BME Seminar: Shanna Hamilton
Monday, September 25, 2023 - 12:00 p.m.
Shanna Hamilton
Assistant Professor, Cellular and Molecular Medicine
University of Arizona
"Hyperactivity of the Rryanodine Receptor in Cardiac Disease Promotes Structural and Functional Remodeling of Mitochondria"
Keating 103
Zoom link | Password: BearDown
Hosts: Dr. Mario Romero-Ortega and Dr. Shang Song
(Instructor permission required for enrolled students to attend via Zoom)
Persons with a disability may request a reasonable accommodation by contacting the Disability Resource Center at 621-3268 (V/TTY).
Abstract:
Increased activity of the ryanodine receptor (RyR2) calcium release channel is a common finding incardiac disease. RyR2 gain-of-function not only leads to dysregulated calcium release in the heart, but can evoke remodeling of mitochondrial structure and function. In a vicious feedback cycle, mitochondrial dysfunction drive semission of reactive oxygen species (ROS) that further increase RyR2 activity. Molecular mechanisms linking the increase in RyR2 activity with mitochondrial remodeling remain elusive. Here, using a novel rat model of RyR2 gain-of-function and new genetic biosensors, we explore the hypothesis that RyR2 gain-of-function increasescalcium in the intermembrane space of mitochondria, which activates the calcium-activated protease calpain. Using electron and confocal microscopy, as well as overexpression/knockdown approaches, we show that activation of calpain drives cleavage of structural protein OPA1, leading to changes in mitochondrial cristaearchitecture and ROS emission. Furthermore, using in vivo gene editing and ex vivo whole heart optical mapping, we show that inhibition of calpain in mitochondria can significantly improve calcium handling in the diseased heart. We conclude that RyR2 gain-of-function drives mitochondrial remodeling by increasing intermembrane space calcium and activating calpains. Targeting calpains in this sub-compartment of mitochondria may be beneficial in patients at risk for sudden cardiac death.
Bio:
Dr. Shanna Hamilton received her Ph.D. in biophysics at Cardiff University, Wales, in 2018. She completed postdoctoral training in cardiovascular physiology at Brown University and Ohio State University, before joining the University of Arizona’s Department of Cellular and Molecular Medicine in July of 2023. The overarching goal of her laboratory is to decipher molecular mechanisms regulating calcium handling in the healthy and diseased heart. This will uncover new therapeutic approaches to prevent calcium-dependent arrhythmias and treat heart disease. The laboratory uses confocal microscopy, electrophysiology, ex vivo whole heart optical mapping and gene editing approaches to study these mechanisms in rat models of cardiac disease, from molecule-cell-organ-organism.