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Mitochondrial SIRT3 confers neuroprotection in Huntington's disease by regulation of oxidative challenges and mitochondrial dynamics.

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journal contribution
posted on 07.01.2021, 16:48 by Luana Naia, Catarina Carmo, Susanna Campesan, Lígia Fão, Victoria E Cotton, Jorge Valero, Carla Lopes, Tatiana R Rosenstock, Flaviano Giorgini, A Cristina Rego
SIRT3 is a major regulator of mitochondrial acetylome. Here we show that SIRT3 is neuroprotective in Huntington's disease (HD), a motor neurodegenerative disorder caused by an abnormal expansion of polyglutamines in the huntingtin protein (HTT). Protein and enzymatic analysis revealed that increased SIRT3 is a signature in several HD models, including human HD brain, which is regulated by oxidative species. While loss of SIRT3 further aggravated the oxidative phenotype, antioxidant treatment regularized SIRT3 levels. SIRT3 overexpression promoted the antioxidant effect in cells expressing mutant HTT, leading to enhanced mitochondrial function and balanced dynamics. Decreased Fis1 and Drp1 accumulation in mitochondria induced by SIRT3 expression favored mitochondrial elongation, while the SIRT3 activator ε-viniferin improved anterograde mitochondrial neurite transport, sustaining cell survival. Notably, SIRT3 fly-ortholog dSirt2 overexpression in HD flies ameliorated neurodegeneration and extended lifespan. These findings provide a link between oxidative stress and mitochondrial dysfunction hypotheses in HD and offer an opportunity for therapeutic development.

Funding

Support for this work was provided by grants from the ‘Fundação para a Ciência e a Tecnologia’ (FCT) (Grant: EXPL/BIM-MEC/2220/2013), ‘Gabinete de Apoio à Investigação’ (GAI) funded by Faculty of Medicine of the University of Coimbra and Santander Totta Bank, and ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD)—Life Science 2020, Portugal. L.N. was supported by FCT (Grant: SFRH/BD/86655/2012). S.C., V.E.C. and F.G were supported by the Medical Research Council, UK (Grant: MR/M013847/1). CNC is supported by the European Regional Development Fund (ERDF), through Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000012- HealthyAging2020, and through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, under projects POCI-01-0145-FEDER-007440 and UIDB/04539/2020.

History

Citation

Free Radical Biology and Medicine Volume 163, 1 February 2021, Pages 163-179

Author affiliation

Department of Genetics and Genome Biology

Version

AM (Accepted Manuscript)

Published in

Free Radic Biol Med

Volume

161

Pagination

163-179

Publisher

Elsevier BV

issn

0891-5849

eissn

1873-4596

Acceptance date

25/11/2020

Copyright date

2020

Available date

04/12/2021

Spatial coverage

United States

Language

eng