BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis


Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.

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Fig. 1
Fig. 2
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Fig. 4



Activating transcription factor 4


Bcl-2 homologous antagonist killer


Bcl-2–associated X protein


B cell lymphoma 2


B-cell lymphoma-extra large


Bcl-2 homology


BH3 interacting-domain death agonist


CCAAT-enhancer-binding proteins


CCAAT-enhancer-binding protein homologous protein




Death-inducing signaling complex


Death receptor


Death receptor 4


Death receptor 5


Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid


Eukaryotic initiation factor 2α


Endoplasmic reticulum




Green fluorescent protein


Homogenization buffer


4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid


Horseradish peroxidase


5,50,6,60-Tetrachloro-1,10,3,30-tetraethylbenzimidazol carbocyanineiodid


Poly [ADP-ribose] polymerase 1


Protein kinase RNA-like endoplasmic reticulum kinase


p53 upregulated modulator of apoptosis


Standard deviation


Tumor necrosis factor-related apoptosis-inducing ligand




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We thank Christine Burr (Department of Surgery, University of Pittsburgh) for her critical review of the manuscript.


Grant sponsor: NCI R03CA205267, R03CA212125, and P30CA047904

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Y.S.L. K.K., and Y.S.P. were responsible for the data collection and analysis. X.L., M.H.A.C, D.L.B., and Y.J.L. were responsible for interpretation of the data. Y.S.L and Y.J.L. were responsible for the study concept and design. Y.S.L. and Y.J.L. were responsible for writing the manuscript.

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Correspondence to Yong J. Lee.

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Lee, YS., Kalimuthu, K., Park, Y.S. et al. BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis. Apoptosis 25, 625–631 (2020).

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  • Ferroptosis
  • Apoptosis
  • Crosstalk
  • BAX
  • Mitochondria-dependent pathway