Limited Mitochondrial Permeabilization Causes DNA Damage and Genomic Instability in the Absence of Cell Death

摘要

class="head no_bottom_margin" id="sec1title">IntroductionFollowing most apoptotic stimuli, the pro-apoptotic BCL-2 family members Bax and Bak permeabilize the outer membrane of the mitochondria, an event termed “mitochondrial outer membrane permeabilization” (MOMP). MOMP leads to rapid cell death by releasing mitochondrial proteins including cytochrome c that activate caspases (). However, even in the absence of caspase activity, cells typically die once MOMP has occurred, most likely due to progressive mitochondrial dysfunction (). Due to these catastrophic effects, MOMP is often considered the point of no return in the apoptotic program. Mitochondrial apoptosis plays numerous important pathophysiological roles. In cancer, inhibition of apoptosis both promotes tumorigenesis and impedes anti-cancer therapeutic efficacy (). Apoptotic inhibition is often achieved by upregulation of anti-apoptotic BCL-2 family members that prevent MOMP. This has led to the development of new anticancer drugs, called BH3-mimetics, which neutralize anti-apoptotic BCL-2 function ().Live-cell imaging has demonstrated that mitochondrial permeabilization is often an all-or-nothing event (). Widespread mitochondrial permeabilization underpins the lethal effects of MOMP by ensuring robust caspase activity, or in its absence, massive mitochondrial dysfunction. In some limited circumstances, cells can survive MOMP. For example, growth factor-deprived neurons can survive MOMP due to a failure to properly engage caspase activity (). In proliferating cells, expression of the key glycolytic enzyme GAPDH can promote cell survival following MOMP provided caspase activity is inhibited (). We have previously found that the ability of cells to survive MOMP depends on a few mitochondria that evade permeabilization and re-populate the cell ().Whereas earlier studies demonstrated that strong pro-apoptotic stimuli lead to rapid, synchronous, and complete MOMP, technical limitations have made it impossible to study the effects of sub-lethal stresses on individual mitochondria. Here, we use newly developed imaging techniques to demonstrate that MOMP can occur in a limited subset of mitochondria following a sub-lethal stress. Crucially, this limited MOMP leads to caspase activation, which, while insufficient to trigger cell death, leads to limited cleavage of key caspase substrates. This in turn drives DNA-damage and genomic instability, promoting transformation and tumorigenesis. Importantly, our data argue that the mitochondrial apoptotic pathway may exert either a tumor suppressor or oncogenic function depending upon the extent of MOMP.