Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo

• 成果类型: Article
• 署名作者: Brinkmann, Kerstin; Mcarthur, Kate; Malelang, Shezlie; Gibson, Leonie; Tee, Annli; Elahee Doomun, Sheik Nadeem; Rowe, Caitlin L.; Arandjelovic, Philip; Marchingo, Julia M.; D'Silva, Damian; Bachem, Annabell; Monard, Simon; Whelan, Lauren G.; Dewson, Grant; Putoczki, Tracy L.; Bouillet, Philippe; Fu, Nai Yang; Brown, Kristin K.; Kueh, Andrew J.; Wimmer, Verena C.; Herold, Marco J.; Thomas, Tim; Voss, Anne K.; Strasser, Andreas
• 署名单位: Walter & Eliza Hall Institute; University of Melbourne; Monash University; University of Melbourne; University of Melbourne; Peter Doherty Institute; National University of Singapore; Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; University of Melbourne; La Trobe University; Olivia Newton-John Cancer Research Institute; La Trobe University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw1836
• 发表日期: 2025-09-04
• 页码: 1003-1011
• 关键词: endoplasmic-reticulum; nuclear-envelope; outer-membrane; cell-death; bcl-2; survival; pathogenesis; progression; expression; neurons

摘要

The anti-apoptotic protein MCL-1 (myeloid cell leukemia-1) is essential for embryogenesis and the survival of many cell types that tolerate loss of its relatives, BCL-XL and BCL-2. Apoptosis-unrelated roles of MCL-1 in metabolism may contribute to this requirement, although their relevance for embryogenesis and postnatal life remains unclear. We hypothesized that BCL-XL and BCL-2 may substitute MCL-1's anti-apoptotic but not its apoptosis-unrelated functions. Replacing MCL-1 with BCL-XL or BCL-2 supported embryo development by rescuing the Mcl-1-/- preimplantation lethality. Mcl-1Bcl-xL/Bcl-xL but not Mcl-1Bcl-2/Bcl-2 mice were born on a mixed background, although they showed metabolic defects. Thus MCL-1's apoptosis-unrelated functions appear critical in later development, with BCL-XL, but not BCL-2, partially compensating. These findings clarify MCL-1's distinct physiological roles, critically informing MCL-1 inhibitor development as cancer therapeutics.