Principal Investigator:    Mark Payne
Grant Title:    Mitochondrial Protein Acetylation and Heart Failure in Friedreich’s Ataxia
Status:    Closed
Start Date:    7/1/2013
Duration:    24 months
Description:    Friedreich’s Ataxia (FRDA) is a progressive and fatal disease of the heart and brain with no definite treatment modality. Patients die at a young age with severe hypertrophic cardiomyopathy due to mitochondrial proliferation and heart failure, and are at increased risk of poor cardiovascular outcome and death with surgical stress. There is an urgent and unmet need to understand the mechanism(s) of heart failure in FRDA to guide the rational development of effective treatments and identify patients at greatest risk of death. This project is a collaborative effort between Dr. Mark Payne, MD, at the Indiana University School of Medicine, and Dr. Matt Hirschey, PhD, at Duke University School of Medicine, to understand the biochemical basis of heart failure in FRDA. Both of our labs have independently made recent novel findings that may represent critical events in the mitochondrial dysfunction that underlies the fatal cardiomyopathy of FRDA: The Hirschey lab has made the fundamental finding that mitochondrial proteins can be modified (‘acetylated’) and become less active, and that a specific enzyme (‘SIRT3’) is responsible for restoring their activity to normal. The Payne lab has made the disease-related finding that mitochondrial proteins from the heart in FRDA are heavily modified (‘acetylated’), and this may reduce their ability to use normal fuels (fat) for energy, thus causing heart failure. We propose to combine the strengths of both labs to explore and determine the mechanism of mitochondrial dysfunction underlying heart failure in FRDA. If correct, these findings would identify an important mechanism underlying mitochondrial dysfunction in FRDA, and would explain why FRDA patients develop a fatal hypertrophic cardiomyopathy. Furthermore, these findings would identify a new treatment strategy for FRDA patients by pharmacologically targeting protein acetylation, resulting in new and innovative approaches for FRDA treatment.