Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction (original) (raw)

  1. Madhavi Bathina1,
  2. John Lynch3,
  3. Brian Koss1,
  4. Christopher Calabrese4,
  5. Sharon Frase5,
  6. John D. Schuetz3,
  7. Jerold E. Rehg6 and
  8. Joseph T. Opferman1
  9. 1Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38163, USA;
  10. 2Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA;
  11. 3Pharmaceutical Sciences,
  12. 4Animal Imaging Center,
  13. 5Cell and Tissue Imaging,
  14. 6Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA

Abstract

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the _Mcl-1_-, _Bax_-, and _Bak_-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.

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