Elsevier

Drug Discovery Today

Volume 19, Issue 7, July 2014, Pages 951-955
Drug Discovery Today

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Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission

https://doi.org/10.1016/j.drudis.2014.03.020Get rights and content

Highlights

  • Mitochondrial dysfunction plays a large role in Huntington's disease.

  • Mutant Htt interacts with Drp1 and causes mitochondrial fragmentation.

  • Drp1-mutant Htt complexes disrupt axonal transport of mitochondria.

  • Fission inhibitor(s) enhances synaptic activity and neuronal function.

  • Mdivi, Dynasore and P110 molecules are promising HD therapeutic molecules.

Huntington's disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.

Section snippets

Mitochondrial abnormalities

Recent research has revealed multiple alterations in mitochondria, in HD progression and pathogenesis, including: (i) reduced enzymatic activity in several components of oxidative phosphorylation, including complexes II, III and IV of the electron transport chain, in HD postmortem brains and HD mouse models 22, 23, 24, suggesting that mitochondria are involved in HD pathogenesis; (ii) low mitochondrial ATP and decreased mitochondrial ADP uptake in HD knock-in striatal cells and lymphoblasts

Abnormal mitochondrial dynamics

Mounting evidence suggests that structural and functional abnormalities in mitochondria are involved in HD pathogenesis 16, 18, 19, 20, 21. In neurons that express mHtt, an imbalance between fission and fusion was found to lead to abnormalities in mitochondrial structure and function, and to damaged neurons. Several studies have reported such abnormal mitochondrial dynamics in patients with HD 16, 17, 18, 19, 20, HD mouse models 17, 18, damaged HD lymphoblasts, HD cell lines and primary neurons

Mechanisms underlying mitochondrial fragmentation

Recent evidence is revealing that several mechanisms are likely to be involved in excessive mitochondrial fission in HD-affected neurons, including the evidence that: (i) excessive production of ROS activates fission proteins and increases GTPase Drp1 enzymatic activity; (ii) mHtt interacts with Drp1 and increases GTPase Drp1 enzymatic activity, which in turn increases mitochondrial fission and creates an imbalance in mitochondrial dynamics 17, 18; (iii) S-nitrosylation of Drp1 in relation to

Inhibitors of excessive mitochondrial fission as therapeutic targets

Progress is being made in developing therapeutic molecules that can reduce excessive mitochondrial fission and still maintain the fission–fusion balance in mitochondria, mitochondrial function and neuronal activity in diseases that are involved with oxidative stress and mitochondrial dysfunction. Several groups have independently screened chemical libraries and have found three different molecules: Mdivi [37], Dynasore [38] and P110 [39]. Among these, the Mdivi molecule has been extensively

Concluding remarks and future directions

Since the discovery of the HD gene in 1993, significant progress has been made in understanding the toxic effects of mHtt and cellular changes that are associated with it. Among multiple cellular mechanisms that might be involved in HD pathogenesis, abnormal mitochondrial dynamics and excessive mitochondrial fission might be crucial conditions and events associated with mitochondrial dysfunction and neuronal damage in HD-affected neurons. Considerable progress has also been made in identifying

Acknowledgments

This research was supported by National Institutes of Health Grants AG028072, AG042178 and RR000163, and a Grant from the Medical Research Foundation of Oregon.

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