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Propagation of the apoptotic signal by mitochondrial waves
1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, 1020 Locust str Suite 253 JAH, PA 19107, USA.
Abstract:
Generation of mitochondrial signals is believed to be important in the commitment to apoptosis, but the mechanisms coordinating the output of individual mitochondria remain elusive. We show that in cardiac myotubes exposed to apoptotic agents, Ca2+ spikes initiate depolarization of mitochondria in discrete subcellular regions, and these mitochondria initiate slow waves of depolarization and Ca2+ release propagating through the cell. Traveling mitochondrial waves are prevented by Bcl-x(L), involve permeability transition pore (PTP) opening, and yield cytochrome c release, caspase activation and nuclear apoptosis. Mitochondrial Ca2+ uptake is critical for wave propagation, and mitochondria at the origin of waves take up Ca2+ particularly effectively, providing a mechanism that may underlie selection of the initiation sites. Thus, apoptotic agents transform the mitochondria into an excitable state by sensitizing PTP to Ca2+. Expansion of the local excitation by mitochondrial waves propagating through the whole cell can be especially important in activation of the apoptotic machinery in large cells.
Insights
Mitochondria generate waves of calcium and depolarization, crucial for apoptosis initiation. These waves, regulated by Bcl-x(L) and involving the permeability transition pore (PTP), drive cell death signaling.
Area of Science:
- Cell Biology
- Biochemistry
- Physiology
Background:
- Mitochondrial signaling is critical for apoptosis.
- Mechanisms coordinating mitochondrial output in apoptosis are not fully understood.
Purpose of the Study:
- To investigate the role of mitochondrial depolarization and calcium (Ca2+) waves in apoptosis initiation.
- To elucidate the mechanisms underlying the coordination and propagation of mitochondrial signals during apoptosis.
Main Methods:
- Utilized cardiac myotubes exposed to apoptotic agents.
- Observed mitochondrial depolarization and Ca2+ release using live-cell imaging.
- Investigated the role of Bcl-x(L) and permeability transition pore (PTP) opening.
Main Results:
- Apoptotic agents induced localized mitochondrial depolarization and Ca2+ spikes, initiating propagating waves.
- These mitochondrial waves involve PTP opening, cytochrome c release, and caspase activation.
- Mitochondrial Ca2+ uptake was essential for wave propagation, with specific mitochondria showing higher uptake efficiency.
- Bcl-x(L) was found to inhibit these traveling mitochondrial waves.
Conclusions:
- Apoptotic agents render mitochondria excitable by sensitizing the PTP to Ca2+.
- Propagating mitochondrial waves coordinate apoptotic signaling, particularly in large cells.
- This mechanism provides insight into the coordinated regulation of mitochondrial function during programmed cell death.