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Revisiting the Role of Metabolism During Development Hidenobu Miyazawa and Alexander Aulehla*

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Revisiting the Role of Metabolism During Development Hidenobu Miyazawa and Alexander Aulehla* © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev131110. doi:10.1242/dev.131110 REVIEW Revisiting the role of metabolism during development Hidenobu Miyazawa and Alexander Aulehla* ABSTRACT regulated, in both time and space, in order to match context- An emerging viewemphasizesthat metabolism is highly regulated in both dependent cellular demands (Vander Heiden and DeBerardinis, time and space. In addition, it is increasingly being recognized that 2017). A well-known example of such a canonical yet specialized metabolic pathways are tightly connected to specific biological processes function of metabolism is the Warburg effect (Warburg, 1956). This such as cell signaling, proliferation and differentiation. As we obtain a particular metabolic state, which is characterized by increased better view of this spatiotemporal regulation of metabolism, and of glycolytic activity regardless of oxygen conditions, has been found the molecular mechanisms that connect metabolism and signaling, in various highly proliferating cells, including cancer cells (Vander we can now move from largely correlative to more functional studies. Heiden et al., 2009). A common view on this particular metabolic It is, therefore, a particularly promising time to revisit how state is that, even though ATP generation from carbon sources is less metabolism can affect multiple aspects of animal development. In efficient compared with oxidative phosphorylation (OXPHOS), this Review, we discuss how metabolism is mechanistically linked to aerobic glycolysis efficiently meets the metabolic demands for the cellular and developmental programs through both its bioenergetic production of macromolecules, such as nucleic acids, in order to and metabolic signaling functions. We highlight how metabolism is facilitate cell proliferation (Christofk et al., 2008a; Lunt et al., 2015; regulated across various spatial and temporal scales, and discuss Vander Heiden and DeBerardinis, 2017). How cells acquire such a how this regulation can influence cellular processes such as cell specialized metabolic state is not entirely clear and has been the signaling, gene expression, and epigenetic and post-translational focus of intense research for decades. Nonetheless, this intricate modifications during embryonic development. regulation of a particular metabolic program exemplifies the tight adjustment of energy metabolism to specific metabolic demands. KEY WORDS: Metabolic dynamics, Metabolic signaling, Moreover, it is becoming clear that metabolic pathways can Moonlighting enzymes, Sentinel metabolites also play modulatory or instructive roles in the regulation of cellular programs, which can be summarized as metabolic signaling Introduction functions. In addition to known mechanisms, such as the activation Central carbon metabolism is well recognized for its indispensable of redox signaling by reactive oxygen species (ROS), recent findings bioenergetic functions that underlie all cellular processes (Fig. 1). emphasize the roles of metabolites as rate-limiting substrates for However, recent studies have shed new light on previously epigenetic modifications and protein post-translational modifications unrecognized roles of central carbon metabolism in the regulation (PTMs). Furthermore, it is increasingly appreciated that metabolic of specific biological processes, such as cell signaling, proliferation enzymes also play non-bioenergetic ‘moonlighting’ functions (e.g. and differentiation (Pavlova and Thompson, 2016; Shyh-Chang non-enzymatic nuclear roles of glycolytic enzymes) (Boukouris et al., 2013). This emerging view is stimulating metabolic research et al., 2016; Jeffery, 1999). These non-canonical signaling functions in the field of developmental biology, which is uncovering the key of metabolism can establish unexpected and direct ties between roles of glucose metabolism during embryonic development in a seemingly distant cellular processes. range of species (Gandara and Wappner, 2018; Krejci and In this Review, we first provide examples of how metabolism can Tennessen, 2017). Considering the intimate connection between be compartmentalized with regard to space and time. We then discuss metabolism and the environment, these lines of research also have the molecular mechanisms by which spatiotemporally regulated the potential of yielding a better understanding of developmental metabolism signals to cellular pathways, focusing on metabolic and phenotypic plasticity, which relies on the integration of both intermediates as rate-limiting substrates for epigenetic and protein genotype and environmental cues. modifications, and on the non-canonical signaling functions of To help address the often complex and interconnected functions metabolic enzymes and metabolites. Finally, we highlight recent of metabolism, we suggest that it is helpful to first distinguish studies that address the spatiotemporal regulation of metabolism and between two types of metabolic functions: bioenergetic functions its signaling roles in various developmental contexts. and metabolic signaling functions (Fig. 2). Here, we define a bioenergetic function as one carrying out canonical metabolic Metabolic regulation in time and space activity, i.e. providing energy and/or cellular building blocks. An In contrast to the general view of metabolism as being homogeneous emerging view emphasizes that bioenergetic activities are highly within and between cells, recent findings indicate striking spatial compartmentalization of metabolism at both the intercellular/tissue and subcellular levels. In addition, it is becoming clear that energy Developmental Biology Unit, European Molecular Biology Laboratory, metabolism is dynamically regulated not only in space, but also in Heidelberg, 69117, Germany. time, across many scales. Below, we highlight a few examples of *Author for correspondence ([email protected]) such spatiotemporal compartmentalization of metabolism. H.M., 0000-0001-6164-5134; A.A., 0000-0003-3487-9239 Regulation at the intercellular/tissue level This is an Open Access article distributed under the terms of the Creative Commons Attribution Metabolic activity is spatially regulated at the cellular and tissue License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. level. In the brain, for example, glucose metabolism is DEVELOPMENT 1 REVIEW Development (2018) 145, dev131110. doi:10.1242/dev.131110 Glucose Fig. 1. An overview of glucose metabolism. Glucose, transported into cells via glucose transporters, is Cytoplasm catabolized in a series of enzymatic Glucose reactions, eventually yielding pyruvate. ATP HK Pyruvate is then either converted into ADP Pentose phosphate lactate or transported into mitochondria and G6P pathway metabolized into acetyl-CoA, fueling the PGI TCA cycle. NADH and FADH2, produced Hexosamine through glycolysis and the TCA cycle, synthesis F6P are used by the mitochondrial electron ATP PFK-1 transport chain for generating an ADP electrochemical proton gradient, which Nucleotide FBP drives OXPHOS for ATP production. synthesis Aldolase Glycolytic metabolites (shown in blue) also Phospholipid TPI feed into metabolic pathways that branch synthesis DHAP GA3P from glycolysis. These include the pentose NAD+ GAPDH phosphate pathway, the one-carbon NADH metabolism pathway, and the hexosamine 1,3-BPG and phospholipid synthesis pathways. ADP PGK Enzymes are shown in red. 1,3-BPG, ATP One-carbon 1,3-bisphosphoglyceric acid; 3PG, 3PG Serine/Glycine metabolism 3-phosphoglyceric acid; DHAP, dihydroxyacetone phosphate; F6P, + NADH NAD NADH fructose 6-phosphate; G6P, glucose PEP 6-phosphate; GA3P, glyceraldehyde NAD+ ADP PK ADP 3-phosphate; HK, hexokinase; PEP, ATP PDH TCA phosphoenolpyruvic acid; PGI, Pyruvate Acetyl- OXPHOS phosphoglucose isomerase; PK, pyruvate CoA cycle NADH LDH ATP kinase; TPI, triose phosphate isomerase. + NAD FAD Lactate NADH + NAD FADH 2 Mitochondrion compartmentalized between neurons and astrocytes. Neurons show that this Myc asymmetry is maintained by the differential activation a lower glycolytic activity than astrocytes because of the constant of mammalian target of rapamycin complex 1 (mTORC1) between degradation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6- daughter cells via the asymmetric distribution of amino acid bisphosphatese-3 (PFKFB3), which produces a potent allosteric transporters during cell division. Functionally, daughter cells with activator of a key glycolytic enzyme phosphofructokinase 1 (PFK-1) high Myc levels show elevated glycolysis and glutaminolysis (Almeida et al., 2004; Herrero-Mendez et al., 2009). Such compared with cells that have low Myc levels and are more prone to intercellular compartmentalization generates a gradient of the differentiate into actively proliferating effector T cells than into glycolytic end-product lactate from astrocytes to neurons memory T cells (Verbist et al., 2016). This metabolic switch to a (Mächler et al., 2016), which leads to lactate flow from astrocytes high glycolytic state also has important functional consequences to neurons via facilitated transport. Neurons, in turn, oxidize lactate (discussed below). into CO2 through the tricarboxylic acid (TCA) cycle, facilitating generation of ATP via OXPHOS (Pellerin and Magistretti, 2012). This Regulation at the subcellular level astrocyte-neuron lactate shuttle allows neurons to use glucose Cellular energy metabolism
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