Metabolic Regulation of Cell Fate and Function

Abstract

Increasing evidence implicates metabolic pathways as key regulators of cell fate and function. Although the metabolism of glucose, amino acids, and fatty acids is essential to maintain overall energy homeostasis, the choice of a given metabolic pathway and the levels of particular substrates and intermediates increasingly appear to modulate specific cellular activities. This connection is likely related to the growing appreciation that molecules such as acetyl-CoA act as a shared currency between metabolic flux and chromatin modification. We review recent evidence for a role of metabolism in modulating cellular function in four distinct contexts. These areas include the immune system, the tumor microenvironment, the fibrotic response, and stem cell function. Together, these examples suggest that metabolic pathways do not simply provide the fuel that powers cellular activities but instead help to shape and determine cellular identity.

Figure 1:

Metabolic regulation of T cell function. Manipulation of diverse metabolic pathways can impact T cell activation, as assessed by IFNγ production. This includes genetic disruption of Complex II of the mitochondrial electron transport chain (top), altering cytosolic glycolysis by deletion of LDHA (middle), or altering intracellular lipid metabolism (bottom).

Figure 2:

Metabolic influences in the tumor microenvironment. Numerous metabolites appear to play a role in the tumor microenvironment, and help govern the growth of the tumor and the corresponding strength of the immune response. High rates of tumor glucose and tryptophan consumption can limit the availability of these metabolites for invading immune cells. Moreover, tumor production and subsequent excretion of lactate can have a paracrine influence on a wide range of immune cells. Recent evidence also suggests that the nutrient deprivation tumor create can trigger signaling pathways within immune cells such as activation of the unfolded protein response (e.g. XBP1) or directly trigger growth arrest by reducing the levels of critical nutrients (e.g. PEP).

Figure 3:

The compartmentation of acetyl-CoA. Acetyl-CoA can be generated in different compartments of the cell including the mitochondria, cytosol and nucleus. The pool of mitochondrial acetyl-CoA is higher and not in equilibrium with the cytosolic-nuclear pool. Citrate export from the mitochondria can be re-converted to acetyl-CoA by the action of the enzyme ACLY. Moreover, acetate, taken up from the extracellular milieu or produced intracellularly, can also generate acetyl-CoA by the action of the enzyme ACSS2. ACLY and ACSS2 are found in the cytosol and nucleus. In the nucleus, these enzymes are believed to generate locally high concentrations of acetyl-CoA, presumably near sites of active chromatin acetylation.

Figure 4:

The role of αKG-dependent enzymes. This family of enzymes, all requiring the TCA metabolite αKG, exert influences on all aspects of the central dogma of biology, from DNA to RNA to protein modification. Multiple different enzymes and substrates are involved and reactions include αKG-dependent demethylation and αKG-dependent hydroxylation.