MEETING REVIEW Metabolic decisions in development and disease Lluc Mosteiro 1 , Hanaa Hariri 2 and Jelle van den Ameele 3, * ABSTRACT The intimate relationships between cell fate and metabolism have long been recognized, but a mechanistic understanding of how metabolic pathways are dynamically regulated during development and disease, how they interact with signalling pathways, and how they affect differential gene expression is only emerging now. We summarize the key findings and the major themes that emerged from the virtual Keystone Symposium ‘Metabolic Decisions in Development and Disease’ held in March 2021. KEY WORDS: Metabolism, Cell fate, Metabolic plasticity, Nutrition, Development Introduction Metabolism and biochemistry have long been studied in vitro or in homogenized cells and tissues. This has led to an in-depth knowledge of core metabolic pathways. However, we are only now beginning to understand the diverse roles and dynamic regulation of these metabolic pathways in the context of specific cells, tissues, organisms and stages of life. The observation of Otto Warburg (Warburg, 1956), that aerobic glycolysis was a hallmark of cancer cells, has long been the go-to example of how central carbon metabolism can be rewired to meet the biosynthetic needs of proliferation. But a lack of sensitive and tailored tools has prevented researchers from moving beyond correlation and from distinguishing cause from consequence. In this virtual Keystone Symposia on ‘Metabolic Decisions in Development and Disease’, organized by Irene Miguel-Aliaga, Ralph DeBerardinis and Marian Walhout, it became clear that the field of developmental and disease metabolism is maturing and moving on. Over the course of these 2 days, the work of Warburg, and the important influence it long had on this budding field, was mentioned only a few times. Instead, Warburg’s contemporaries were cited, and the many different physiological and pathological aspects of metabolism they explored (e.g. Spratt, 1950). Building on these early correlative studies, we were nurtured with a wide range of energizing stories, ranging from bioenergetic pathways that adopt signalling functions, over metabolic compartmentalization, metabolic plasticity and metabolic cooperation between different organelles, organs and organisms, to the impact of nutrition on development and disease. All of this was topped with exciting new technologies to feed the next steps in this dynamic and highly interdisciplinary field. Metabolic regulation of cell fate decisions After early studies into metabolic requirements of development and disease in the 19th and early 20th century (Spratt, 1950; Warburg, 1956), the golden era of genetics and molecular biology that followed meant metabolism had to make room for signalling pathways and transcription factors as the main players in developmental and tumour biology. More recently, it has become evident that metabolic pathways are not only there to support cell- type- and context-specific bio-energetic demands, but also to play instructive roles with clear metabolic signalling functions that ultimately determine normal and pathological cell fate decisions. The keynote talk by Olivier Pourquié (Harvard Medical School, Boston, MA, USA) gave an excellent example of how the field is moving from correlative to more functional studies. Working in the posterior presomitic mesoderm, a classic model for developmental patterning and morphogenesis, his lab found spatial differences in expression of glycolytic genes that control tail bud elongation (Oginuma et al., 2017). Similar findings were reported by Alexander Aulehla (EMBL, Heidelberg, Germany) (Bulusu et al., 2017), and both speakers gave fascinating accounts of their work to dissect the interactions between glycolysis and developmental signalling pathways. The Pourquié lab identified complementary extra- and intracellular pH gradients along the elongating body axis. Taking advantage of an in vitro system of pluripotent stem cell-derived presomitic mesoderm differentiation (Diaz-Cuadros et al., 2020), they found that manipulation of glycolysis and the pH affect Wnt activity. Intriguingly, non-enzymatic acetylation of β-catenin is dependent on intracellular pH and promotes mesodermal, rather than neuro-ectodermal, differentiation, providing a possible mechanism through which glycolysis-dependent pH controls a Wnt-mediated developmental switch (Oginuma et al., 2020). It will be interesting to see how widespread this non-enzymatic modification of proteins is and whether, for example, it may also apply to the tightly regulated acetylation of histones. Axis elongation is linked to periodic somite formation. Aulehla’s group developed a transgenic mouse model to increase glycolytic activity by PFKFB3 overexpression (Yalcin et al., 2009), resulting in Wnt signalling downregulation and also in a slowing of segmentation clock oscillations. They next showed that the segmentation clock can be entrained not only by periodic Notch inhibition, but also by manipulating glucose concentration. This demonstrates the power of tailored functional perturbations, even in a living embryo, thanks to the development of advanced genetic tools. Combining these with an expanding range of genetically encoded metabolite sensors will allow for more mechanistic in vivo studies on the instructive roles played by key metabolic pathways and states such as glycolysis and the pH. Further demonstrating the power of mouse genetics, Navdeep Chandel (Northwestern University, Evanston, IL, USA) sketched how, over the past three decades, our appreciation of mitochondria has evolved from simple ‘potato-shaped organelles’ that support bioenergetics and biosynthesis to highly dynamic signalling organelles that drive key cell fate decisions. The best-established mitochondrial-derived signalling molecules are reactive oxygen species (ROS), which, for example, act downstream of the 1 Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA. 2 Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA. 3 Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK. *Author for correspondence ( jv361@cam.ac.uk) L.M., 0000-0003-4041-9706; H.H., 0000-0002-2953-7536; J.v., 0000-0002- 2744-0810 1 © 2021. Published by The Company of Biologists Ltd | Development (2021) 148, dev199609. doi:10.1242/dev.199609 DEVELOPMENT