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Sci Rep. 2018 Sep 19;8(1):14034. doi: 10.1038/s41598-018-32228-1.

Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo.

Author information

1
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
2
The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 12325, Israel.
3
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
4
Behavioral and Functional Neuroscience Laboratory, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
5
Department of Biomedical Sciences, University of Padova, Padova, 35122, Italy.
6
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. mochly@stanford.edu.

Abstract

Mitochondria form a dynamic network governed by a balance between opposing fission and fusion processes. Because excessive mitochondrial fission correlates with numerous pathologies, including neurodegeneration, the mechanism governing fission has become an attractive therapeutic strategy. However, targeting fission is a double-edged sword as physiological fission is necessary for mitochondrial function. Fission is trigged by Drp1 anchoring to adaptors tethered to the outer mitochondrial membrane. We designed peptide P259 that distinguishes physiological from pathological fission by specifically inhibiting Drp1's interaction with the Mff adaptor. Treatment of cells with P259 elongated mitochondria and disrupted mitochondrial function and motility. Sustained in vivo treatment caused a decline in ATP levels and altered mitochondrial structure in the brain, resulting in behavioral deficits in wild-type mice and a shorter lifespan in a mouse model of Huntington's disease. Therefore, the Mff-Drp1 interaction is critical for physiological mitochondrial fission, motility, and function in vitro and in vivo. Tools, such as P259, that differentiate physiological from pathological fission will enable the examination of context-dependent roles of Drp1 and the suitability of mitochondrial fission as a target for drug development.

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