Jie Yang, PhD, assistant professor in the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine, has received a five-year, $3.8 million R01 award from the National Heart, Lung, and Blood Institute (NHLBI) to investigate the molecular mechanisms of mitochondrial stress signaling in cardiovascular disease.
Mitochondria are essential for meeting the extraordinary energy demands of the heart. When mitochondria become damaged or dysfunctional, cells activate specialized stress-response pathways that sense mitochondrial damage and coordinate cellular adaptations to maintain function and survival. Malfunction of these protective signaling mechanisms, including either insufficient or dysregulated stress responses, can contribute to heart disease such as cardiomyopathy. However, the molecular mechanisms that control mitochondrial stress signaling in the heart remain poorly understood.
“Mitochondrial dysfunction is closely associated with cardiovascular disease, but we still have a limited understanding of how heart cells sense mitochondrial damage and mount an appropriate response,” Yang said. “By understanding the underlying molecular mechanisms, we hope to uncover new opportunities to precisely control mitochondrial stress signaling and ultimately inform the development of new therapeutic strategies for heart disease.”
Yang’s laboratory studies DELE1, a mitochondrial stress sensor that communicates mitochondrial dysfunction to the rest of the cell. The newly funded project, “Defining and Targeting DELE1-Mediated Mitochondrial Stress Response in Cardiomyopathy,” will define the molecular mechanisms that regulate DELE1-mediated stress signaling in the heart and determine how disruption of this pathway contributes to cardiomyopathy. A major goal of the study is to understand this pathway at a fundamental mechanistic level while using those insights to inform new therapeutic strategies. By combining structural biology, biochemistry, cellular studies, and cardiovascular disease models, the investigators will determine how mitochondrial stress is sensed and transmitted through the DELE1 pathway and explore approaches to selectively modulate this signaling network. Ultimately, these studies could provide a molecular foundation for developing new strategies to restore appropriate mitochondrial stress responses in cardiovascular disease.
The project is led by Yang in collaboration with David Kashatus, PhD, at the University of Virginia and Brian Kuhlman, PhD, at the University of North Carolina at Chapel Hill. Yang also acknowledges the early pilot support provided by the UVA Comprehensive Cancer Center and the continued support of the UVA Department of Biochemistry and Molecular Genetics, which have been instrumental in the development of his research program.
Filed Under: Research