Relative importance of MCL-1’s Anti-Apoptotic versus Non-Apoptotic Functions in vivo

MCL-1 is an anti-apoptotic member of the BCL-2 protein family that ensures cell survival by blocking the intrinsic apoptotic cell death pathway[1][1]. MCL-1 is unique in being essential for early embryonic development and the survival of many cell types, including many cancer cells, which are not affected by the loss of the other anti-apoptotic BCL-2 family members[1][1]–[4][2]. Non-apoptotic functions of MCL-1 controlling mitochondrial ATP production and dynamics have been proposed to underlie this unique requirement for MCL-1[5][3]–[9][4]. The relative contributions of the anti-apoptotic versus the non-apoptotic functions of MCL-1 in normal physiology have not been addressed. Here we replaced the coding sequence for MCL-1 with those for the anti-apoptotic proteins BCL-XL, BCL-2 or A1. We hypothesised that BCL-XL, BCL-2 and A1 may substitute for MCL-1 in the inhibition of apoptosis, but that they will not be able to replace MCL-1’s non-apoptotic function. Strikingly, Mcl-1Bcl-xL/Bcl-xL and Mcl-1Bcl- [2][5] /Bcl- [2][5] embryos survived to embryonic day 14.5, greatly surpassing the pre-implantation lethality of Mcl-1 −/− embryos at E3.5. This demonstrates that the non-apoptotic functions of MCL-1 are dispensable for early development. However, at later stages of development and life after birth many cell types, particularly ones with high energy demand, were found to require both the anti-apoptotic and the non-apoptotic functions of MCL-1. These findings reveal the relative importance of these distinct functions of MCL-1 in physiology, providing important information for basic biology and the advancement of MCL-1 inhibitors in cancer therapy. ### Competing Interest Statement KB, AK, AT, SM, KM, VW, LG, PA, NF, TP, GD, PB, AKV, TT, MJH and AS are or were for some time employees of The Walter and Eliza Hall Institute. The Walter and Eliza Hall Institute receives and milestone payments and royalties from the sale of Venetoclax, parts of which are distributed to current and former employees. MJH and AS collaborated with Servier on the development of MCL-1 inhibitors and received financial support for some of their research. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-9 [5]: #ref-2