Mcl-1-mediated mitochondrial fission protects against stress but impairs cardiac adaptation to exercise

J Mol Cell Cardiol. 2020 Sep;146:109-120. doi: 10.1016/j.yjmcc.2020.07.009. Epub 2020 Jul 25.

Abstract

Myeloid cell leukemia-1 (Mcl-1) is a structurally and functionally unique anti-apoptotic Bcl-2 protein. While elevated levels of Mcl-1 contribute to tumor cell survival and drug resistance, loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial dysfunction and heart failure development. Although Mcl-1 is an anti-apoptotic protein, previous studies indicate that its functions extend beyond regulating apoptosis. Mcl-1 is localized to both the mitochondrial outer membrane and matrix. Here, we have identified that Mcl-1 in the outer mitochondrial membrane mediates mitochondrial fission, which is independent of its anti-apoptotic function. We demonstrate that Mcl-1 interacts with Drp1 to promote mitochondrial fission in response to various challenges known to perturb mitochondria morphology. Induction of fission by Mcl-1 reduces nutrient deprivation-induced cell death and the protection is independent of its BH3 domain. Finally, cardiac-specific overexpression of Mcl-1OM, but not Mcl-1Matrix, contributes to a shift in the balance towards fission and leads to reduced exercise capacity, suggesting that a pre-existing fragmented mitochondrial network leads to decreased ability to adapt to an acute increase in workload and energy demand. Overall, these findings highlight the importance of Mcl-1 in maintaining mitochondrial health in cells.

Keywords: Drp1; Fission; Heart; Mcl-1; Mitochondria.

Publication types

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

MeSH terms

  • Adaptation, Physiological*
  • Animals
  • Cell Nucleus / metabolism
  • Heart / physiopathology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Physical Conditioning, Animal*
  • Protein Domains
  • Stress, Physiological*

Substances

  • Mcl1 protein, mouse
  • Mitochondrial Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein