Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

Susanna Campesan*, Ivana del Popolo, Kyriaki Marcou, Anna Straatman-Iwanowska, Mariaelena Repici, Kalina V. Boytcheva, Victoria E. Cotton, Natalie Allcock, Ezio Rosato, Charalambos P. Kyriacou, Flaviano Giorgini

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number106236
Pages (from-to)106236
Number of pages14
JournalNeurobiology of Disease
Early online date24 Jul 2023
Publication statusPublished - Sept 2023

Bibliographical note

Copyright © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (

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.


  • Huntingtin
  • Huntington's disease
  • Mitochondrial dysfunction
  • Neurodegeneration
  • Parkin


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