Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Liu, Bin

Committee Member

Gordon, Donna

Committee Member

Lawton, Andrew

Committee Member

Zhang, Jialin

Date of Degree

4-30-2021

Original embargo terms

Complete embargo for 2 years

Document Type

Graduate Thesis - Open Access

Major

Biological Sciences

Degree Name

Master of Science

College

College of Arts and Sciences

Department

Department of Biological Sciences

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) and pre-diabetic cardiomyopathy (pre-DC) are two cardiac diseases characterized by dysfunction in sarcoplasmic reticulum (SR) Ca2+ release channel RyR2. Despite similar defects in RyR2 leading to aberrant Ca2+ release (ACR), CPVT and pre-DC display divergent pathological phenotypes. Recent findings suggest SR-mitochondria interplay could contribute to pathological development; therefore, the role of SR-mitochondria interplay in shaping intracellular Ca2+ signaling was examined in CPVT and pre-DC by pharmacologically modulating mitochondria Ca2+ handling. Mitochondria can affect cytosolic/global Ca2+ dynamics through at least two mechanisms: buffering cytosolic Ca2+, or generating ROS to modulate RyR2 functionality via posttranslational modifications. Our data from cellular experiments suggests that CPVT mitochondria buffer Ca2+ to alleviate ACR, while pre-DC mitochondria cannot handle excess Ca2+, generating excess ROS to exacerbate ACR. These results were further consolidated by genetic models specifically targeting mitochondria Ca2+ handling proteins, which provided additional evidence SR-mitochondria crosstalk shapes cardiac pathological phenotypes.

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