scholarly journals Decision letter: Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak

2017 ◽  
eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jason Karch ◽  
Tobias G Schips ◽  
Bryan D Maliken ◽  
Matthew J Brody ◽  
Michelle A Sargent ◽  
...  

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.


2017 ◽  
Author(s):  
Jason Karch ◽  
Tobias G Schips ◽  
Bryan D Maliken ◽  
Matthew J Brody ◽  
Michelle A Sargent ◽  
...  

2018 ◽  
Vol 51 (4) ◽  
pp. 133
Author(s):  
I-ShengThomas Hwang ◽  
Hung-En Chen ◽  
Ji-Fan Lin ◽  
Yi-Chia Lin ◽  
Shen-I Wen ◽  
...  

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jason Karch ◽  
Tobias G Schips ◽  
Matthew J Brody ◽  
Onur Kanisicak ◽  
Michelle A Sargent ◽  
...  

In times of energy depletion, a cell will attempt to maintain metabolic homeostasis and viability by degrading and recycling organelles and intracellular components and proteins in a process referred to as autophagy. However, if the energy depletion persists, the cell will be overwhelmed by the autophagic process and will succumb to autophagic cell death. This form of cell death has been implicated in cardiac remodeling during heart failure and damage during ischemic injury. Two proteins that have been previously shown to play a role in virtually every form of regulated cell death, including autophagy, are Bax and Bak. These effectors are responsible for cytochrome-c release during apoptosis and effect mitochondrial permeability transition pore opening during regulated necrosis. Although the expression of either Bax or Bak is required for autophagic cell death to occur, the role of Bax/Bak in this type of cell death is poorly understood, although the lysosome appears to be centrally involved. Here we show that Bax/Bak DKO MEFs subjected to several days of serum starvation contain intact lysosomes compared to WT MEFs. Furthermore, the acidity of the lysosomes in starved DKO MEFs is preserved compared with starved WT MEFs. Bax and Bak are both found in isolated lysosomal preparations and Bax targeted to the lysosome can completely restore autophagic cell death in DKO MEFs. Finally, although Bax oligomerization is required for apoptosis, it is not necessary for autophagic cell death, as DKO MEFs expressing an oligomerization defective mutant of Bax are still susceptible to this form of death, as monomeric Bax can still increase membrane permeability. In conclusion our results suggest that lysosomal membrane permeability through Bax or Bak is required for autophagic cell death to occur and without Bax or Bak the lysosomes remain intact where they can function as an energy source during times of nutrient deprivation.


2016 ◽  
Vol 27 (2) ◽  
pp. S5 ◽  
Author(s):  
Hung-En Chen ◽  
Ji-Fan Lin ◽  
Te-Fu Tsai ◽  
Yi-Chia Lin ◽  
Kuang-Yu Chou ◽  
...  

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