BBA - Molecular Basis of Disease 1866 (2020) 165887 Contents lists available at ScienceDirect BBA - Molecular Basis of Disease journal homepage: www.elsevier.com/locate/bbadis Intermediary metabolism: An intricate network at the crossroads of cell fate T and function Leonardo M.R. Ferreiraa, Albert M. Lib, Teresa L. Serafimc, Margarida C. Sobrald, ⁎ M. Carmen Alpoime, Ana M. Urbanof, a Department of Surgery and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA b Cancer Biology Program, Stanford University, Stanford, CA 94305, USA c Instituto de Medicina Molecular João Lobo Antunes, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal d Molecular Physical Chemistry Research Unit and Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal e CNC - Center for Neuroscience and Cell Biology, Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO) and Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal f Molecular Physical Chemistry Research Unit (QFM-UC), Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO) and Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal ARTICLE INFO ABSTRACT Keywords: Intermediary metabolism is traditionally viewed as the large, highly integrated network of reactions that pro- Metabolism vides cells with metabolic energy, reducing power and biosynthetic intermediates. The elucidation of its major Historical perspective pathways and molecular mechanisms of energy transduction occupied some of the brightest scientific minds for Metabolic regulation almost two centuries. When these goals were achieved, a sense that intermediary metabolism was mostly a Epigenetics solved problem pervaded the broader biochemical community, and the field lost its vitality. However, inter- Apoptosis mediary metabolism has recently been re-energized by several paradigm-shifting discoveries that challenged its Immunometabolism perception as a self-contained system and re-positioned it at the crossroads of all aspects of cell function, from cell growth, proliferation and death to epigenetics and immunity. Emphasis is now increasingly placed on the involvement of metabolic dysfunction in human disease. In this review, we will navigate from the dawn of intermediary metabolism research to present day work on this ever-expanding field. 1. Foreword biochemistry traditionally concerned with the vast and highly in- tegrated network of biochemical reactions that provides cells with Intermediary, or intermediate, metabolism is the subfield of forms of energy for immediate use (i.e., metabolic energy), reducing Abbreviations: Acetyl CoA, acetyl coenzyme A; ACLY, ATP-citrate lyase; ADP, adenosine diphosphate; AIF, apoptosis-inducing factor; AKT, protein kinase B; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; APC, antigen presenting cell; ATP, adenosine triphosphate; BAD, BCL-2 associated agonist of cell death; BAK, BCL-2 homologous antagonist/killer; BAX, BCL-2-like protein 4; BCL-2, B-cell lymphoma 2; BCL-xL, B-cell lymphoma-extra large; DNA, deoxyribonucleic acid; DNMT, DNA methyltransferase; ETC, electron transport chain; FAD, flavin adenine dinucleotide, oxidized form; FADH2, flavin adenine dinucleotide, reduced form; Fru1,6P2, fructose 1,6-bisphosphate; FTO, fat mass and obesity-associated protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLUT1, glucose transporter 1; GPX, glutathione peroxidase; GSH, glutathione; GSSG, glutathione disulfide; HAT, histone acetyltransferase; HDAC, histone deacetyltransferase; 2HG, 2-Hydroxyglutarate; HIF-1α, hypoxia inducible factor 1 α; HK, hexokinase; IDH, isocitrate dehydrogenase; IDO, indoleamine oxygenase; IL-2, interleukin-2; IMM, inner mitochondrial membrane; ITAM, immunoreceptor tyrosine-based activation motif; JHDM, Jumonji domain-containing histone demethylase; KEAP1, Kelch-like 6 ECH-associated protein 1; αKG, α-Ketoglutarate; Km, Michaelis constant; LCK, lymphocyte-specific protein tyrosine kinase; LKB1, liver kinase B1;m A, methylation at the N6 position of adenine; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; mtDNA, mitochondrial DNA; mTOR, mechanistic target of rapamycin; mTORC1, mTOR complex 1; NAD+, nicotinamide adenine dinucleotide, oxidized form; NADH, nicotinamide adenine dinucleotide, reduced form; NADP+, nicotinamide adenine dinucleotide phosphate, oxidized form; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NOX, NADPH oxidase; NRF2, nuclear factor erythroid-2-related factor 2; OAA, oxaloacetate; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PI3K, phosphoinositide-3-kinase; PPP, pentose phosphate pathway; PRX, peroxiredoxin; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RNA, ribo- nucleic acid; ROS, reactive oxygen species; SAM, S-Adenosyl methionine; SOD, superoxide dismutase; TCA, tricarboxylic acid; TCR, T cell receptor; Teff, effector T; TET, ten-eleven translocation; TNFα, tumor necrosis factor α; TRX, thioredoxin; TSC, tuberous sclerosis complex; VDAC, voltage-dependent anion channel ⁎ Corresponding author at: Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal. E-mail address: [email protected] (A.M. Urbano). https://doi.org/10.1016/j.bbadis.2020.165887 Received 18 March 2020; Received in revised form 1 June 2020; Accepted 17 June 2020 Available online 26 June 2020 0925-4439/ © 2020 Elsevier B.V. All rights reserved. L.M.R. Ferreira, et al. BBA - Molecular Basis of Disease 1866 (2020) 165887 power and biosynthetic intermediates. Its establishment as a research few selected topics, referencing researchers whose work was of funda- field dates back to the first decades of the twentieth century, whenit mental importance for the advancement of each subfield. Importantly, became a very active area of investigation; yet, its foundations were our discussion will be restricted to the cellular level. We apologize in laid more than a century before, by the work of Antoine Lavoisier on advance to all researchers, past and present, whose collective sub- the chemical nature of respiration [1]. In spite of intensive research stantial contributions to the field we could not discuss. efforts, progress in this emerging field throughout most of the nine- teenth century was restricted by very limited conceptual knowledge and the inexistence of suitable analytical methods. Nonetheless, sig- 2. Historical background nificant advances were made, paving the way for the groundbreaking discoveries of the first four decades of the twentieth century. Themany Antoine de Lavoisier, often described as the “father of chemistry”, Nobel Prizes awarded to researchers working in this field from the late could also, with equal justice, be acknowledged as the “father of phy- 1910s to the 1950s attest to the enormous vitality of intermediary siological chemistry” and, ultimately, the “father of intermediary me- metabolism during this period, seen by many as its Golden Age. At the tabolism”. Indeed, it was Lavoisier who, at the end of the eighteenth end of this period, intermediary metabolism was already contending century, first described a physiological process from a chemical per- with the growing influence of molecular biology, whose own Golden spective (Timeline). Specifically, he proposed that respiration is aslow Age started with the publication of the double-helix structure of combustion (oxidation) that burns foodstuffs, forming carbon dioxide deoxyribonucleic acid (DNA), by James Watson and Francis Crick, in and water. He hypothesized that respiration took place in the lungs, 1953 [2] – interestingly, the year Hans Krebs and Fritz Lipmann were producing the heat that maintains animal temperature, and was awarded the Nobel in Physiology or Medicine for the discovery of the somewhat connected to mechanical work [1]. It was also Lavoisier who citric acid cycle and coenzyme A, respectively. Despite having receded first described chemically the global conversion of grape must into into the background, the field progressed steadily and, by the 1970s, ethanol and carbon dioxide, i.e., alcoholic fermentation. However, the the classical pathways of intermediary metabolism were firmly estab- fact that this conversion is a metabolic process, taking place in a living lished, as were the mechanistic principles behind the energy transdu- cell, eluded him and his contemporaries [3]. That alcoholic fermenta- cing processes. Between the 1960s and the 1990s, major advances were tion requires the action of microorganisms was first acknowledged in made in our understanding of intermediary metabolism regulation. the first half of the nineteenth century by Charles Cagniard-Latour, Nonetheless, the field's vitality gradually waned. Then, at the turnof Friedrich Kützing and Theodor Schwann, but this was outright rejected the millennium, interest was rekindled by a succession of seminal dis- and even ridiculed by three of the most influential scientists of the time, coveries which repositioned intermediary metabolism at the crossroad Jöns Berzelius, Justus von Liebig and Friedrich Wöhler. However, ex- of all aspects of cellular function, ultimately touching on all facets of tensive work by Louis Pasteur in the 1850s established, once and for all, physiology and pathology. In particular, it is now clear that the study of that fermentation involves the action of a microorganism. Pasteur's