Research

Research Focus:

Role of Mitochondria in Cardiac Fibrosis 

 

 

 

Mitochondrial Fission, Calcium, and ROS in Right Ventricular Fibrosis 

Right Ventricular (RV) failure is the leading cause of death in pulmonary arterial hypertension (PAH), and maintaining RV function in PAH is associated with improved patient survival. Unfortunately, there are currently no therapies that specifically target the major factors contributing to RV failure, such as fibrosis. Therefore, identifying the molecular mechanisms specific to RV fibrosis is urgently needed to develop new therapeutic approaches to target RV failure in PAH. 

 

The Jhun lab recently found significant activation of stress-responsive protein kinase D (PKD) and its substrates at the mitochondria in RV fibroblasts during PAH. This activation leads to increased mitochondrial fission, reactive oxygen species (ROS) generation, and RV fibroblast proliferation, resulting in RV fibrosis in PAH. Based on these findings, we have developed a novel genetic tool to selectively inhibit PKD at the mitochondria in cardiac fibroblasts (CFs) in vivo and validated its specificity in adult rats (Physiol Rep., 2024). Currently, we are testing its therapeutic efficacy to mitigate RV fibrosis and dysfunction in a preclinical rat model of PAH (Funding Source: NIH/NHLBI R01HL160699, PI: Jhun). 

ER-Mitochondrial Conta Sites in Right Ventricular Fibrosis Images

ER-Mitochondrial Contact Sites in Right Ventricular Fibrosis 

The Jhun lab recently obtained exciting preliminary data, suggesting that the mitochondrial c-Src activation and its novel substrate Mfn2 phosphorylation can alter the ER-mitochondria tethering structure, which enhances mitochondrial calcium uptake, mitochondrial ROS generation, and ROS-sensitive proliferative signaling activation in CFs, leading to cardiac fibrosis and dysfunction in the RVs under PAH. Based on these findings, we are developing a new genetic tool for inhibiting c-Src in CFs specifically at the mitochondria and testing whether the genetic inhibition of mitochondrial c-Src in CFs can prevent RV fibrosis and dysfunction in PAH. (Funding Source: NIH/NHLBI R01HL171710, Contact PI: O-Uchi & Co-PI: Jhun).

Support

Current research in the lab is supported by NIH/NHLBI R01HL160699 and R01HL171710.