Differential regulation of BAX and BAK apoptotic activity revealed by small molecules

Date

2025

Authors

Li, K.
Yap, Y.Q.
Moujalled, D.M.
Sumardy, F.
Khakham, Y.
Georgiou, A.
Jahja, M.
Lew, T.E.
De Silva, M.
Luo, M.X.

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Advisors

Journal Title

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Volume Title

Type:

Journal article

Citation

Science Advances, 2025; 11(10):eadr8146-1-eadr8146-14

Statement of Responsibility

Kaiming Li, Yu Q. Yap, Donia M. Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas E. Lew, Melanie De Silva, Meng-Xiao Luo, Jia-nan Gong, Zheng Yuan, Richard W. Birkinshaw, Peter E. Czabotar, Kym Lowes, David C. S. Huang, Benjamin T. Kile, Andrew H. Wei, Grant Dewson, Mark F. van Delft, Guillaume Lessene

Conference Name

DOI

10.1126/sciadv.adr8146

Abstract

Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2-associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.

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Copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. Distributed under acreative commons Attribution NonCommercial License 4.0 (CC BY-NC).

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Grant ID

http://purl.org/au-research/grants/nhmrc/1043149
 http://purl.org/au-research/grants/nhmrc/1156024
 http://purl.org/au-research/grants/nhmrc/2016894
 http://purl.org/au-research/grants/nhmrc/2009062
 http://purl.org/au-research/grants/nhmrc/1117089
 http://purl.org/au-research/grants/nhmrc/2018071
 http://purl.org/au-research/grants/nhmrc/2004446
 http://purl.org/au-research/grants/nhmrc/158137
 http://purl.org/au-research/grants/nhmrc/1158137
 http://purl.org/au-research/grants/nhmrc/1158137

Published Version

https://doi.org/10.1126/sciadv.adr8146

Call number

Persistent link to this record

https://hdl.handle.net/2440/146398