We are in the midst of a worldwide epidemic in type 2 diabetes (T2D) that is exacerbated by an increasingly conservative pharmaceutical industry that is now desperate for new targets. A growing body of evidence implicates altered mitochondrial function in the pathogenesis of T2D and obesity. For example, mitochondrial metabolism is critical in the control of glucose stimulated insulin secretion, hepatic gluconeogenesis, and peripheral fuel oxidation. The only known direct target of metformin, one of the most useful agents for treating T2D, is a mitochondrial complex. Reduced mitochondrial mass/function have been documented in the skeletal muscle of humans with obesity and T2D, and during aging, and reversible with exercise. Brown fat, which expends chemical energy through mitochondrial uncoupling, has recently emerged as a possible therapeutic target for human obesity. Collectively, these observations raise the exciting hypothesis that modulating mitochondrial physiology may help prevent or reverse the pathophysiology of T2D and obesity. The goal of this R24 project is to discover a mechanistically diverse collection of small molecules with desirable pharmacologic properties that can modulate mitochondrial energetics in vivo by targeting transcriptional programs, translational programs, and direct mitochondrial physiology. Our highly integrated project brings together experts in mitochondrial biogenesis, bioenergetics, chemical screening, and medicinal chemistry, to build and pursue this bold therapeutic hypothesis.
In Aim 1 we will follow-up on exciting preliminary data that has revealed a novel small molecule and its target, a plasma membrane ion channel that controls mitochondrial biogenesis via a transcriptional mechanism. Using this validated screening strategy, we will screen for additional novel small molecules acting via transcriptional mechanisms that promote brown fat differentiation.
In Aim 2 we will follow-up on a large-scale chemical screen that is designed to discover small molecules that work at the level of post-translational modifications to influence mitochondrial biogenesis.
In Aim 3 we will capitalize on the recent discovery of mitochondrial calcium channel subunits, enabled by the previous funding period of this grant, and screen for novel drugs that directly target mitochondrial physiology and energetics through targeting mitochondrial calcium flux. For all three aims we will collaborate closely with leading chemists at Broad Institute and Scripps to perform in-depth lead optimization and formulation and evaluate the novel drugs both in cultured cells as well as in rodent models. If successful, this collaborative project could result in the discovery of mechanistically diverse small molecules that will advance our fundamental understanding of the contribution of mitochondrial metabolism to the development of T2D, while also helping to launch a potentially brand new class of therapeutics for this growing epidemic.

Public Health Relevance

We are experiencing a worldwide epidemic of type II diabetes and obesity, and it is imperative that biomedical scientists find new drug targets that can improve these conditions. This group of investigators is using chemical biology methods to identify tractable drug targets that can improve metabolic diseases through actions on mitochondrial biology and cellular energetics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (M2))
Program Officer
Blondel, Olivier
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Kamer, Kimberli J; Mootha, Vamsi K (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep 15:299-307
Kovács-Bogdán, Erika; Sancak, Yasemin; Kamer, Kimberli J et al. (2014) Reconstitution of the mitochondrial calcium uniporter in yeast. Proc Natl Acad Sci U S A 111:8985-90
Lee, Yoonjin; Dominy, John E; Choi, Yoon Jong et al. (2014) Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510:547-51
Csordás, György; Golenár, Tünde; Seifert, Erin L et al. (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²? uniporter. Cell Metab 17:976-87
Plovanich, Molly; Bogorad, Roman L; Sancak, Yasemin et al. (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8:e55785
Ye, Li; Wu, Jun; Cohen, Paul et al. (2013) Fat cells directly sense temperature to activate thermogenesis. Proc Natl Acad Sci U S A 110:12480-5
Sancak, Yasemin; Markhard, Andrew L; Kitami, Toshimori et al. (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379-82
Kitami, Toshimori; Logan, David J; Negri, Joseph et al. (2012) A chemical screen probing the relationship between mitochondrial content and cell size. PLoS One 7:e33755
Baughman, Joshua M; Perocchi, Fabiana; Girgis, Hany S et al. (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341-5
Wagner, Bridget K; Gilbert, Tamara J; Hanai, Jun-ichi et al. (2011) A small-molecule screening strategy to identify suppressors of statin myopathy. ACS Chem Biol 6:900-4

Showing the most recent 10 out of 13 publications