Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration
Xing Guo, … , Daria Mochly-Rosen, Xin Qi
Xing Guo, … , Daria Mochly-Rosen, Xin Qi
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5371-5388. https://doi.org/10.1172/JCI70911.
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Research Article Neuroscience

Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration

Abstract

Huntington’s disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell–derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell–derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT–like inhibitor may prevent or slow the progression of HD.

Authors

Xing Guo, Marie-Helene Disatnik, Marie Monbureau, Mehrdad Shamloo, Daria Mochly-Rosen, Xin Qi

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Figure 4

p53 is required for Drp1-induced mitochondrial dysfunction in HD striatal cells.

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p53 is required for Drp1-induced mitochondrial dysfunction in HD striata...
HD striatal cells were transfected with either control siRNA (psiRNA-GFP) or p53 siRNA (psiRNA-mp53-GFP) for 2 days in the presence or absence of P110-TAT (P110, 1 μM). (A) Cells were stained with Tom20 antibody (red), and mitochondrial morphology was analyzed in GFP-labeled cells using a ×40 oil lens. Scale bars: 10 μm. A Western blot shows p53 levels after siRNA treatments. (B) GFP-positive cells with fragmented mitochondria as percentage of total number of GFP-positive cells. (C) Mitochondrial membrane potential was determined using TMRM. The red fluorescence was quantitated in GFP-positive cells. (D) Mitochondrial superoxide production was determined using the mitochondrial superoxide indicator, MitoSOX red, in the indicated groups. Red fluorescence was quantitated in GFP-positive cells. Data are the mean ± SEM of 3 independent experiments, counted by an observer blinded to the experimental conditions. At least 100 cells were counted per treatment group. (E) Cell viability was measured using an MTT assay after 20 hours of serum starvation. Data are presented as mean ± SEM of 3 independent experiments. *P < 0.05 vs. HdhQ7 and #P < 0.05 vs. HhdQ111 cells with control siRNA under normal or serum starvation conditions.