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Cytochrome c: functions beyond respiration

Nature Reviews Molecular Cell Biology volume 9, pages 532–542 (2008)Cite this article

Key Points

  • Cytochrome c is one of the mitochondrial proteins that is released into the cytosol when the cell is activated by an apoptotic stimulus.

  • In the cytosol, cytochrome c engages the apoptotic protease activating factor-1 (APAF1), and forms the apoptosome, which activates caspase-9.

  • The release of cytochrome c has been suggested to occur in two phases: mobilization from the mitochondrial intermembrane space and translocation through the outer mitochondrial membrane.

  • The mechanisms of cytochrome c release are controversial. Whether the permeabilization of the outer or the inner membrane is responsible for the downstream events is one of the debated topics. Most evidence supports a model in which the outer membrane is permeabilized without inner membrane events.

  • The release of cytochrome c and cytochrome-c-mediated apoptosis are controlled by multiple layers of regulation, with the most prominent players being members of the B-cell lymphoma protein-2 (BCL2) family.

Abstract

Cytochrome c is primarily known for its function in the mitochondria as a key participant in the life-supporting function of ATP synthesis. However, when a cell receives an apoptotic stimulus, cytochrome c is released into the cytosol and triggers programmed cell death through apoptosis. The release of cytochrome c and cytochrome-c-mediated apoptosis are controlled by multiple layers of regulation, the most prominent players being members of the B-cell lymphoma protein-2 (BCL2) family. As well as its role in canonical intrinsic apoptosis, cytochrome c amplifies signals that are generated by other apoptotic pathways and participates in certain non-apoptotic functions.

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Figure 1: Intrinsic versus extrinsic apoptotic pathways.
Figure 2: Release of cytochrome c and its downstream effects.
Figure 3: Structure of cytochrome c.
Figure 4: Mobilization of cytochrome c.

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Authors and Affiliations

  1. The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, M5G 2C1, Ontario, Canada

    Yong-Ling P. Ow, Zhenyue Hao & Tak W. Mak

  2. Department of Immunology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Douglas R. Green

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  1. Yong-Ling P. Ow
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Glossary

Caspase

A signalling Cys protease that cleaves after Asp residues. Caspases have an important role in apoptosis. An initiator caspase cleaves and activates itself to initiate the apoptotic programme. An executioner caspase executes the apoptotic programme through the cleavage of an array of vital proteins.

Extrinsic pathway

An apoptotic pathway that is mediated by the binding of an extracellular ligand to a transmembrane receptor.

Intrinsic pathway

An apoptotic pathway in which the crucial step is the permeabilization of the outer mitochondrial membrane.

Death-inducing signalling complex

(DISC). The signalling platform of the extrinsic pathway.

Cristae junction

An inner membrane projection into the matrix by tubular structures of uniform diameter.

Redox intermediate

An electron carrier in a reaction in which electrons are transferred from donor molecules to acceptor molecules.

Apoptosome

A signalling platform that activates the intrinsic pathway.

SMAC

A pro-apoptotic protein that is released from the intermembrane space that neutralizes the inhibitory activity of inhibitors of apoptosis proteins.

Reactive oxygen species

(ROS). Byproducts of oxidative metabolism that are highly reactive owing to unpaired electrons.

Mitochondrial outer membrane permeabilization

(MOMP). The permeabilization of the outer mitochondrial membrane to proteins.

Caspase recruitment domain

(CARD). A homotypic protein interaction motif that consists of six α-helices.

WD40

A sequence of ∼40 amino acids that usually ends with Try-Asp (W-D). This is found in some regulatory proteins.

AAA+ family

A family of ATPases in which the defining feature is the formation of an oligomer that has a circular structure. This occurs as a result of one ATPase domain nested next to the ATPase domain of its neighbour.

Permeability transition pore

(PTP). A large high-conductance multimeric complex that spans the outer and inner mitochondrial membranes. Its opening leads to mitochondrial permeability transition, a sudden increase of the permeability of the membrane to solutes.

Adenine nucleotide translocator

(ANT). A carrier that is found in the inner mitochondrial membrane that transports ADP into, and ATP out of, the mitochondrial matrix. It is thought to be a component of the permeability transition pore.

Cyclophilin D

(CypD). An enzyme that is found in the mitochondrial matrix and that catalyses the cis/trans-isomerization of prolyl peptide bonds. It is thought to be a component of the permeability transition pore.

Membrane potential

(Δψm). The proton-motive force that results from the generation of a proton gradient across the inner mitochondrial membrane. This enables the F0F1 ATPase to synthesize ATP from ADP and inorganic phosphate as the protons flow spontaneously across the membrane.

BH3-only proteins

Pro-apoptotic BCL2-family members that have only the third of four BCL2 homology domains.

Heat-shock protein

A protein that functions as a molecular chaperone that is upregulated during stress.

Rhomboid proteases

A class of highly hydrophobic proteases. They contain a Ser-protease catalytic dyad which suggests that they can cleave the transmembrane domains of integral membrane proteins.

Apocytochrome c

The cytochrome c protein that is produced by translation and co-translational modification in the cytosol.

Holocytochrome c

The mature cytochrome c protein that contains the haem moiety.

Inhibitors of apoptosis proteins

(IAPs). A family of proteins that associates with and inhibits caspases. These are defined by baculovirus-repeat domains and, in some cases, a RING zinc-finger domain.

Autophagy

A process in which the parts of a cell that are sequestered within double-membraned vacuoles are digested by lysosomal hydrolases.

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Ow, YL., Green, D., Hao, Z. et al. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 9, 532–542 (2008). https://doi.org/10.1038/nrm2434

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