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Mitochondrial fusion and fission in cell life and death

Nature Reviews Molecular Cell Biology volume 11, pages 872–884 (2010)Cite this article

Subjects

Key Points

  • Live cell imaging studies showed that mitochondria are highly dynamic organelles that frequently fuse and divide.

  • Two evolutionarily conserved large GTPases constitute the core machinery of fusion: mitofusins are found in the outer membrane, and Mgm1 and optic atrophy protein 1 (OPA1) are found in the inner membrane of yeast and mammals, respectively.

  • Mitochondrial fission is mediated by dynamin-related proteins (DRPs) and cofactors that are required for assembly of DRP rings and spirals on the mitochondrial surface. Only little is known about division of the inner membrane.

  • The machineries of mitochondrial fusion and fission are regulated by many cellular pathways, including proteolytic processing, ubiquitylation, sumoylation, phosphorylation and dephosphorylation.

  • Mitochondrial fusion and fission are required for faithful inheritance and proper intracellular distribution of the organelle.

  • Mitochondrial dynamics counteracts cellular ageing by allowing complementation of gene products after fusion of impaired mitochondria, and it constitutes an important part of organellar quality control as it facilitates the elimination of damaged mitochondria by autophagy. Furthermore, mitochondrial division is an important step in apoptosis.

  • Dysfunctions of mitochondrial dynamics contribute to several inherited and age-associated neurodegenerative diseases.

Abstract

Mitochondria are dynamic organelles that constantly fuse and divide. These processes (collectively termed mitochondrial dynamics) are important for mitochondrial inheritance and for the maintenance of mitochondrial functions. The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion and fission of a double membrane-bound organelle. Mitochondrial dynamics was recently recognized as an important constituent of cellular quality control. Defects have detrimental consequences on bioenergetic supply and contribute to the pathogenesis of neurodegenerative diseases. These findings open exciting new directions to explore mitochondrial biology.

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Figure 1: Mitochondrial morphology.
Figure 2: Domain structures of mitochondrial fusion and fission components.
Figure 3: Assembly and post-translational modifications of mitochondrial fusion and fission machineries.
Figure 4: Biological functions of mitochondrial dynamics.

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Acknowledgements

The author thanks S. Arimura, J. Förtsch, S. Geimer and S. Jakobs for the contribution of images, and J. Förtsch, J. Herrmann, T. Klecker and S. Geimer for comments on the manuscript. Research in the author's laboratory is supported by grants from the Deutsche Forschungsgemeinschaft.

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    Benedikt Westermann

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Glossary

β-oxidation

Biochemical pathway of fatty acid catabolism in mitochondria and peroxisomes.

SNARE

A protein belonging to a family of membrane proteins that mediate fusion of vesicles and organelles in the secretory pathway of eukaryotic cells.

Haemagglutinin

A glycoprotein of enveloped viruses, such as influenza virus. Haemagglutinins mediate fusion of the viral envelope with endosomal membranes to release the viral particle into the host cytosol.

Heptad repeat

A structural protein motif that is commonly found in coiled coils that contain two or more α-helices coiled together forming a rope-like structure.

Dynamin

A large GTPase involved in membrane scission events.

Rhomboid

The founding member of a conserved family of intramembrane Ser proteases that have their active sites buried in the plane of the membrane.

AAA proteases

Large multisubunit proteases that belong to the superfamily of ATPases that are associated with diverse cellular activities.

Liposome

Artificial lipid bilayer vesicle composed of membrane lipids.

Mitochondrial carrier family signature

A protein sequence motif that is commonly found in mitochondrial carrier proteins that function in the transport of metabolites and other biomolecules across the mitochondrial inner membrane.

Tetratricopeptide repeat motif

A motif that consists of a degenerate 34 amino acid sequence and functions as a protein–protein interaction module in various functionally different proteins.

WD40 repeat

A protein-binding motif that typically contains several regions of about 40 amino acids with conserved Trp-Asp dipeptides that form characteristic β-propeller structures.

F-box protein

A protein that contains an F-box as a protein interaction domain. Most F-box proteins are substrate recognition subunits of SCF ubiquitin ligases and have roles in ubiquitin-dependent protein degradation.

Ubiquitin ligase

An enzyme that mediates the covalent attachment of ubiquitin to substrate proteins to label them for degradation by the proteasome or other regulatory pathways. This process is termed ubiquitylation.

Small ubiquitin-like modifier

A small protein that is covalently attached to and removed from other proteins to modify their activity.

Nucleoid

A compact structure that contains DNA and proteins. Mitochondrial nucleoids contain several copies of the mitochondrial genome and are attached to the inner membrane.

Purkinje neuron

A large neuron in the cerebellar cortex with a single long axon and many branched dendritic extensions.

Reactive oxygen species

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen, such as superoxide anions, peroxides and hydroxyl radicals. Mitochondrial ROS are generated by incomplete reduction of molecular oxygen in the respiratory chain.

Cytochrome c

A small protein in the mitochondrial intermembrane space that transports electrons in the respiratory chain. It activates cell death pathways when released into the cytosol.

Caspase

An enzyme belonging to a family of proteases that execute cell death events late in the apoptotic pathway.

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Westermann, B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11, 872–884 (2010). https://doi.org/10.1038/nrm3013

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