Principles and functions of metabolic compartmentalization

Abstract

Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization-the spatial and temporal separation of pathways and components-shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or 'pillars': establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as 'command-and-control centres' and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.

Fig. 1 |. Metabolic compartmentalization across scales.

For multicellular organisms, compartmentalization is found throughout physiology. a, Tasks such as metabolite storage, synthesis and consumption are distributed between organs and tissues at the systemic level, and between different cell types within a tissue or organ. Within cells, membrane-bound organelles subdivide the cytoplasm into chemically and physically unique reaction compartments. These compartments are further parsed into unique environments at the level of multi-enzyme assemblies and condensates. b, As an example, glucose is distinctively stored and used between organs, tissues and cells. Storage occurs in the liver and skeletal muscle as glycogen, and glucose is the predominant fuel for the brain and substrate for lipid synthesis in adipocytes. Within liver lobules, zonation between periportal and periventricular areas compartmentalizes glycogen and glucose synthesis. At the cellular level, an early step in glucose breakdown in the cytosol occurs by the action of 6-phosphofructokinase, which has been described to form large filaments. Glycogen granules in the cytosol serve as glucose storage sites.

Fig. 2 |. The three pillars of metabolic compartmentalization.

At its essence, compartmentalization fulfils three functions in metabolism, by establishing the prerequisites for: (1) unique chemical and biophysical environments that facilitate biochemical reactions and metabolite storage; (2) detoxification and protection from toxic intermediates and by-products; and (3) providing metabolic control to regulate metabolite storage and release, prevent futile cycles and provide a mechanism by which metabolites function directly as signalling molecules.