Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder.

Publication DOI: https://doi.org/10.1016/j.nbd.2023.106236
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
Funding Information: We acknowledge the Advanced Imaging Facility at the University of Leicester for support and thank Dr. Kees Straatman for helping with confocal imaging. We also thank the individuals and repositories that provided the various fly lines and antibodies utili
Additional Information: Copyright © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). Funding Information: SC, MR, VEC and FG were supported by Medical Research Council research grants ( MR/M013847/1 ; MR/L003503/1 ). KVB was supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) funded by the Biotechnology and Biological Sciences Research Council.
Uncontrolled Keywords: Huntingtin,Huntington's disease,Mitochondrial dysfunction,Neurodegeneration,Parkin,Neurology
Publication ISSN: 1095-953X
Last Modified: 23 May 2024 07:27
Date Deposited: 17 Aug 2023 16:56
Full Text Link:
Related URLs: https://www.sci ... 969996123002516 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-09
Published Online Date: 2023-07-24
Accepted Date: 2023-07-22
Authors: Campesan, Susanna
del Popolo, Ivana
Marcou, Kyriaki
Straatman-Iwanowska, Anna
Repici, Mariaelena (ORCID Profile 0000-0002-9420-528X)
Boytcheva, Kalina V.
Cotton, Victoria E.
Allcock, Natalie
Rosato, Ezio
Kyriacou, Charalambos P.
Giorgini, Flaviano

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