Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo
- Kerstin Brinkmann
- Kate McArthur
- Shezlie Malelang
- Leonie Gibson
- Annli Tee
- Sheik Nadeem Elahee Doomun
- Caitlin L. Rowe
- Philip Arandjelovic
- Julia M. Marchingo
- Damian D’Silva
- Annabell Bachem
- Simon Monard
- Lauren G. Whelan
- Grant Dewson
- Tracy L. Putoczki
- Philippe Bouillet
- Nai Yang Fu
- Kristin K. Brown
- Andrew J. Kueh
- Verena C. Wimmer
- Marco J. Herold
- Tim Thomas
- Anne K. Voss
- Andreas Strasser
2025-07-03
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-1 Bcl-xL/Bcl-xL but not Mcl-1 Bcl-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.