Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak

Elife. 2017 Nov 17;6:e30543. doi: 10.7554/eLife.30543.

Abstract

Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and previous we have shown that these two effectors are also needed for mitochondrial-dependent cellular necrosis (Karch et al., 2013). Here we show that mouse embryonic fibroblasts deficient in Bax/Bak1 are resistant to the third major form of cell death associated with autophagy through a mechanism involving lysosome permeability. Indeed, specifically targeting Bax only to the lysosome restores autophagic cell death in Bax/Bak1 null cells. Moreover, a monomeric-only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in Bax/Bak1 double-deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of Bax/Bak1 restores autophagic cell death, collectively indicting that Bax/Bak integrate all major forms of cell death through direct effects on membrane permeability of multiple intracellular organelles.

Keywords: apoptosis; autophagy; cell death; developmental biology; mouse; necrosis; stem cells.

Publication types

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

MeSH terms

  • Animals
  • Autophagy*
  • Cell Membrane / metabolism*
  • Cells, Cultured
  • Fibroblasts / physiology*
  • Gene Deletion
  • Lysosomes / metabolism*
  • Mice
  • Permeability*
  • bcl-2 Homologous Antagonist-Killer Protein / deficiency
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-2-Associated X Protein / deficiency
  • bcl-2-Associated X Protein / metabolism*

Substances

  • Bak1 protein, mouse
  • Bax protein, mouse
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein