Abstract
In cells undergoing cell-intrinsic apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically marks an irreversible step in the cell death process. However, in some cases, a subpopulation of treated cells can exhibit a sublethal response, termed “minority MOMP.” In this phenomenon, the affected cells survive, despite a low level of caspase activation and subsequent limited activation of the endonuclease caspase-activated DNase (DNA fragmentation factor subunit beta). Consequently, these cells can experience DNA damage, increasing the probability of oncogenesis. However, little is known about the minority MOMP response. To discover genes that affect the MOMP response in individual cells, we conducted an imaging-based phenotypic siRNA screen. We identified multiple candidate genes whose downregulation increased the heterogeneity of MOMP within single cells, among which were genes related to mitochondrial dynamics and mitophagy that participate in the mitochondrial quality control (MQC) system. Furthermore, to test the hypothesis that functional MQC is important for reducing the frequency of minority MOMP, we developed an assay to measure the clonogenic survival of caspase-engaged cells. We found that cells deficient in various MQC genes were indeed prone to aberrant post-MOMP survival. Our data highlight the important role of proteins involved in mitochondrial dynamics and mitophagy in preventing apoptotic dysregulation and oncogenesis.
Highlights
Apoptosis is a ubiquitous cellular self-elimination process that is critical for the homeostasis of various cell populations
Venus-B-cell lymphoma 2 (BCL2)-associated X (BAX) is translocated to mitochondria and OMI-mCherry is released into the cytoplasm and degraded
The release of proteins from the mitochondrial interior can only be restricted under special circumstances, for example, cristae junction remodeling by overexpression of a mutant form of the optic atrophy 1 (OPA1) protein [25] or mitochondrial outer membrane permeabilization (MOMP) inhibition by a recently described endolysosome-linked mechanism [26]
Summary
Apoptosis is a ubiquitous cellular self-elimination process that is critical for the homeostasis of various cell populations. Downregulation of MQC-related genes would tend to allow cells to survive stresses that produce a degree of caspase activation, as a result of limited MOMP.
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