Mitochondrial control of apoptosis: an overview

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• The mitochondrial permeability transition (PT) pore is a multiprotein complex.
• It is located at the contact site between mitochondrial membranes.
• It regulates matrix Ca2+, pH, transmembrane potential, and volume.

Purpose of the Study:

• To investigate the role of the mitochondrial PT pore in apoptosis.
• To provide evidence implicating the PT pore in the apoptotic process.

Main Methods:

• Studied PT pore activity in intact cells and cell-free systems.
• Utilized specific PT pore inhibitors and apoptosis-inhibitory proteins (Bcl-2, Bcl-XL).
• Reconstituted purified PT pore complex into liposomes.

Main Results:

• Apoptosis is accompanied by early dissipation of mitochondrial transmembrane potential (Δψm).
• PT pore inhibitors abolished Δψm dissipation and prevented caspase/endonuclease activation.
• Isolated mitochondria released apoptogenic factors upon PT pore opening.
• Bcl-2 and Bcl-XL inhibited PT pore opening in vitro and in cells.

Conclusions:

• Mitochondrial PT pore opening is sufficient and necessary for triggering apoptosis.
• PT pore opening is a critical event in the apoptotic process.
• Findings have implications for pharmacological interventions in apoptosis.