MAY 2013CANCER DISCOVERY | 497 VIEWS IN FOCUS A Tale of Metabolites: The Cross-Talk between Chromatin and Energy Metabolism Barbara Martinez-Pastor, Claudia Cosentino, and Raul Mostoslavsky Authors’ Affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts B. Martinez-Pastor and C. Cosentino contributed equally to this work. Corresponding Author: Raul Mostoslavsky, The Massachusetts Gen- eral Hospital, 185 Cambridge Street, Simches Bldg CPZN 4208, Boston, MA 02114. Phone: 617-643-3146; Fax: 617-643-3170; E-mail: rmostoslavsky@mgh.harvard.edu doi: 10.1158/2159-8290.CD-13-0059 ©2013 American Association for Cancer Research. Summary: Mitochondrial metabolism influences histone and DNA modifications by retrograde signaling and activa- tion of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this perspective article that epigenetic modifications might impinge on cellular metabo- lism by affecting the pool of acetyl-CoA and S -adenosylmethionine. Cancer Discov; 3(5); 497–501. ©2013 AACR. INTRODUCTION Metabolism can be defined as the sum of chemical reac- tions that occur within a cell to sustain life. It is also the way that a cell interacts with energy sources: In other words, it is the coordination of energy intake and its use and storage that ultimately allows growth and cell division. In animal cells, mitochondria have evolved to become the most efficient system to generate energy. This organelle consumes carbon sources via oxidative phosphorylation to produce ATP, the energy currency of the cell. In addition, the mitochondria produces intermediate metabolites for the biosynthesis of DNA, proteins, and lipids. Under basic dividing conditions, uptake of nutrients is tightly regulated through growth signaling pathways, and thus differ- entiated cells engage in oxidative metabolism, the most efficient mechanism to produce energy from nutrients. Cells metabolize glucose to pyruvate through glycolysis in the cytoplasm, and this pyruvate is then oxidized into CO 2 through the mitochondrial tricarboxylic acid (TCA) cycle. The electrochemical gradient gen- erated across the inner mitochondrial membrane facilitates ATP production in a highly efficient manner. Studies in recent years indicate that under conditions of nutrient excess, cells increase their nutrient uptake, adopting instead what is known as aero- bic glycolysis, an adaptation that converts pyruvate into lactate, enabling cells to produce intermediate metabolites to sustain growth (anabolic metabolism; ref. 1). Interestingly, most cancer cells undergo the same metabolic switch (Warburg effect), a unique evolutionary trait that allows them to grow unabated. Although aerobic glycolysis generates much less ATP from glucose compared with oxidative phosphorylation, it provides critical intermediate metabolites that are used for anaplerotic reactions and therefore is an obligatory adaptation among highly proliferative cells. In response to variations in nutrient availability, cells regulate their metabolic output, coordinat- ing biochemical reactions and mitochondrial activity by alter- ing transcription of mitochondrial genes through activation of transcription factors such as PGC1α and chromatin modulators that exert epigenetic changes on metabolic genes. Mitochondrial dysfunction has been implicated in aging, degenerative diseases, and cancer. Proper mitochondrial func- tion can be compromised by the accumulation of mutations in mitochondrial DNA that occur during aging. In addi- tion, reactive oxygen species (ROS) produced during oxidative phosphorylation can promote oxidative damage to DNA, pro- tein, and lipids, in turn adversely affecting global cellular func- tions. In recent years, several studies have illustrated a novel unexpected link between metabolism and gene activity: Fluc- tuations in mitochondrial and cytoplasmic metabolic reac- tions can reprogram global metabolism through their impact on epigenetic dynamics. These studies are briefly summarized in the first part of this article. In the second part, we pro- pose a provocative novel hypothesis: The cross-talk between metabolism and epigenetics is a two-way street, and defects in chromatin modulators may affect availability of intermediate metabolites, in turn influencing energy metabolism. METABOLISM AFFECTS EPIGENETICS A regulated cross-talk between metabolic pathways in the mitochondria and epigenetic mechanisms in the nucleus allows cellular adaptations to new environmental conditions. Fine- tuning of gene expression is achieved by changes in chromatin dynamics, including methylation of DNA and posttransla- tional modifications of histones: Acetyl, methyl, and phosphate groups can be added by acetyltransferases, methyltransferases, and kinases, respectively, to different residues on histones. Given the number of residues that can potentially undergo modifications in histone tails and in the DNA, it is reasonable to consider that metabolic changes affecting the availability of these metabolites will affect epigenetics (as discussed below). Recently, acetylation of proteins was revealed to be as abun- dant as phosphorylation (2). This posttranslational modifica- tion involves the covalent binding of an acetyl group obtained from acetyl-CoA to a lysine. In histones, acetylation can modify higher-order chromatin structure and serve as a docking site for histone code readers. Recent mass spectrometry studies have uncovered the complete acetylome in human cells and revealed that protein acetylation occurs broadly in the nucleus, cytoplasm, and mitochondria, affecting more than 1,700 pro- teins (2). Acetylation of proteins depends on the availability of on May 11, 2013. © 2013 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from