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.
| Original language | English |
|---|---|
| Article number | 14034 |
| Journal | Scientific Reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - 19 Sep 2018 |
Bibliographical note
Publisher Copyright:© 2018, The Author(s).
Funding
The authors thank S. Hwang for her critical reading of the manuscript, M.-H. Disatnik for her feedback and advice on the experimental design, M. Halpain, N.L. Saw, and B. Yi for the collection of mouse behavioral data and instruction on primary neuronal isolation, K. Mruk for her help and advice with molecular biology and imaging experiments, and J. Perrino for technical support with EM. This work was supported, in part, by Takeda Pharmaceuticals’ Science Frontier Fund to D.M.‐R. Although Takeda sponsored, in part, the cost of the project, experiments were designed and executed entirely at Stanford University and Takeda has no ownership on the findings. The animal behavioral study was supported in part by a NINDS center core grant (2 P30 NS069375 06). O.S.K. is funded by a Smith Stanford Graduate Fellowship and The Molecular Pharmacology T32 Training Program.
| Funders | Funder number |
|---|---|
| Smith Stanford | |
| Takeda Pharmaceuticals’ Science Frontier Fund | |
| National Institute of General Medical Sciences | 1T32GM113854-01 |
| National Institute of Neurological Disorders and Stroke | P30NS069375 |