Theses and Dissertations
ORCID
https://orcid.org/0009-0003-6685-0358
Issuing Body
Mississippi State University
Advisor
Liu, Bin
Committee Member
Gordon, Donna M.
Committee Member
Lawton, Andrew K
Committee Member
Thornton, Justin A.
Date of Degree
8-8-2023
Document Type
Graduate Thesis - Open Access
Major
Biological Sciences
Degree Name
Master of Science (M.S.)
College
College of Arts and Sciences
Department
Department of Biological Sciences
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmia, caused by genetic defects in sarcoplasmic reticulum (SR) Ca-release channel RyR2, or its accessory proteins. Our previous studies demonstrated that CPVT mitochondria can absorb RyR2-mediated aberrant Ca release (ACR) and behave as an efficient Ca buffer which is critical in mitigating harmful consequences of ACR. In this study, we test the hypothesis that modulating mitochondrial phosphate (Pi) transport or the tethering between SR-mitochondria, known as Mitochondria-associated-membrane (MAMs), impacts arrhythmogenesis in CPVT. We found that inhibiting mitochondrial Pi carrier (PiC) exacerbated cellular arrhythmias whereas overexpressing PiC in CPVT alleviated both cellular and in vivo arrhythmias. In parallel, disrupting MAMs exacerbated arrhythmogenesis in CPVT, but promoting MAMs by overexpressing mitofusin2 tethering protein reduced cellular arrhythmias. Our study provided both pharmacological and genetic evidence that directing more Ca to mitochondria by enhancing mitochondrial Pi transport or targeting MAMs could be promising therapeutic strategies to reduce CPVT arrhythmia.
Recommended Citation
Deb, Arpita, "Targeting SR-mitochondria crosstalk to treat calcium-dependent arrhythmias in catecholaminergic polymorphic ventricular tachycardia" (2023). Theses and Dissertations. 5971.
https://scholarsjunction.msstate.edu/td/5971