Role of Mitochondrial c-Src in Right Ventricular Dysfunction in Pulmonary Hypertension

Project Summary/Abstract Pulmonary hypertension (PH) is associated with poor prognosis. Right ventricular (RV) dysfunction/failure consequent to high RV afterload is the primary cause of morbidity and mortality in PH, yet no RV targeted therapies are available. This contrasts with several drug classes that are beneficial in LV dysfunction. Therefore, there remains an unmet need to therapeutically target the mechanisms underlying RV dysfunction to improve long-term outcomes in PH. Cardiomyocytes determine RV function in PH. Mitochondria through oxidative phosphorylation (OXPHOS) are the major source of energy in the heart. Targeting RV mitochondrial bioenergetics and function in settings of PH may provide novel therapeutic strategies to improve RV function in PH. Respiratory complexes in the mitochondrial electron transport chain play a critical role in oxidative phosphorylation (OXPHOS) and generation of reactive oxygen species. OXPHOS machinery subunits have been found to be highly phosphorylated, implicating phosphorylation as a means whereby OXPHOS is regulated. To date, tyrosine phosphorylation (P-Tyr) is recognized as a critical regulatory mechanism in mitochondria and c-Src is the major tyrosine kinase localized in mitochondria. The overall goal of this proposal is to delineate the mechanisms underlying impaired RV mitochondrial energetics and function in PH. Our preliminary findings strongly support a novel mechanism governing RV complex I assembly and function in PH that is mediated by P-Tyr of complex proteins. Completion of this study is expected to identify a new targeted strategy to preserve/restore electron transfer chain function in RV cardiomyocytes in vivo in settings of PH.