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: Genomic instability can promote oncogenic transformation. Therefore, we investigated if minority MOMP-induced DNA damage leading to genomic instability could potentiate E1A/KRAS-induced transformation in primary mouse embryonic fibroblasts (MEF). Primary MEFs were treated with sub-lethal doses of ABT-737 prior to transformation with E1A/KRAS. Remarkably, BH3-only stress was able to potentiate the transforming ability of E1A/KRAS in primary cells in a dose-dependent manner (Figures 7A and 7B). We next tested if minority MOMP could promote transformation in a different setting. Primary MEF deficient in the tumor suppressor p19Arf were treated with enantiomer or ABT-737 in the presence or absence of caspase-inhibitor Q-VD-OPh (Figure S7A). Additionally, primary p19Arf deficient MEF expressing BCL-xL or empty vector were treated with ABT-737 (Figures S7B and S7C). Following treatment, cellular transformation was assessed by anchorage-independent growth in soft agar. Strikingly, ABT-737 treatment led to transformation that was completely prevented by inhibiting caspases (with Q-VD-OPh) or by inhibiting MOMP through BCL-xL expression (Figures 7C and 7D). We next compared ABT-737 or enantiomer treated p19Arf MEF for their tumorigenic potential in vivo following subcutaneous injection in CD1-Nude mice. Significantly, ABT-737 treated MEF formed tumors much more rapidly than enantiomer-treated MEF (Figure 7E). Collectively, these results demonstrate that minority MOMP promotes both cellular transformation and tumorigenesis.
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.