Fueling the cytoskeleton - links between cell metabolism and actin remodeling

Abstract

Attention has long focused on the actin cytoskeleton as a unit capable of organizing into ensembles that control cell shape, polarity, migration and the establishment of intercellular contacts that support tissue architecture. However, these investigations do not consider observations made over 40 years ago that the actin cytoskeleton directly binds metabolic enzymes, or emerging evidence suggesting that the rearrangement and assembly of the actin cytoskeleton is a major energetic drain. This Review examines recent studies probing how cells adjust their metabolism to provide the energy necessary for cytoskeletal remodeling that occurs during cell migration, epithelial to mesenchymal transitions, and the cellular response to external forces. These studies have revealed that mechanotransduction, cell migration, and epithelial to mesenchymal transitions are accompanied by alterations in glycolysis and oxidative phosphorylation. These metabolic changes provide energy to support the actin cytoskeletal rearrangements necessary to allow cells to assemble the branched actin networks required for cell movement and epithelial to mesenchymal transitions and the large actin bundles necessary for cells to withstand forces. In this Review, we discuss the emerging evidence suggesting that the regulation of these events is highly complex with metabolism affecting the actin cytoskeleton and vice versa.

Keywords: Actin; Cytoskeleton; Force; Mechanotransduction.

Fig. 1.

Oxidative glucose metabolism. Once glucose enters the cell, it must be phosphorylated to remain in the cytosol. After phosphorylation, the 6-carbon glucose molecule goes through a serious of nine enzymatic reactions breaking it down to two molecules of pyruvate. Pyruvate is then shuttled into the mitochondrial matrix, where it is converted into acetyl CoA, which can be further oxidized in the citric acid cycle. Two electron carriers, NADH and FADH₂ are produced from the citric acid cycle and are components of a series of redox reactions in a process called the electron transport chain. The flow of electrons through the electron transport chain produces an electrochemical proton gradient that drives the synthesis of ATP via ATP synthase. IMM, inner mitrochondrial membrane; OMM, outer mitochondrial membrane.

Fig. 2.

Glycolytic enzymes bind to filamentous actin. (A) PFK-1, aldolase and GAPDH bind to F-actin with unique properties. (B) Insulin stimulates PI3K and Rac signaling, which triggers cytoskeleton rearrangements, causing F-actin-bound aldolase to be released. This release event leads to an increase in total aldolase activity, which aids in driving glycolytic flux.

Fig. 3.

Force-induced E-cadherin signaling for increased metabolism. In response to external forces, E-cadherin stimulates AMPK via its upstream activator, LKB1, both of which are activated and recruited to the E-cadherin adhesion complex. Increased AMPK signaling has two effects. It acts on a series of kinases to increase phosphorylation of vinculin at Y822; this triggers activation of the RhoA–ROCK–MLCK–MLC pathway, culminating in reinforcement of the actin cytoskeleton. AMPK also signals for increased glucose uptake and its conversion into ATP. The ATP produced provides the energy to polymerize new actin filaments in order to reinforce the actin cytoskeleton. ROCK, Rho-associated protein kinase; MLCK, myosin light chain kinase; MLC, myosin light chain.

Fig. 4.

Integrins respond to changes in matrix stiffness. On soft extracellular matrices, active E3 ubiquitin ligase TRIM21 binds and ubiquitylates PFK-1 in the cytosol, leading to the targeted degradation of PFK-1, which keeps glycolysis relatively low. When cells are transferred to a stiff extracellular matrix, contractility is elevated and F-actin binding to talin-bound integrins is increased, thereby stimulating actin bundling and TRIM21 sequestration and inactivation. As a result, PFK-1 accumulates in the cytosol and increases glycolysis. Ub, ubiquitin.

Fig. 5.

Migrating cells increase energy production at the leading edge. Localized activation of AMPK at the leading edge of a migrating cell causes the recruitment of mitochondria to this location where increased actin cytoskeleton polymerization takes place. Miro1 mediates mitochondria trafficking from the cell body to the leading edge. Activated AMPK at the leading edge causes increased mitochondrial flux, ATP levels and membrane ruffling in cell protrusions. This localized synthesis of ATP contributes to the actin cytoskeletal dynamics required at the leading edge of a migrating cell. In addition to localized energy production at sites of highly dynamic actin polymerization, migrating cells upregulate glycolysis to contribute to the ATP levels in the cell to provide energy to migrate.

Fig. 6.

Epithelial to mesenchymal transitions alter cell metabolism. Epithelial cells that undergo EMT generally upregulate glycolysis and downregulate mitochondrial oxidative respiration. Cells can increase their glycolytic rate by upregulating the expression of glucose transporters (GLUTs) and various glycolytic enzymes. Concurrently, cells downregulate mitochondrial-associated genes, resulting in a decrease in oxidative phosphorylation. These metabolic and genetic changes coincide with increased actin cytoskeletal rearrangements that fuel the transition from an epithelial to a mesenchymal phenotype.