Abstract P042: Loss of Mcl-1 in the Heart Leads to Rapid Mitochondrial Dysfunction and Development of Heart Failure
Mcl-1 is an anti-apoptotic Bcl-2 family protein that is expressed at high levels in the heart. However, the functional importance of Mcl-1 in the heart has not been investigated. To study the function of Mcl-1 in cardiac myocytes, we generated inducible, myocyte-specific Mcl-1 knock-out mice using a tamoxifen-driven loxP/α-MHC-Cre-recombinase system. We found that deletion of Mcl-1 by tamoxifen injections resulted in rapid development of cardiac hypertrophy, pulmonary edema and cardiac dysfunction in adult mice. Although Mcl-1 is known to inhibit apoptosis in cells, Mcl-1 deficient hearts were TUNEL negative and showed no activation of caspase-3. The anti-apoptotic proteins Bcl-2 and Bcl-X L have also been reported to inhibit autophagy, but we found no increase in autophagy upon loss of Mcl-1. Western blot analysis of other Bcl-2 family members revealed that Bcl-2 was significantly increased in Mcl-1 deficient hearts, suggesting a compensatory mechanism. Interestingly, ultrastructural analysis revealed the presence of swollen mitochondria, ruptured cells, and intracellular contents in the extracellular space. These signs are characteristics of necrotic cell death. Mcl-1 deficient hearts also exhibited reduced mitochondrial respiration and significantly lower cellular ATP levels compared to wild type, suggesting that the loss of Mcl-1 impairs mitochondrial function. Moreover, mitochondria isolated from Mcl-1-/- hearts showed pronounced swelling at baseline that could be alleviated by polyethylene glycol-induced shrinkage. Calcium release experiments also showed higher baseline Ca2+ levels in mitochondria from Mcl-1-/- hearts compared to wild type, suggesting that Mcl-1 deletion increases permeability to Ca2+. Our data suggest that loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial impairment and necrotic cell death. Thus, in addition to its anti-apoptotic role, Mcl-1 has an essential but unidentified role in maintaining mitochondrial function in cardiac myocytes.
- © 2011 by American Heart Association, Inc.