Abstract P1154: Loss Of Bcl-Rambo Is Protective Against Ischemia-Reperfusion Injury

Abstract

Myocardial infarction (MI) is a leading cause of mortality worldwide. Various forms of cell death have been implicated to occur during MI, including apoptosis, necrosis, and autophagic cell death. Unfortunately, death of cardiomyocytes (CMs) in the adult heart is permanent, which demonstrates a need to therapeutically regulate death pathways during MI. To identify novel cell death regulators, we performed a screen in which we exogenously expressed over 13,000 human cDNAs into murine fibroblasts, which were subsequently challenged by a necrotic insult. From these screening efforts, we identified Bcl-Rambo, a B-cell lymphoma 2 (Bcl-2) family member, as a protective regulator against necrosis. We also determined that Bcl-Rambo is the most abundantly expressed Bcl-2 family member in wild-type (WT) mouse heart mitochondria. However, whether Bcl-Rambo is pro- or anti-apoptotic remains controversial in the literature. Recent studies have indicated Bcl-Rambo is a mediator of mitophagy, yet it is unclear how this is connected to its involvement with cell death. To determine the role of Bcl-Rambo in the heart, we generated a novel Bcl-Rambo genetic deletion mouse model and determined that key regulators of mitophagy and mitochondrial fusion are reduced. Additionally, we found that total levels of autophagy are severely blunted in the Bcl-Rambo null heart compared to WT hearts. Furthermore, Bcl-Rambo null mouse embryonic fibroblasts (MEFs) exhibit elongated mitochondria and are susceptible to multiple forms of cell death. Surprisingly, after subjecting these mice to I/R injury, we observed that Bcl-Rambo null hearts exhibit significantly smaller infarct size than their WT counterparts, suggesting that Bcl-Rambo expression is deleterious in this model. In summary, Bcl-Rambo is a unique Bcl-2 family member that regulates mitochondrial dynamics, mitophagy, and cell death. Identifying the diverse roles that Bcl-Rambo plays in mitochondrial health is critical for clinically targeting pathways during MI.