Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death.
Bottom Line: Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis.Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event.Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death.
Affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.Show MeSH
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Mentions: Based on our results, we hypothesized that by causing DNA damage, minority MOMP may promote genomic instability and transformation. To test this possibility, we repeatedly treated HeLa and U2OS cells with sub-lethal doses of ABT-737 for five (P5) or ten passages (P10). Following blockage of cytokinesis, we then quantified the number of cells with micronuclei, a well-established marker for chromosomal damage (Figure S6A) (Fenech, 2007). Strikingly, U2OS and HeLa cells displayed a significant increase in micronuclei number following ABT-737 treatment in a dose-dependent manner (Figures 6A and S6B). Ectopic BCL-xL expression inhibited micronuclei accumulation in U2OS cells, confirming that the observed genomic instability required mitochondrial permeabilization (Figure 6B). In an analogous manner, induction of sub-lethal levels of the BH3-only protein tBID in MelJuSo cells also promoted micronuclei accumulation in a dose-dependent manner (Figure 6C). Micronuclei accumulation following tBID expression was reduced to control levels by the caspase inhibitor Q-VD-OPh, demonstrating a requirement for caspases in minority MOMP-induced chromosomal damage (Figure 6C).
Affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.