Our research focuses on deciphering the molecular mechanisms of metabolic disease, and using this information to develop targeted therapeutic strategies. We apply mass spectrometry, biochemical, and genetic approaches to identify mitochondrial metabolic pathways that control protective and pathological cascades initiated by this organelle.
Dana Farber Cancer Institute
Center for Life Sciences, Room 11142
3 Blackfan Circle
Boston, MA 02115
Lab Size: Between 5-10
Our research focuses on deciphering the molecular mechanisms of metabolic disease and dysfunction, and using this information to develop targeted therapeutic strategies. Dysfunction in a particular cellular locale – the mitochondrion – is implicated most age-related disease pathology. We apply mass spectrometry, biochemical, and genetic approaches to identify mitochondrial metabolic pathways that control the protective and pathological cascades initiated by this organelle. Our work to date has focused on elucidating these mechanisms of damage and protection in pre-clinical models of cardiovascular and metabolic disease:
Manipulating fat function
Obesity is a global epidemic fueled by ageing populations and poor dietary habits. The health consequences are widespread and escalating, as obesity is a major risk factor for leading causes of death including diabetes, cardiovascular disease, and cancer.
While accumulation of white fat drives obesity, we now know of a second type of healthy “brown” fat that can counteract obesity and diabetes. We hypothesize that if we can understand how metabolic signals control healthy versus unhealthy adipose function, we can manipulate them as a new way of treating metabolic disease.
Recently, we uncovered new metabolic signaling mechanisms that define the anti-obesity and anti-diabetic actions of thermogenic adipose tissue. In particular, we newfound role for redox signaling in control of healthy thermogenic brown adipose function.
Protecting the heart
Cell death and tissue damage due to myocardial infarction (heart attack) underlies this leading cause of mortality. With collaborators, we have focused on unraveling mechanisms of, and targeting therapies against, the metabolic dysfunction that drives injury in myocardial infarction.
We developed in vivo biochemical and proteomic methods to establish the mechanistic basis for cardioprotection by nitric oxide within mitochondria, and developed a long sought-after targeted therapy for treatment of acute myocardial infarction. Following on from this, we developed in vivo metabolomic methods to identify how novel metabolic pathways fuel mitochondrial reactive oxygen species (ROS) production during myocardial infarction.
1. Edward T. Chouchani, Lawrence Kazak, Mark P. Jedrychowski, Gina Z. Lu, Brian K. Erickson, John Szpyt, Kerry A. Pierce, Dina Laznik-Bogoslavski, Ramalingam Vetrivelan, Clary B. Clish, Alan J. Robinson, Steve P. Gygi, and Bruce M. Spiegelman. Mitochondrial ROS control thermogenic energy expenditure and sulfenylation of UCP1. Nature, 532: 112-116 (2016)
2. Edward T. Chouchani, Victoria R. Pell, Andrew M. James, Lorraine M. Work, Kourosh Saeb-Parsy, Christian Frezza, Thomas Krieg, and Michael P. Murphy. A Unifying Mechanism for Mitochondrial Superoxide Production During Ischemia-Reperfusion Injury. Cell Metabolism, 23: 254-263 (2016)
3. Edward T. Chouchani, Victoria R. Pell, Edoardo Gaude, Dunja Aksentijević, Stephanie Sundier, Ellen L. Robb, Angela Logan, Sergiy M. Nadtochiy, Anthony C. Smith, Filmon Eyassu, Emily N. J. Ord, Rachel Shirley, Chou-Hui Hu, Anna J. Dare, Andrew M. James, Sebastian Rogatti, Simon Eaton, Paul S. Brookes, Sean M. Davidson, Michael R. Duchen, Kourosh Saeb-Parsy, Michael J. Shattock, Alan J. Robinson, Lorraine M. Work, Christian Frezza, Thomas Krieg & Michael P. Murphy. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature, 515: 431-435 (2014)
4. Edward T. Chouchani, Carmen Methner, Sergiy M. Nadtochiy, Angela Logan, Victoria R. Pell, Shujing Ding, Andrew M. James, Helena M. Cochemé, Johannes Reinhold, Kathryn S. Lilley, Linda Partridge, Ian M. Fearnley, Alan J. Robinson, Richard C. Hartley, Robin A.J. Smith, Thomas Krieg, Paul S. Brookes, and Michael P. Murphy. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nature Medicine, 19: 753–759. (2013)
5. Edward T. Chouchani, Thomas R. Hurd, Sergiy M. Nadtochiy, Paul S. Brookes, Ian M. Fearnley, Kathryn S. Lilley, Robin A.J. Smith, Michael P. Murphy. Identification of S-nitrosated mitochondrial proteins by S-nitrosothiol difference in gel electrophoresis (SNO-DIGE): Implications for the regulation of mitochondrial function by reversible S-nitrosation. Biochemical Journal, 430, 49-59. (2010)