Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure

Genes Dev. 2013 Jun 15;27(12):1365-77. doi: 10.1101/gad.215871.113.

Abstract

Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is up-regulated in several human cancers. MCL-1 is also highly expressed in myocardium, but its function in myocytes has not been investigated. We generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that ablation of Mcl-1 in the adult heart led to rapid cardiomyopathy and death. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. Mitochondria isolated from MCL-1-deficient hearts exhibited reduced respiration and limited Ca(2+)-mediated swelling, consistent with opening of the mitochondrial permeability transition pore (mPTP). Double-knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally induced by myocardial stress, but induction of autophagy was impaired in MCL-1-deficient hearts. These data demonstrate that MCL-1 is essential for mitochondrial homeostasis and induction of autophagy in the heart. This study also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1.

Keywords: BCL-2; MCL-1; autophagy; heart failure; mitochondria; necrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Cardiomegaly / genetics
  • Cell Respiration / genetics
  • Cyclophilin D
  • Cyclophilins / genetics
  • Heart Failure / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Necrosis / genetics
  • Proto-Oncogene Proteins c-bcl-2 / deficiency
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Survival Analysis

Substances

  • Cyclophilin D
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • PPIF protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Cyclophilins