Mitochondria in Huntington's Disease: Implications in Pathogenesis and Mitochondrial-targeted Therapeutic Strategies

Overview

Journal Neural Regen Res

Date 2022 Dec 26

PMID 36571344

Authors

Anamaria Jurcau

Carolina Maria Jurcau

Affiliations

Soon will be listed here.

Abstract

Huntington's disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4. Compelling evidence implicates impaired mitochondrial energetics, altered mitochondrial biogenesis and quality control, disturbed mitochondrial trafficking, oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder. Unfortunately, conventional mitochondrial-targeted molecules, such as cysteamine, creatine, coenzyme Q10, or triheptanoin, yielded negative or inconclusive results. However, future therapeutic strategies, aiming to restore mitochondrial biogenesis, improving the fission/fusion balance, and improving mitochondrial trafficking, could prove useful tools in improving the phenotype of Huntington's disease and, used in combination with genome-editing methods, could lead to a cure for the disease.

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References

Wang S, Shi X, Wei S, Ma D, Oyinlade O, Lv S . Krüppel-like factor 4 (KLF4) induces mitochondrial fusion and increases spare respiratory capacity of human glioblastoma cells. J Biol Chem. 2018; 293(17):6544-6555. PMC: 5925822. DOI: 10.1074/jbc.RA117.001323. View

Liu T, Im W, Mook-Jung I, Kim M . MicroRNA-124 slows down the progression of Huntington's disease by promoting neurogenesis in the striatum. Neural Regen Res. 2015; 10(5):786-91. PMC: 4468771. DOI: 10.4103/1673-5374.156978. View

Naia L, Ferreira I, Ferreiro E, Rego A . Mitochondrial Ca handling in Huntington's and Alzheimer's diseases - Role of ER-mitochondria crosstalk. Biochem Biophys Res Commun. 2016; 483(4):1069-1077. DOI: 10.1016/j.bbrc.2016.07.122. View

Qi X, Qvit N, Su Y, Mochly-Rosen D . A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci. 2012; 126(Pt 3):789-802. PMC: 3619809. DOI: 10.1242/jcs.114439. View

Johri A, Calingasan N, Hennessey T, Sharma A, Yang L, Wille E . Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum Mol Genet. 2011; 21(5):1124-37. PMC: 3277311. DOI: 10.1093/hmg/ddr541. View

Roe A, Qi X . Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington's disease. Biochem Biophys Res Commun. 2018; 496(2):706-711. PMC: 6057844. DOI: 10.1016/j.bbrc.2018.01.114. View

Hurley J, Young L . Mechanisms of Autophagy Initiation. Annu Rev Biochem. 2017; 86:225-244. PMC: 5604869. DOI: 10.1146/annurev-biochem-061516-044820. View

Dubois C, Kong G, Tran H, Li S, Pang T, Hannan A . Small Non-coding RNAs Are Dysregulated in Huntington's Disease Transgenic Mice Independently of the Therapeutic Effects of an Environmental Intervention. Mol Neurobiol. 2021; 58(7):3308-3318. DOI: 10.1007/s12035-021-02342-9. View

Primeau J, Armanious G, Fisher M, Young H . The SarcoEndoplasmic Reticulum Calcium ATPase. Subcell Biochem. 2018; 87:229-258. DOI: 10.1007/978-981-10-7757-9_8. View

10.

Julayanont P, Heilman K, McFarland N . Early-Motor Phenotype Relates to Neuropsychiatric and Cognitive Disorders in Huntington's Disease. Mov Disord. 2020; 35(5):781-788. DOI: 10.1002/mds.27980. View

11.

Askeland G, Dosoudilova Z, Rodinova M, Klempir J, Liskova I, Kusnierczyk A . Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients. Sci Rep. 2018; 8(1):9817. PMC: 6026140. DOI: 10.1038/s41598-018-27985-y. View

12.

Rawlins M, Wexler N, Wexler A, Tabrizi S, Douglas I, Evans S . The Prevalence of Huntington's Disease. Neuroepidemiology. 2016; 46(2):144-53. DOI: 10.1159/000443738. View

13.

Kim H, Lee J, Park K, Kim W, Roh G . A mitochondrial division inhibitor, Mdivi-1, inhibits mitochondrial fragmentation and attenuates kainic acid-induced hippocampal cell death. BMC Neurosci. 2016; 17(1):33. PMC: 4902937. DOI: 10.1186/s12868-016-0270-y. View

14.

Moumne L, Betuing S, Caboche J . Multiple Aspects of Gene Dysregulation in Huntington's Disease. Front Neurol. 2013; 4:127. PMC: 3806340. DOI: 10.3389/fneur.2013.00127. View

15.

Onyango I, Bennett J, Stokin G . Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases. Neural Regen Res. 2021; 16(8):1467-1482. PMC: 8323696. DOI: 10.4103/1673-5374.303007. View

16.

Qin Z, Wang Y, Sapp E, Cuiffo B, Wanker E, Hayden M . Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci. 2004; 24(1):269-81. PMC: 6729557. DOI: 10.1523/JNEUROSCI.1409-03.2004. View

17.

MacAskill A, Kittler J . Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 2009; 20(2):102-12. DOI: 10.1016/j.tcb.2009.11.002. View

18.

Wang Y, Guo X, Ye K, Orth M, Gu Z . Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease. Proc Natl Acad Sci U S A. 2021; 118(30). PMC: 8325154. DOI: 10.1073/pnas.2014610118. View

19.

Wu J, Ryskamp D, Birnbaumer L, Bezprozvanny I . Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease. J Huntingtons Dis. 2018; 7(1):35-50. PMC: 6309623. DOI: 10.3233/JHD-170266. View

20.

Grewal A, Singh T, Sharma D, Sharma V, Singh M, Rahman M . Mechanistic insights and perspectives involved in neuroprotective action of quercetin. Biomed Pharmacother. 2021; 140:111729. DOI: 10.1016/j.biopha.2021.111729. View