Metabolism and disease
Most organisms rely on food as a source of the basic building blocks needed for essential cellular components, such as DNA, RNA, proteins, and membranes. Within cells, a multitude of biochemical pathways exist to break down or build these important macromolecules. At the same time, communication between cells and organs coordinates cellular biochemical pathways at the organismal level to regulate food intake, fat storage, and glucose regulation. Not surprisingly, dysregulation at any of these steps can be both the cause and effect of a number of different diseases, including diabetes and cancer. While efforts to correct metabolic dysfunction may be valuable in some cases, these changes may allow specific targeting of cancer cells. Research in several MCCB labs focuses on these different aspects of metabolism to gain a better understanding of its link to disease processes. Areas of study include the complex interactions between food intake and glucose regulation and the impact they have on organismal health and aging. In addition, research on metabolic changes and their interpretation at the level of gene expression has begun to provide new insights into how energy balance is maintained. Finally, MCCB researchers are investigating how metabolic re-wiring of cancer cells occurs and how it may be used for developing selectively targeted treatments.
Click on the links below to learn more details about MCCB research concerning metabolism and disease.
Ceramide, a central sphingolipid, affects cellular metabolism with important consequences on the onset and progression of metabolic diseases such as obesity, diabetes and cardiovascular disorders. To understand what metabolic pathways are affected by increased ceramide, the Acharya lab has profiled metabolites and transcripts in Drosophila mutants of the sphingolipid biosynthetic pathway that accumulate ceramide and followed this up with detailed genetic and biochemical experiments. Results from these studies show increased ceramide levels affect energy producing pathways such as mitochondrial oxidative phosphorylation and lipolysis leading to hypertriglyceridemia, cardiac abnormalities and ultimately reduced lifespan of the mutant animals.
- Rahman et al (2014). Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase b and regulates complex V activity. J. Cell. Biol. 206, 289-305.
- Nirala et al (2013). Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis. PLoS Genetics. (6):e1003556 doi: 10.1371.
Our laboratory studies how autophagy (self-eating) is regulated and functions in complex multi-cellular organisms. Autophagy has been implicated in multiple human disorders, including neurodegeneration and cancer, and is considered a promising therapeutic target. Autophagy is a catabolic process that helps to provide fuel as bioenergetics substrates during nutrient deprivation, and is thought to influence growth of tissues. A goal of our research is to understand how signaling pathways that regulate autophagy, cell growth and cell bioenergetics interface to control tissue growth and animal health.
- Shravage BV, Hill JH, Powers CM, Wu L, Baehrecke EH. Atg6 is required for multiple vesicle trafficking pathways and hematopoiesis in Drosophila. Development. 2013 Mar;140(6):1321-9. PubMed PMID: 23406899; PubMed Central PMCID: PMC3585664.
- Pérez E, Das G, Bergmann A, Baehrecke EH. Autophagy regulates tissue overgrowth in a context-dependent manner. Oncogene. 2014 Sep 1;0PubMed PMID: 25174403; PubMed Central PMCID: PMC4345156.
- Lin L, Rodrigues FSLM, Kary C, Contet A, Logan M, Baxter R, Wood W and Baehrecke EH (2017) Complement-related regulates autophagy in neighboring cells. Cell 2017 Jun 29;170(1):158-171. PMID: 2866617 PubMed Central PMCID: PMC5533186.
- Anding AL, Wang C, Chang TK, Sliter DA, Powers CM, Hofmann K, Youle RJ, Baehrecke EH. Vps13D encodes a ubiquitin binding protein that is required for the regulation of mitochondrial size and clearance. Curr Biol. 2018 Jan 22;28(2):287-295. PMID: 29307555; PubMed Central PMCID: PMC5787036.
- Zhao S, Fortier TM, Baehrecke EH. Autophagy Promotes Tumor-like Stem Cell Niche Occupancy. Curr Biol. 2018 Oct 8;28(19):3056-3064.PMID: 30270184; PubMed Central PMCID: PMC6185742.
- Velentzas PD, Zhang L, Das G, Chang TK, Nelson C, Kobertz WR, Baehrecke EH. The proton-coupled monocarboxylate transporter Hermes is necessary for autophagy during cell death. Dev Cell. 2018 Oct 9: 47:281-293. PMID: 30318245 PubMed Central PMCID: in progress.
Deterioration of mitochondria and metabolism is a common component of numerous diseases such as cancer and neurodegeneration as well as the aging process. The Haynes Lab focuses on mechanisms utilized by cells to maintain or recover mitochondrial activity and cellular health in a number of physiologic and pathologic scenarios focusing on a stress response known as the mitochondrial UPR.
- Lin YF, Haynes CM. (2016) Metabolism and the UPRmt. Molecular Cell. Mar 3:61(5): 677-682.
- Lin YF, Schulz AM, Pellegrino MW, Lu Y, Shaham S, Haynes CM. (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature. May 2:533(7603): 416-419.
- Nargund AN*, Pellegrino MW*, Fiorese CJ, Baker BM, Haynes CM. (2012) Mitochondrial import of ATFS-1 regulates mitochondrial UPR activation. Science. Aug 3;337(6094): 587-90.
- Nargund AN, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM. (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Molecular Cell. April 2;58(1):123-33.
The goal of the Kim lab is to understand how changes in metabolic pathways support cancer cells and their survival within the tumor environment, and to exploit these changes for therapeutic purposes. Cancer cells are dependent on metabolic pathways which involve the formation of toxic metabolites. The lab aims to understand the role of these pathways, and to target these pathways to poison cancer cells with their own metabolites. Furthermore, as widespread changes in cellular metabolism accompany various physiological and pathological changes in cellular state, the lab is also interested in the potential roles of toxic metabolites in contexts outside of cancer.
- Kim et al. SHMT2 drives glioma cell survivalin ischaemia but imposes a dependence on glycine clearance. (2015) Nature, 520(7547):363-367
The Shaw lab studies the IGF-1R/insulin signaling pathway, with a focus on the Insulin Receptor Substrate (IRS) proteins and the mechanism by which these signaling adaptors regulate tumor progression. The IRS proteins are essential for transmitting signals from the insulin and IGF-1 receptors to regulate growth and metabolic homeostasis in both normal and pathological settings. Research in the Shaw lab investigates how the IRS proteins regulate tumor metabolism, as well as the tumor cell response to the metabolic microenvironment of tumors.
- Pankratz SL, Tan EY, Fine Y, Mercurio AM, Shaw LM. (2009) Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. J Biol Chem. 284(4):2031-7.
- Mardilovich K, Shaw LM. (2009) Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion. Cancer Res. 69(23):8894-901.
- Landis J, Shaw LM. (2014) Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3β to regulate aerobic glycolysis. J Biol Chem. 289(26):18603-13.
Aging is a process that involves the coordination of many physiological inputs. The Tissenbaum lab focuses on dissecting the aging process with an emphasis on changes in metabolism, stress, immunity and lifespan. They use C. elegans and an interdisciplinary approach to identify and study the molecular players that define the aging process to identify anti-aging therapies that promote health and not simply prolong life. The Tissenbaum Lab strives to push to their studies to ultimately understand how to promote health in the context of a whole organism.
- Tissenbaum, H. A. (2012) Genetics, Life Span, Health Span, and the Aging Process in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 67(5):503-10.
- Bansal et al. (2015) Uncoupling lifespan and healthspan in C. elegans longevity mutants. PNAS, 2015 Jan 5. pii: 201412192. PMC4311797
- Bansal, A. and Tissenbaum, H. A. (2015). Quantity or quality? The Scientist
Aneuploidy, which represents a cellular state of having an abnormal number of chromosomes, is associated with human diseases including mental retardation, neurodegenerative diseases and cancer. Recently, the Torres lab discovered that lipid metabolism is altered by aneuploidy and they investigate the molecular mechanisms that alters lipid synthesis in aneuploid cells. The research from the Torres laboratory will significantly contribute to our understanding how normal cells regulate the levels of, and respond to changes in lipid composition potentially leading to a better rationale for utilizing drugs that target lipid metabolism in the clinic.
The Wang Lab is interested in transcriptional and epigenetic mechanisms that control brown fat fate determination and maintenance. They explore whether the identified mechanisms can be utilized to convert white fat to brown-like fat, with the goal to reveal potential therapeutic targets for obesity and associated metabolic diseases.
- Pan et al. (2014) MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun, 5:4725 .
- Pan et al. (2012) The histone demethylase Jhdm1a regulates hepatic gluconeogenesis. PLoS Genet, 8(6):e1002761.
- Pan et al. (2009) Twist-1 is a PPARdelta-inducible, negative-feedback regulator of PGC-1alpha in brown fat metabolism. Cell, 137(1):73-86.