Glycolysis: A multifaceted metabolic pathway and signaling hub

Abstract

Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilized by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g., hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signaling hub, producing several metabolic intermediates which serve roles in both signaling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype, and fate and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signaling molecules in eukaryotic cells, emphasizing the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.

Keywords: ATP; bioenergetics; cellular metabolism; cellular signaling; glycolysis; lactate; metabolon.

Figure 1

Glycolytic products and intermediates influence a wide range of cellular processes, beyond the provision of energy. Schematic outlining the various roles of glycolytic products, ATP and NADH, and glycolytic intermediates (bold text), beyond their roles in energy production. These roles include the synthesis of biomolecules essential for cellular structure, function, redox balance, and the regulation of immune responses, for example. NAD⁺, nicotinamide adenine dinucleotide; NADH, nicotinamide adenosine dinucleotide.

Figure 2

Lactate as a pleiotropic signaling molecule. Schematic summarizing the various roles of lactate including its role as a major gluconeogenic precursor, a regulator of gene expression via lactylation of histones, and a signaling molecule with both autocrine and paracrine effects. MCT, monocarboxylate transport protein.