Related Experiment Videos
The mitochondrial death/life regulator in apoptosis and necrosis
G Kroemer1, B Dallaporta, M Resche-Rigon
1Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France. kroemer@infobiogen.fr
Abstract:
Both physiological cell death (apoptosis) and, in some cases, accidental cell death (necrosis) involve a two-step process. At a first level, numerous physiological and some pathological stimuli trigger an increase in mitochondrial membrane permeability. The mitochondria release apoptogenic factors through the outer membrane and dissipate the electrochemical gradient of the inner membrane. Mitochondrial permeability transition (PT) involves a dynamic multiprotein complex formed in the contact site between the inner and outer mitochondrial membranes. The PT complex can function as a sensor for stress and damage, as well as for certain signals connected to receptors. Inhibition of PT by pharmacological intervention on mitochondrial structures or mitochondrial expression of the apoptosis-inhibitory oncoprotein Bcl-2 prevents cell death, suggesting that PT is a rate-limiting event of the death process. At a second level, the consequences of mitochondrial dysfunction (collapse of the mitochondrial inner transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins) entails a bioenergetic catastrophe culminating in the disruption of plasma membrane integrity (necrosis) and/or the activation of specific apoptogenic proteases (caspases) by mitochondrial proteins that leak into the cytosol (cytochrome c, apoptosis-inducing factor) with secondary endonuclease activation (apoptosis). The relative rate of these two processes (bioenergetic catastrophe versus protease and endonuclease activation) determines whether a cell will undergo primary necrosis or apoptosis. The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from mitochondria. The fact that mitochondrial events control cell death has major implications for the development of cytoprotective and cytotoxic drugs.
Insights
Mitochondrial permeability transition (PT) is a key two-step process in cell death, releasing factors that trigger apoptosis or necrosis. Inhibiting PT can prevent cell death, highlighting its role in drug development.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Cell death, including apoptosis and necrosis, is a complex two-step process.
- Mitochondria play a crucial role in initiating cell death pathways.
- Mitochondrial permeability transition (PT) is a critical event in this process.
Purpose of the Study:
- To elucidate the role of mitochondrial permeability transition (PT) in physiological and pathological cell death.
- To investigate the mechanisms by which PT triggers apoptosis and necrosis.
- To explore the potential of targeting PT for therapeutic interventions.
Main Methods:
- Analysis of mitochondrial membrane permeability changes.
- Investigation of apoptogenic factor release from mitochondria.
- Pharmacological inhibition of PT and assessment of cell death outcomes.
- Study of mitochondrial dysfunction consequences.
Main Results:
- Physiological and pathological stimuli increase mitochondrial membrane permeability, leading to PT.
- PT involves a multiprotein complex acting as a stress sensor.
- Inhibition of PT prevents cell death, indicating it's a rate-limiting step.
- Mitochondrial dysfunction leads to bioenergetic catastrophe or protease activation, determining cell fate.
Conclusions:
- Mitochondrial permeability transition (PT) is a central event controlling both apoptosis and necrosis.
- The balance between bioenergetic collapse and protease activation dictates the mode of cell death.
- Mitochondrial events are critical targets for developing cytoprotective and cytotoxic drugs.