Mitochondrial and redox-based therapeutic strategies in Huntington's disease

Detalhes bibliográficos
Autor(a) principal: Fão, Lígia
Data de Publicação: 2020
Outros Autores: Rego, Ana Cristina
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/93149
https://doi.org/10.1089/ars.2019.8004
Resumo: Significance: The molecular processes that determine Huntington's disease (HD) pathogenesis are not yet fully understood, and until now no effective neuroprotective therapeutic strategies have been developed. Mitochondria are one of most important organelles required for neuronal homeostasis, by providing metabolic pathways relevant for energy production, regulating calcium homeostasis, or controlling free radical generation and cell death. Because augmented reactive oxygen species (ROS) accompanied by mitochondrial dysfunction are relevant early HD mechanisms, targeting these cellular mechanisms may constitute relevant therapeutic approaches. Recent Advances: Previous findings point toward a close relationship between mitochondrial dysfunction and redox changes in HD. Mutant huntingtin (mHTT) can directly interact with mitochondrial proteins, as translocase of the inner membrane 23 (TIM23), disrupting mitochondrial proteostasis and favoring ROS production and HD progression. Furthermore, abnormal brain and muscle redox signaling contributes to altered proteostasis and motor impairment in HD, which can be improved with the mitochondria-targeted antioxidant mitoquinone or resveratrol, an SIRT1 activator that ameliorates mitochondrial biogenesis and function. Critical Issues: Various antioxidants and metabolic enhancers have been studied in HD; however, the real outcome of these molecules is still debatable. New compounds have proven to ameliorate mitochondrial and redox-based signaling pathways in early stages of HD, potentially precluding selective neurodegeneration. Future Directions: Unraveling the molecular etiology of deregulated mitochondrial function and dynamics, and oxidative stress opens new prospects for HD therapeutics. In this review, we explore the role of redox unbalance and mitochondrial dysfunction in HD progression, and further describe advances on clinical trials in HD based on mitochondrial and redox-based therapeutic strategies.
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spelling Mitochondrial and redox-based therapeutic strategies in Huntington's diseaseHuntington’s Disease, mitochondrial dysfunction, oxidative stress, mutant huntingtin, therapiesSignificance: The molecular processes that determine Huntington's disease (HD) pathogenesis are not yet fully understood, and until now no effective neuroprotective therapeutic strategies have been developed. Mitochondria are one of most important organelles required for neuronal homeostasis, by providing metabolic pathways relevant for energy production, regulating calcium homeostasis, or controlling free radical generation and cell death. Because augmented reactive oxygen species (ROS) accompanied by mitochondrial dysfunction are relevant early HD mechanisms, targeting these cellular mechanisms may constitute relevant therapeutic approaches. Recent Advances: Previous findings point toward a close relationship between mitochondrial dysfunction and redox changes in HD. Mutant huntingtin (mHTT) can directly interact with mitochondrial proteins, as translocase of the inner membrane 23 (TIM23), disrupting mitochondrial proteostasis and favoring ROS production and HD progression. Furthermore, abnormal brain and muscle redox signaling contributes to altered proteostasis and motor impairment in HD, which can be improved with the mitochondria-targeted antioxidant mitoquinone or resveratrol, an SIRT1 activator that ameliorates mitochondrial biogenesis and function. Critical Issues: Various antioxidants and metabolic enhancers have been studied in HD; however, the real outcome of these molecules is still debatable. New compounds have proven to ameliorate mitochondrial and redox-based signaling pathways in early stages of HD, potentially precluding selective neurodegeneration. Future Directions: Unraveling the molecular etiology of deregulated mitochondrial function and dynamics, and oxidative stress opens new prospects for HD therapeutics. In this review, we explore the role of redox unbalance and mitochondrial dysfunction in HD progression, and further describe advances on clinical trials in HD based on mitochondrial and redox-based therapeutic strategies.2020-06-04info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/93149http://hdl.handle.net/10316/93149https://doi.org/10.1089/ars.2019.8004engFão, LígiaRego, Ana Cristinainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2021-10-18T07:48:14Zoai:estudogeral.uc.pt:10316/93149Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:12:07.852034Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Mitochondrial and redox-based therapeutic strategies in Huntington's disease
title Mitochondrial and redox-based therapeutic strategies in Huntington's disease
spellingShingle Mitochondrial and redox-based therapeutic strategies in Huntington's disease
Fão, Lígia
Huntington’s Disease, mitochondrial dysfunction, oxidative stress, mutant huntingtin, therapies
title_short Mitochondrial and redox-based therapeutic strategies in Huntington's disease
title_full Mitochondrial and redox-based therapeutic strategies in Huntington's disease
title_fullStr Mitochondrial and redox-based therapeutic strategies in Huntington's disease
title_full_unstemmed Mitochondrial and redox-based therapeutic strategies in Huntington's disease
title_sort Mitochondrial and redox-based therapeutic strategies in Huntington's disease
author Fão, Lígia
author_facet Fão, Lígia
Rego, Ana Cristina
author_role author
author2 Rego, Ana Cristina
author2_role author
dc.contributor.author.fl_str_mv Fão, Lígia
Rego, Ana Cristina
dc.subject.por.fl_str_mv Huntington’s Disease, mitochondrial dysfunction, oxidative stress, mutant huntingtin, therapies
topic Huntington’s Disease, mitochondrial dysfunction, oxidative stress, mutant huntingtin, therapies
description Significance: The molecular processes that determine Huntington's disease (HD) pathogenesis are not yet fully understood, and until now no effective neuroprotective therapeutic strategies have been developed. Mitochondria are one of most important organelles required for neuronal homeostasis, by providing metabolic pathways relevant for energy production, regulating calcium homeostasis, or controlling free radical generation and cell death. Because augmented reactive oxygen species (ROS) accompanied by mitochondrial dysfunction are relevant early HD mechanisms, targeting these cellular mechanisms may constitute relevant therapeutic approaches. Recent Advances: Previous findings point toward a close relationship between mitochondrial dysfunction and redox changes in HD. Mutant huntingtin (mHTT) can directly interact with mitochondrial proteins, as translocase of the inner membrane 23 (TIM23), disrupting mitochondrial proteostasis and favoring ROS production and HD progression. Furthermore, abnormal brain and muscle redox signaling contributes to altered proteostasis and motor impairment in HD, which can be improved with the mitochondria-targeted antioxidant mitoquinone or resveratrol, an SIRT1 activator that ameliorates mitochondrial biogenesis and function. Critical Issues: Various antioxidants and metabolic enhancers have been studied in HD; however, the real outcome of these molecules is still debatable. New compounds have proven to ameliorate mitochondrial and redox-based signaling pathways in early stages of HD, potentially precluding selective neurodegeneration. Future Directions: Unraveling the molecular etiology of deregulated mitochondrial function and dynamics, and oxidative stress opens new prospects for HD therapeutics. In this review, we explore the role of redox unbalance and mitochondrial dysfunction in HD progression, and further describe advances on clinical trials in HD based on mitochondrial and redox-based therapeutic strategies.
publishDate 2020
dc.date.none.fl_str_mv 2020-06-04
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/93149
http://hdl.handle.net/10316/93149
https://doi.org/10.1089/ars.2019.8004
url http://hdl.handle.net/10316/93149
https://doi.org/10.1089/ars.2019.8004
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