Mitochondrial network remodeling and the glutamine-proline axis in pulmonary vascular disease associated with CHD.

Florida International University, Miami FL

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Abstract

Project Summary (Project #3) Pulmonary vascular disease (PVD) in infants and children with congenital heart defects (CHD) causes significant morbidity due to increased pulmonary blood flow and pressure. A major challenge in treating these patients is the limited mechanistic understanding of endothelial dysfunction in CHD-associated PVD. In the current research cycle, Project #3 identified that disruptions in mitochondrial network dynamics, specifically an imbalance between mitochondrial fission and fusion, play a critical role in metabolic reprogramming, leading to endothelial dysfunction. Increased mitochondrial fission, driven by dynamin related protein 1 (Drp1), shifts the metabolism toward a Warburg phenotype, while the loss of the fusion protein mitofusin-2 (MFN2) plays a significant role in suppressing fusion and maintaining elevated glycolysis. These changes promote glutamine-proline metabolism, collagen biosynthesis, cell proliferation, and survival, further driving endothelial dysfunction and proximal pulmonary artery (PA) stiffness. New findings indicate that the JNK-Huwe1 axis contributes to MFN2 degradation, disrupting mitochondrial network dynamics and promoting the angiogenic phenotype in pulmonary artery endothelial cells (PAEC). The research plan aims to investigate the mechanisms behind JNK-mediated MFN2 degradation, its effects on mitochondrial function and metabolic reprogramming, and its role in endothelial dysfunction. The study will explore how JNK activation leads to the proteasomal degradation of MFN2 via Huwe1, and how this process disrupts mitochondrial dynamics and rewires cellular metabolism. In addition, the therapeutic potential of targeting mitochondrial dynamics to restore endothelial function will be assessed. The research will explore strategies to prevent MFN2 degradation using Huwe1 inhibitors and attenuate mitochondrial fission using a novel Drp1 inhibitor developed by us. These therapeutic approaches will be tested in lamb models of CHD-PVD, with the goal of reversing metabolic reprogramming, improving endothelial function, and reducing pulmonary vascular remodeling. Ultimately, this project aims to uncover novel regulatory mechanisms and therapeutic targets to improve outcomes for children with CHD-associated PVD.