Mitochondrial residence of the apoptosis inducer BAX is more important than BAX oligomerization in promoting membrane permeabilization

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2020
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Kuwana, Tomomi
King, Louise E.
Cosentino, Katia
Garcia-Saez, Ana J.
Gilmore, Andrew P.
Newmeyer, Donald D.
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The Journal of biological chemistry. American Society for Biochemistry and Molecular Biology. 2020, 295(6), pp. 1623-1636. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.RA119.011635
Zusammenfassung

Permeabilization of the mitochondrial outer membrane is a key step in the intrinsic apoptosis pathway, triggered by the release of mitochondrial intermembrane space proteins into the cytoplasm. The BCL-2-associated X apoptosis regulator (BAX) protein critically contributes to this process by forming pores in the mitochondrial outer membrane. However, the relative roles of the mitochondrial residence of BAX and its oligomerization in promoting membrane permeabilization are unclear. To this end, using both cell-free and cellular experimental systems, including membrane permeabilization, size-exclusion chromatography-based oligomer, and retrotranslocation assays, along with confocal microscopy analysis, here we studied two BAX C-terminal variants, T182I and G179P. Neither variant formed large oligomers when activated in liposomes. Nevertheless, the G179P variant could permeabilize liposome membranes, suggesting that large BAX oligomers are not essential for the permeabilization. However, when G179P was transduced into BAX/BCL2 agonist killer (BAK) double-knockout mouse embryonic fibroblasts, its location was solely cytoplasmic, and it then failed to mediate cell death. In contrast, T182I was inefficient in both liposome insertion and permeabilization. Yet, when transduced into cells, BAXT182I resided predominantly on mitochondria, because of its slow retrotranslocation and mediated apoptosis as efficiently as WT BAX. We conclude that BAX's mitochondrial residence in vivo, regulated by both targeting and retrotranslocation, is more significant for its pro-apoptotic activity than its ability to insert and to form higher-order oligomers in model membranes. We propose that this finding should be taken into account when developing drugs that modulate BAX activity.

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570 Biowissenschaften, Biologie
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apoptosis, Bax, mitochondrial apoptosis, molecular cell biology, translocation, anticancer drug, liposome, mitochondrial localization, mitochondrial outer membrane permeabilization (MOMP), protein oligomers
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ISO 690KUWANA, Tomomi, Louise E. KING, Katia COSENTINO, Julian SUESS, Ana J. GARCIA-SAEZ, Andrew P. GILMORE, Donald D. NEWMEYER, 2020. Mitochondrial residence of the apoptosis inducer BAX is more important than BAX oligomerization in promoting membrane permeabilization. In: The Journal of biological chemistry. American Society for Biochemistry and Molecular Biology. 2020, 295(6), pp. 1623-1636. ISSN 0021-9258. eISSN 1083-351X. Available under: doi: 10.1074/jbc.RA119.011635
BibTex
@article{Kuwana2020-02-07Mitoc-49032,
  year={2020},
  doi={10.1074/jbc.RA119.011635},
  title={Mitochondrial residence of the apoptosis inducer BAX is more important than BAX oligomerization in promoting membrane permeabilization},
  number={6},
  volume={295},
  issn={0021-9258},
  journal={The Journal of biological chemistry},
  pages={1623--1636},
  author={Kuwana, Tomomi and King, Louise E. and Cosentino, Katia and Suess, Julian and Garcia-Saez, Ana J. and Gilmore, Andrew P. and Newmeyer, Donald D.}
}
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