and body fat, autophagy) and inhibits anabolic processes (e.g., storing glucose as glycogen, storing body fat, building muscle). This makes logical sense since any anabolic process (cell growth, protein translation) requires both available substrates and ATP.

The primary trigger for AMPK activation is metabolic stress/energy shortage. Exercise and fasting are the most potent ways of achieving this. Essentially, the body needs to be “hungry” for energy (ATP).

Maintaining this “hungry” state = AMPK activation, since to reiterate, AMPK activity is required for the breakdown of macromolecules to produce energy and replenish ATP stores.

Once activated, AMPK has numerous targets, and because AMPK is a protein kinase, it “phosphorylates” its target proteins to alter their activity.

The target proteins influenced by AMPK activation, in turn, regulate the pathways and genes involved in:

Protein metabolism

• Inhibits mTOR, which decreases cell growth and protein synthesis

Fat metabolism

• Activates lipolysis and beta-oxidation (the breakdown of fat for energy)

Carbohydrate metabolism

• Increases glucose uptake and glycolysis (the breakdown of glucose for energy)
• Decreases glycogen storage and gluconeogenesis (formation of glucose from non-carbohydrate sources)

Autophagy

• Initiate autophagy
• Activates the transcription proteins in the control of autophagy and lysosomes (organelle responsible for degrading cellular debris)

Mitochondrial homeostasis

• Initiates “mitophagy” (turnover of damaged/aged mitochondria)
• Increases mitochondrial biogenesis (formation of new mitochondria)

Since I am borderline obsessed with the mitochondria and metabolic health, I want to dive into greater detail on AMPK and the mitochondria.

Mitochondria are the primary site of energy (ATP) production, and AMPK is involved in finding ways to produce more energy. In an attempt to do just that, AMPK increases the growth and division of pre-existing mitochondria.

Increased mitochondrial mass = more/improved sites for energy production.

The signal for mitochondrial biogenesis is the increased expression of genes encoding mitochondrial proteins. We need to activate the pathways that will help grow and sustain the growth of new mitochondria (mitochondrial proteins and lipid membrane components).

One of the most well-studied conditions for observing increased mitochondrial mass is exercise.

Exercise and muscle activity increases mitochondrial biogenesis to increase the energy production capacity of muscles.

Exercise also happens to be a potent activator of AMPK.

The link becomes stronger when we consider that chronic AMPK activation leads to increased mitochondrial biogenesis, and a specific drug known to activate AMPK induces changes that mimic exercise — together suggesting that AMPK is participating in the exercise-induced increase of mitochondrial biogenesis.

Many of the genes involved in mitochondrial biogenesis are under the control of PGC1a — PGC1a expression has been found to be involved in the upregulation of several genes involved in mitochondrial metabolism and chronic activation of AMPK increases PGC1a expression, suggesting a potential downstream mechanism for which AMPK works through.

Autophagy, Mitophagy, and AMPK

Autophagy = “self-eating”

It is essentially the cell’s housekeeper — the process that clears out cellular components such as proteins, whole organelles, and pathogens and recycles their building blocks for new cellular components.

Autophagy serves two primary functions:

1. Recycles old/damaged molecules
2. Replenishes nutrient stores during times of starvation

AMPK is intimately involved in regulating autophagy, which makes sense since both respond to energy status.

Mitophagy describes mitochondria-specific autophagy — the removal of damaged mitochondria.

An overly simplified explanation for how AMPK leads to mitochondrial biogenesis: Low ATP = AMPK activation = mTOR inactivation = removal of damaged mitochondria via mitophagy + activation of mitochondrial biogenesis, thereby generating new and healthier mitochondria.

Bottom line: AMPK activation = healthy mitochondria.

The effect of AMPK on mitochondrial health and autophagy is worth exploring as it is crucial for understanding the impact of nutrition and exercise on metabolic health, which has obvious implications for diseased states and improving health conditions.

Remember, AMPK is the signal for low ATP, and mitochondria are where the cells generate ATP. It makes sense that systems are in place to ensure mitochondria (and therefore energy production) are functioning optimally in response to AMPK activation.

Mitochondrial health is essential to human health, suggesting that interventions that work through AMPK activation may serve as metabolic optimizers. These mechanisms may also explain the health and longevity benefits of fasting and exercise.