Differential regulation of BAX and BAK apoptotic activity revealed by small molecules
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.
Authors
- Andrew H. Wei (ORCID: https://orcid.org/0000-0002-7514-3298)
- Yelena Khakham
- Fransisca Sumardy
- Donia M. Moujalled (ORCID: https://orcid.org/0000-0002-1076-3496)
- Meng-Xiao Luo (ORCID: https://orcid.org/0000-0002-7745-9755)
- Benjamin T. Kile (ORCID: https://orcid.org/0000-0002-8836-8947)
- Jianan Gong (ORCID: https://orcid.org/0000-0003-4977-9775)
- Mark F. van Delft (ORCID: https://orcid.org/0000-0002-3866-4318)
- Angela Georgiou
- David C.S. Huang (ORCID: https://orcid.org/0000-0002-3101-4873)
- Richard W. Birkinshaw (ORCID: https://orcid.org/0000-0003-1825-0182)
- Peter E. Czabotar (ORCID: https://orcid.org/0000-0002-2594-496X)
- Grant Dewson (ORCID: https://orcid.org/0000-0003-4251-8898)
- Kym N. Lowes (ORCID: https://orcid.org/0000-0003-3506-4218)
- Yu Q. Yap
- Kaiming Li (ORCID: https://orcid.org/0000-0001-5545-3419)
- Guillaume Lessène (ORCID: https://orcid.org/0000-0002-1193-8147)
- Thomas E. Lew (ORCID: https://orcid.org/0000-0001-6804-2432)
- Michelle Jahja (ORCID: https://orcid.org/0009-0004-6558-1456)
- Zheng Wei Yuan (ORCID: https://orcid.org/0000-0001-8588-9029)
- Melanie De Silva
Institutions
- The Royal Melbourne Hospital (AU)
- Garvan Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peter MacCallum Cancer Centre (AU)
- Institute of Laboratory Animal Science (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1126/sciadv.adr8146
- Citations
- 7
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 5.64