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bioRxiv · 10.64898/2026.02.06.704006

Spatiotemporal dynamics of Mcl-1 abundance and its influence on apoptosis susceptibility

Klötzer, F.·Pollak, N.·Baatz, A.·Kisakol, B.·Ginty, F.·Longley, D.·Prehn, J.·Rehm, M.
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Abstract

The Bcl-2 protein family defines cellular competence for mitochondrial outer membrane permeabilization (MOMP) and apoptotic cell death. In proliferating cells, the Bcl-2 family member Mcl-1 accumulates across the cell cycle and confers trans-mitotic resistance to extrinsic apoptosis. We show here that Mcl-1, but not Bcl-xL, additionally undergoes a coordinated redistribution from the cytosol to mitochondria, concomitant with its over-proportional accumulation late in the cell cycle. Live-cell monitoring of Mcl-1 dynamics at single-cell resolution, combined with mathematical modelling, enabled us to quantify that Mcl-1 redistribution substantially contributes to elevating MOMP thresholds. Furthermore, we found that Mcl-1 accumulation and redistribution act concomitantly but independently to increase MOMP thresholds as cells approach mitosis and this elevated resistance is reset in daughter cells after division. Notably, heterogeneities in Mcl-1 abundance and subcellular distribution are pronounced even among isogenic cells within the same cell-cycle phase, and thus contribute to substantial cell-to-cell variability in MOMP susceptibility. Analysis of colorectal cancer tissue samples showed that variability in Mcl-1 expression and distribution is likewise prominent between cells in patient tumors and were predicted to drive intra-tumour heterogeneity in responses to treatments that induce MOMP. Overall, we demonstrate how changes in Mcl-1 amounts and localisation integrate with cell-cycle progression to modulate apoptotic susceptibility, thereby shaping cell-fate outcomes and contributing to cell-to-cell heterogeneities in death decision making.

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Klötzer, F., Pollak, N., Baatz, A., Kisakol, B., Ginty, F., Longley, D., Prehn, J., Rehm, M.. 2026-02-09. Spatiotemporal dynamics of Mcl-1 abundance and its influence on apoptosis susceptibility. https://doi.org/10.64898/2026.02.06.704006

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