Abstract
Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death. However, the role of transient MPT (tMPT) because of flickering opening of the mitochondrial permeability transition pore remains elusive. Here we show that tMPT and the associated superoxide flashes (i.e. tMPT/superoxide flashes) constitute early mitochondrial signals during oxidative stress-induced apoptosis. Selenite (a ROS-dependent insult) but not staurosporine (a ROS-independent insult) stimulated an early and persistent increase in tMPT/superoxide flash activity prior to mitochondrial fragmentation and a global ROS rise, independently of Bax translocation and cytochrome c release. Selectively targeting tMPT/superoxide flash activity by manipulating cyclophilin D expression or scavenging mitochondrial ROS markedly impacted the progression of selenite-induced apoptosis while exerting little effect on the global ROS response. Furthermore, the tMPT/superoxide flash served as a convergence point for pro- and anti-apoptotic regulation mediated by cyclophilin D and Bcl-2 proteins. These results indicate that tMPT/superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial ROS signaling in deciding cell fate.
Highlights
Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death
These results indicate that transient mitochondrial permeability transition (MPT) (tMPT)/ superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial reactive oxygen species (ROS) signaling in deciding cell fate
Superoxide Flashes as Optical Measurements of tMPT in HeLa Cells—In HeLa cells stably expressing the superoxide biosensor mt-cpYFP [14], fluorescence seen at 405 nm or 488 nm excitation was localized to the mitochondria, overlapping that of tetramethyl rhodamine methyl ester (TMRM), a mitochondrial membrane potential (⌬⌿m) indicator
Summary
The rate of superoxide flash production can be modulated by oxidative stress or metabolic status [14, 15] These recent findings raise the intriguing possibility that the mPTP, while in flickering gating mode, may regulate apoptosis at the initiation phase, and if so, may serve as a point of convergence for the diverse signaling pathways that regulate cell survival and cell death. We found that superoxide flashes triggered by flickering mPTP openings constitute early and elemental signals for selenite- but not staurosporine-induced apoptosis, while paradoxically contributing little to the global ROS response This finding establishes a heretofore unappreciated role of flickering mPTP in the regulation of cell fate, and provides new insights into local mitochondrial ROS signaling
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