Marcia Haigis, Ph.D.

Marcia Haigis, Ph.D.Assistant Professor of Cell Biology at Harvard Medical School. Dr. Haigis’s lab is focused on understanding the role that mitochondria play in mammalian aging and disease. Mitochondria are dynamic organelles that provide cells with energy even during dramatic changes in diet, stress and development. Mitochondria are also a major site for reactive oxygen species production, ion homeostasis, and apoptosis. Not surprisingly, mitochondrial dysfunction has been implicated in aging, neurodegeneration and metabolic diseases, such as diabetes.

The regulation of aging is highly conserved. For example, an extra copy of SIR2 (silent information regulator; sirtuins) significantly increases the lifespan of yeast, worms and flies. Mammals have seven homologs of SIR2, three of which are found in mitochondria. Recent studies have shown that sirtuins affect mitochondrial biogenesis and energy production. Our lab is interested in understanding how sirtuins mediate the interplay between mitochondrial activity and aging.

The main goals of the lab’s research are: 1) to identify signals generated by mitochondria that contribute to aging and to identify those regulated by mammalian sirtuins, 2) to determine molecular mechanisms for these signals, and 3) to understand how these pathways regulate biological functions that decline during normal aging. To accomplish these goals, the lab’s research integrates biochemistry, proteomics, cell biology and mouse genetics. These studies have the potential to lead to novel therapies that could treat a spectrum of human diseases.

Direct Contact

Harvard Medical School
NRB-954C
77 Ave Louis Pasteur
Boston, MA 02115
Telephone: 617-432-6865
Fax: 617-432-6562
Email:
Lab Website: https://haigis.hms.harvard.edu/

Selected Publications

Jeong SM, Lee A, Lee J, Haigis MC. SIRT4 suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem. 2013 Dec 24. [Epub ahead of print] PMID: 24368766

Bause AS, Matsui MS, Haigis MC. The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation. J Biol Chem. 2013; 288:36484-36491. PMID: 24194516

Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, Cen Y, Jeong SM, Li X, Sauve AA, Haigis MC. SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Mol Cell Biol. 2013; 33:4552-4561. PMID: 24043310

Yang MH, Laurent G, Bause AS, Spang R, German N, Haigis MC, Haigis KM. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Mol Cancer Res. 2013; 11:1072-1077. PMID: 23723075

Laurent G., German NJ, Saha AK, de Boer VCJ, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, Lovitch SB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl-CoA decarboxylase. Molecular Cell. 2013; 50:686-698. PMID: 23746352

Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4. Cell. 2013; 153:840-854. PMID: 23663782

Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, Xu X, Li C, Wang RH, Lee J, Csibi A, Cerione R, Blenis J, Clish CB, Kimmelman A, Deng CX, Haigis MC. SIRT4 Has Tumor-Suppressive Activity and Regulates the Cellular Metabolic Response to DNA Damage by Inhibiting Mitochondrial Glutamine Metabolism. Cancer Cell. 2013; 23:450-463. PMID: 23562301

Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013; 496:101-105. PMID: 23535601

Lee PC, Dodart JC, Aron L, Finley LW, Bronson RT, Haigis MC, Yankner BA, Harper JW. Altered Social Behavior and Neuronal Development in Mice Lacking the Uba6-Use1 Ubiquitin Transfer System. Mol Cell. 2013; 50:172-184. PMID: 23499007

Peserico A, Chiacchiera F, Grossi V, Matrone A, Latorre D, Simonatto M, Fusella A, Ryall JG, Finley LW, Haigis MC, Villani G, Puri PL, Sartorelli V, Simone C. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell Mol Life Sci. 2013; 70:2015-2029. PMID: 23283301

Sebastian C, Satterstrom KF, Haigis MC, Mostoslavsky R. From Sirtuin biology to human diseases: an update. J Biol Chem. 2012; 287:42444-42452. Review. PMID: 23086954

Bause AS, Haigis MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2012; [Epub ahead of print] PMID: 22964489

Carracedo A, Weiss D, Leliaert AK, Bhasin M, de Boer VC, Laurent G, Adams AC, Sundvall M, Song SJ, Ito K, Finley LS, Egia A, Libermann T, Gerhart-Hines Z, Puigserver P, Haigis MC, Maratos-Flier E, Richardson AL, Schafer ZT, Pandolfi PP. A metabolic prosurvival role for PML in breast cancer. J Clin Invest. 2012; 122:3088-3100. PMID: 22886304

Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, Chin YR, Zhai B, Shaik S, Lau AW, Wang Z, Gygi SP, Nakayama K, Teruya-Feldstein J, Toker A, Haigis MC, Pandolfi PP, Wei W. Acetylation-dependent regulation of Skp2 function. Cell. 2012; 150:179-193. PMID: 22770219

Finley LW, Haigis MC. Metabolic regulation by SIRT3: implications for tumorigenesis. Trends Mol Med. 2012; 18:516-523. PMID: 22749020

Yang MH, Nickerson S, Kim ET, Liot C, Laurent G, Spang R, Philips MR, Shan Y, Shaw DE, Bar-Sagi D, Haigis MC, Haigis KM. Regulation of RAS oncogenicity by acetylation. Proc Natl Acad Sci U S A. 2012; 109:10843-10848. PMID: 22711838

Haigis MC, Deng CX, Finley LW, Kim HS, Gius D. SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res. 2012; 72:2468-2472. PMID: 22589271

Cerletti M, Jang YC, Finley LW, Haigis MC, Wagers AJ. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 2012; 10:515-519. PMID: 22560075

Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, Anastasiou D, Ito K, Sasaki AT, Rameh L, Carracedo A, Vander Heiden MG, Cantley LC, Pinton P, Haigis MC, Pandolfi PP. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell. 2012; 149:49-62. PMID: 22401813

Finley LW, Lee J, Souza A, Desquiret-Dumas V, Bullock K, Rowe GC, Procaccio V, Clish CB, Arany Z, Haigis MC. Skeletal muscle PGC-1alpha mediates mitochondrial, but not metabolic, adaptation to calorie restriction. Proc Natl Acad Sci U S A. 2012; 109:2931-2936. PMID: 22308395

De Raedt T, Walton Z, Lucas J, Li D, Chen Y, Maertens O, Jeong SM, Bronson RT, Normant E, Haigis MC, Manning BD, Wong KK, Macleod KF, and Cichowski K. Developing an mTOR-inhibitor based combination cancer therapy. Cancer Cell. 2011; 20:400-413. PMID 21907929.

Finley LW, Haas W, Desquiret-Dumas V, Wallace DC, Procaccio V, Gygi SP, Haigis MC. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One. 2011; 6:e23295. PMID: 21858060.

Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Deill’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC. Pancreatic cancers require autophagy for growth. Genes Dev. 2011; 25:717-729. PMID 21406549.

Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardosa SM, Clish CB, Pandolfi PP, Haigis MC. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011; 19:416-428. PMID: 21397863.

Haigis MC, Yankner BA. The aging stress response. Mol. Cell. 2010; 40:333-344. PMID: 20965426.

Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010; 5:253-295. PMID: 20078221.

Finley LS and Haigis MC. The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Aging Research Reviews. 2009; 8:173-188.

Nakagawa T, Lomb D, Haigis MC, Guarente. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009; 3:560-570.

Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, Settleman J, Giovannini M, Jacks T. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation, and tumor progression in the colon. Nature Genetics. 2008; 40:600-608.

Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV Jr, Weissman S, Verdin E, Schwer B. Mammalian Sir2 Homolog SIRT3 Regulates Global lysine acetylation. Mol Cell Biol. 2007; 27:8807-8814.

Haigis MC, Guarente L. Mammalian sirtuins-emerging roles in physiology, aging and calorie restriction. Genes and Development. 2006; 20:2913-2921.

Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006; 126:941-954.

Blander G, Olejnik, Krzymanska-Olejnik, McDonagh T, Haigis MC, Yaffe M, Guarente L. SIRT1 shows no substrate specificity in vitro. Journal of Biological Chemistry. 2005; 280:9780-9785.

Leissring M, Farris W, Wu, Christodoulou D, Haigis MC, Guarente L, Selkoe D. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochemical Journal. 2004; 116:313-324.

Lin SJ, Ford E, Haigis MC, Liszt G, Guarente L. Calorie restriction extends yeast life span by lowering the level of NADH. Genes and Development. 2004; 18:12-16.

Blander G, de Oliveira R, Conboy C, Haigis MC, Guarente L. Superoxide dismutase I knock-down induces senescence in human fibroblasts. Journal of Biological Chemistry. 2003; 278:38966-38969.