Role of HADHA in regulating right ventricular mitochondrial structure and energetic function in pulmonary hypertension

Providence Va Medical Center, Providence RI

Investigators

Abstract

Pulmonary hypertension (PH) is associated with poor prognosis that is determined by right ventricular (RV) function. No RV targeted therapies are available and the underlying mechanisms of RV dysfunction in PH remain unclear. Thus, there is an unmet need to understand cellular and molecular mechanisms associated with RV dysfunction and to convert this knowledge into therapies. Cardiomyocytes determine RV function in PH. Mitochondria through oxidative phosphorylation (OXPHOS) are the major source of energy in the heart. Targeting RV mitochondrial health, bioenergetics and function in settings of PH may provide novel therapeutic strategies to improve RV function in PH. Cardiolipin, a critical lipid unique to the mitochondria, is important for mitochondrial structure and function. Respiratory complexes in the mitochondrial electron transport chain play a critical role in OXPHOS and generation of reactive oxygen species. Our preliminary data demonstrates a decrease in mature cardiolipin content and complex I proteins and function in dysfunctional RV that correlates with a decrease in expression of alpha subunit of trifunctional protein HADHA. We hypothesize that reduced expression of HADHA results in impaired cardiolipin maturation, complex I, mitochondrial structure, and myocardial energetics that collectively causes RV dysfunction and failure. We will test this hypothesis by determining the underlying mechanism of reduced mature cardiolipin and impaired complex I expression and assembly in dysfunctional RV and determining the resulting consequences on subcellar, cellular, and organ function. In addition, we will test if restoring HADHA expression in vivo will result in improved RV mitochondrial structure/function, metabolism, and function in settings of PH. The proposed studies are expected to further our understanding into role of HADHA in RV dysfunction and identify new therapeutic opportunities to target myocardial mitochondrial function and energetics.