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Mitochondria and cell death: outer membrane permeabilization and beyond

Nature Reviews Molecular Cell Biology volume 11, pages 621–632 (2010)Cite this article

Subjects

Key Points

  • Mitochondrial outer membrane permeabilization (MOMP) is a crucial event for most apoptotic pathways. MOMP leads to the release of mitochondrial intermembrane space (IMS) proteins, such as cytochrome c, that promote caspase activation and apoptosis.

  • Mitochondrial outer membrane integrity is dynamically regulated through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family.

  • The pro-apoptotic BCL-2 proteins BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK) are required for MOMP, although how they permeabilize the mitochondrial outer membrane remains unresolved.

  • Following MOMP, the mitochondrial release of certain IMS proteins can be further regulated.

  • Caspase activity can also be regulated post-MOMP by many different means, both at the level of apoptosome formation and at caspase 9 and executioner caspase activity.

  • MOMP generally commits a cell to death, irrespective of caspase activity, through a process termed caspase-independent cell death (CICD). Exactly how CICD occurs is unclear, but it involves the loss of mitochondrial function.

  • Under some circumstances, cells can survive following MOMP. Cell survival under these conditions requires a pool of mitochondria that remain intact following MOMP. Survival is promoted by glycolysis and autophagy.

Abstract

Mitochondrial outer membrane permeabilization (MOMP) is often required for activation of the caspase proteases that cause apoptotic cell death. Various intermembrane space (IMS) proteins, such as cytochrome c, promote caspase activation following their mitochondrial release. As a consequence, mitochondrial outer membrane integrity is highly controlled, primarily through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family. Following MOMP by pro-apoptotic BCL-2-associated X protein (BAX) or BCL-2 antagonist or killer (BAK), additional regulatory mechanisms govern the mitochondrial release of IMS proteins and caspase activity. MOMP typically leads to cell death irrespective of caspase activity by causing a progressive decline in mitochondrial function, although cells can survive this under certain circumstances, which may have pathophysiological consequences.

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Figure 1: Intrinsic and extrinsic pathways of apoptosis.
Figure 2: BAX and BAK activation and pore formation.
Figure 3: Post-MOMP regulation of caspase activity.
Figure 4: Cellular effects of MOMP.

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Acknowledgements

We thank A. Oberst, F. Llambi and J. Tait-Mulder for critical reading of the manuscript.

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  1. Department of Immunology, St Jude Childrens Research Hospital, 262 Danny Thomas Place, Memphis, 38105, Tennessee, USA

    Stephen W. G. Tait & Douglas R. Green

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Deathbase

Glossary

Tubular mitochondrial network

Multiple fused mitochondria forming filamentous, elongated structures. These networks are highly dynamic owing to constant rounds of mitochondrial fission and fusion.

FRET

(Förster resonance energy transfer). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor.

Liposome

A vesicle made of lipid bilayer in an aqueous environment. Membrane proteins can be incorporated in the bilayer.

Patch clamping

An electrophysiological technique used for measuring ion channel activity over membranes. Typically, a small diameter (1μm) micropipette serves as the electrode and is applied to a small area of membrane (the 'patch'), allowing the activity of one or a few ion channels to be measured.

Micelle

An aggregate (typically spherical) of varying size comprised of lipids. In aqueous environments, the hydrophobic lipid tails orientate to the centre of the micelle and the hydrophilic head groups are on the surface.

Cristae junction

A connection between the mitochondrial cristae and the mitochondrial IMS. The diameter of cristae junctions can be altered, thereby regulating the accessibility of mitochondrial cristae to the IMS.

Nitrosylation

A post-translational protein modification involving the addition of a nitrosyl group to the Cys residue of a target protein, potentially altering target protein function.

Transmembrane potential

The voltage (or electrical potential) difference between one side of a membrane and the other.

Post-mitotic cell

A cell that is neither preparing to nor undergoing cell division.

Pentose–phosphate shunt

A metabolic pathway that generates NADPH and pentose sugars from glucose-6-phosphate. Indirectly, NADPH serves as an important antioxidant by reducing glutathione.

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Tait, S., Green, D. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11, 621–632 (2010). https://doi.org/10.1038/nrm2952

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