11.3 Strategies & Mechanisms of Energy Stress Tolerance

In response to energy stress, cells have evolved a range of strategies to restore homeostasis and maintain optimal energy level. The major strategies that can be used to combat energy limitation stress are increasing available energy and decreasing energy demand. For example, to increase available energy, cells may increase uptake of organic molecules, or intensify the activity of catabolic processes that generate ATP (Figure 11.6). To decrease energy demand, cells can downregulate processes that require lots of ATP, similar to how cells can tolerate hypoxia (Chapter 9.3). Conversely, the major strategies to tolerate energy excess include decreasing available energy and increasing energy demand. To decrease available energy, cells can store organic molecules in larger macromolecules rather than breaking those molecules down for ATP synthesis. To increase energy depend, cells can ramp up the activity of anabolic processes that consume ATP (Figure 11.6). AMPK plays a central role in in coordinating the multiple mechanisms employed by cells to carry out these strategies.

Mechanisms Under the Influence of AMPK

In times of energy limitation, activated AMPK can promote the acquisition of organic molecules such as glucose, and initiate catabolic processes that produce ATP such as glycolysis and fatty acid oxidation (Figure 11.6). In addition, AMPK can inhibit anabolic reactions that consume ATP such as protein synthesis, glucose synthesis (gluconeogenesis), and fatty acid synthesis (Figure 11.6). Under energy excess, AMPK is inactive. The catabolic processes normally stimulated by AMPK will no longer be stimulated. In addition, the anabolic processes normally inhibited by AMPK will be more likely to occur. Below, some of the many mechanisms used by active AMPK to increase energy availability in cells are described.

Carbohydrate & Lipid Metabolism

One way AMPK activation increases energy availability in the cell is by promoting the breakdown of carbohydrates and lipids, while also inhibiting their synthesis into storage molecules. In animal cells, the carbohydrate glucose can be stored as glycogen (decreasing energy availability) or broken down via cellular respiration to make ATP (increasing energy availability). Active AMPK inhibits an enzyme (glycogen synthase) that is important for glycogen synthesis, increasing glucose availability for glycolysis – the first part of cellular respiration (Figure 11.6). Fatty acids, a component of most lipids, can also be broken down to make ATP via a metabolic pathway called β-oxidation. The reverse of this process is fatty acid synthesis, which is anabolic and consumes ATP. AMPK can promote fatty acid oxidation by activating a key enzyme in this pathway (carnitine palmitoyltransferase I). AMPK can also prevent fatty acid synthesis by phosphorylating and inhibiting key enzymes in this anabolic pathway (acetyl-CoA carboxylase 1 and 2) (Figure 11.6).

Cell Growth & Protein Synthesis

During energy limitation, active AMPK can substantially decrease a cell’s energy demand by limiting protein synthesis and cell growth. AMPK can limit protein synthesis by interrupting the synthesis of ribosomal RNA, which subsequently decreases the abundance of functional ribosomes that can synthesize proteins. To inhibits rRNA synthesis, AMPK phosphorylates and inhibits a protein that is important for rRNA synthesis (transcription factor TIF-1A). With limited protein synthesis, cells are less likely to engage in energy-demanding processes like growth and cell division.

Autophagy & Mitophagy

During periods of energy limitation, AMPK can stimulate the break down very large structures through autophagy and mitophagy (Figure 11.7). To release energy via autophagy in mammalian cells, AMPK can phosphorylate and activate ULK (Unc-51 like autophagy activating kinase 1), an enzyme responsible for initiating the process. In times of energy limitation, the cell can also perform mitophagy, a process that leads to the degradation and consumption of defective mitochondria. The in-depth mechanisms of how cells use autophagy to increase energy availability are described in Chapter 11.4.