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.
| Identifer | oai:union.ndltd.org:MSSTATE/oai:scholarsjunction.msstate.edu:td-6156 |
| Date | 30 April 2021 |
| Creators | Tow, Brian |
| Publisher | Scholars Junction |
| Source Sets | Mississippi State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
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