Key Points
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Mitochondria are dynamic organelles that undergo continuous cycles of fission and fusion. These dynamic processes allow mitochondria to communicate, migrate and adapt to changing energy demands and cellular conditions.
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A group of large GTPases mediate mitochondrial fission and fusion. Important players in mammalian cells include mitofusin 1 and 2 (MFN1 and MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1).
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Mutations in the mitochondrial fission and fusion GTPases MFN2, OPA1 and DRP1 cause neurodegenerative diseases. MFN2 mutations cause Charcot-Marie-Tooth subtype 2A (CMT2A) and sensory neuropathy type VI (HMSN VI), OPA1 mutations cause autosomal dominant optic atrophy (ADOA), and a DRP1 mutation caused a lethal defect in a human infant.
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Several triggers, including oxidative stress and altered regulation by cell-cycle kinases, contribute to the cell-specific shift in the balance between fission and fusion that is characteristic of sporadic neurodegenerative diseases.
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The emerging roles of mitochondrial fission and fusion, including synaptic maintenance, bioenergetics and genetic drift of mitochondrial DNA subpopulations, along with an increased appreciation of differences in the mitochondrial proteome in different cell types, might help to explain some of the unique characteristics of sporadic neurodegenerative diseases, such as their late onset and slow progression.
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Transcriptional regulation of mitochondrial biogenesis, exercise and reactive oxygen species management are three potential ways of reversing deleterious changes in mitochondrial dynamics.
Abstract
Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired bioenergetics and mitochondrial migration, and can trigger neurodegeneration. These findings suggest potential new treatment avenues for neurodegenerative diseases.
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Acknowledgements
We apologize to all colleagues whose articles we were unable to cite owing to space limitations. We wish to acknowledge the support of US National Institutes of Health grants RO1 EY016164 (E.B.W.), RO1 NS047456 (E.B.W.), RO1 NS055193 (E.B.W.), P41 RR004050 (G.P.) and P42 ES010337 (G.P.), as well as European Union grants MCEXT-033534 and MCIRG-046536 (R.S.). We thank A. Wilson for help with illustrations.
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DATABASES
OMIM
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Glossary
- Mitochondrial fission
-
The separation of a long, tubular mitochondrion (2–25 μm in length) into two or more smaller parts (∼0.5 μm in diameter).
- Mitochondrial fusion
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The combination of two mitochondria into a single organelle. It occurs at the tips or on the sides of the mitochondria.
- Synapses
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Specialized junctions through which neurons communicate with each other and with other cell types (for example, muscle cells) through the exchange of chemical messengers.
- Oxidative phosphorylation
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The reaction pathway that converts nutrients into ATP by transferring electrons from donors to acceptors, such as molecular oxygen. The enzymes that mediate this process reside in or associate closely with the mitochondrial inner membrane.
- GTPases
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A large family of enzymes that bind and hydrolyse high-energy GTP into low-energy GDP and phosphate; the released energy is used to drive changes in protein conformation.
- Cristae
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Mitochondrial inner membrane portions that protrude into the mitochondrial matrix.
They contain electron transport chain enzymes and ATP synthase.
- Phosphorylation
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The addition of a phosphate group to a protein by a kinase. Phosphorylation is a common post-translational modification that modulates protein activity.
- Sumoylation
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The addition of a small ubiquitin-related modifier (SUMO) to a protein. Sumoylation is a post-translational modification that generally stabilizes and extends the lifespan of a protein.
- Ubiquitylation
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The addition of the small protein ubiquitin to another protein. Ubiquitylation marks proteins for degradation by the proteasome.
- Staurosporine
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A non-selective protein kinase inhibitor that induces apoptosis.
- Etoposide
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An inhibitor of topoisomerase II that induces apoptosis and is an anti-cancer drug.
- Oxidative stress
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A condition in which increased amounts of reactive oxygen species, free radicals and peroxides damage lipids, proteins and DNA.
- Reactive oxygen species
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(ROS). These include oxygen anions, free radicals and peroxides, which form as byproducts of oxygen metabolism. Mitochondria are a major source of ROS.
- Purkinje cells
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Large, GABA (g-aminobutyric acid)-ergic neurons that are found in the cerebellar cortex and that have a role in motor coordination.
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Knott, A., Perkins, G., Schwarzenbacher, R. et al. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9, 505–518 (2008). https://doi.org/10.1038/nrn2417
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DOI: https://doi.org/10.1038/nrn2417
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