Updated: September 24, 2015
Michelle Boland
CBC Scholar: Class of 2013
PhD Candidate, Committee on Molecular Metabolism and Nutrition (BSD), University of Chicago, Advisor: Kay F. Macleod
MACLEOD LAB WEBPAGE
RESEARCH INTERESTS:
Mitochondria are essential for many cellular processes including aerobic ATP generation, lipid biosynthesis, and the regulation of cell death. In order to maintain quality control, cells eliminate damaged mitochondria via mitophagy, a specialized form of autophagy. BNip3 is a hypoxia-inducible member of the Bcl-2 family that integrates into the outer mitochondrial membrane to serve as a molecular adaptor that tethers mitochondria to the growing autophagosome by binding microtubule-associated protein 1 light chain 3 (LC3). We have shown that disruption of mitophagy through deletion of BNip3 results in hepatic metabolic defects including deregulated lipid and glucose homeostasis in otherwise normal, healthy mice. Defects in liver metabolism were linked to increased mitochondrial mass, but diminished mitochondrial function, including reduced oxygen consumption and loss of mitochondrial membrane potential. Whether these defects are solely due to mitophagy disruption, or BNip3 has another role at the mitochondria are questions I am addressing. Interestingly, BNip3 is stabilized post-translationally under fasting conditions and current work is aimed at defining this level of regulation. I am also interested in defining the consequence of BNip3 loss on progression to hepatocellular carcinoma (HCC). In western societies fatty liver disease is the leading condition in 40% of HCC cases, however the molecular mechanism underlying hepatic fat accumulation and initiation of carcinogenesis is undefined. We have shown that loss of BNip3 in mice results in hepatic lipid accumulation, increased immune infiltration, and decreased mitochondrial integrity. In humans, BNip3 is epigenetically silenced in HCC sub-type A2, which is a more common and aggressive form, leading to the hypothesis that BNip3 plays a tumor suppressive role in the liver. This project will advance our current understanding of the regulation and function of BNip3, and will define for the first time the critical role of BNip3 in maintaining metabolic homeostasis and inhibiting liver tumorigenesis. As a result, BNip3 may be targeted for the development of more efficacious treatments for a variety of diseases including those associated with the metabolic syndrome and cancer.
PUBLICATIONS:
Chourasia AH, Tracy K, Frankenberger C, Boland ML, Sharifi MN, Drake LE, Sachleben JR, Asara JM, Locasale JW, Karczmar GS, Macleod KF. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep. 2015 Sep;16(9):1145-63. (PubMed)
Chourasia AH, Boland ML, Macleod KF. Mitophagy and cancer. Cancer Metab. 2015 Mar 26;3:4. (PubMed)
Boland ML, Chourasia AH, Macleod KF. Mitochondrial Dysfunction in Cancer. Front. Oncol. 2013 3:292. (PubMed)
Glick D, Zhang W, Beaton M, Marsboom G, Gruber M, Simon MC, Hart J, Dorn GW 2nd, Brady MJ, Macleod KF. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol. 2012 Jul;32(13):2570-84. (PubMed)
Ukaegbu UE, Kantz A, Beaton M, Gassner GT, Rosenzweig AC. Structure and ligand binding properties of the epoxidase component of styrene monooxygenase. Biochemistry. 2010 Mar 2;49(8):1678-88. (PubMed)
HONORS / FELLOWSHIPS:
- Chicago Biomedical Consortium (CBC) Scholar, 2013-2014
- Selected oral presenter, Keystone Symposia, Mitochondrial Dynamics and Function, Banff, AB Canada, March 2012
- NIH T32 Pre-Doctoral Training Fellow, T32-DK780073, July 2011- Present
- San Francisco State University Summer Research Fellow, Summer 2008
COMMUNITY SERVICE:
- Judge, Chicago Public Schools Student Science Fair, March 2013
- Volunteer at the 61st Farmer’s Market, 2010-2012 season
TEACHING ASSISTANTSHIPS:
- Endrocrinology I: Cell Signaling, The University of Chicago, Autumn 2011
- Introduction of Biochemistry Laboratory, The University of Chicago, Spring 2011
- Nutritional Science, The University of Chicago, Winter 2010
- Metabolism & Nutrition, The University of Chicago, Spring 2010
- General Chemistry Laboratory, Villanova University, Spring 2005