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Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

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posted on 2024-05-09, 09:48 authored by Susanna Campesan, Ivana del Popolo, Kyriaki Marcou, Anna Straatman-Iwanowska, Mariaelena Repici, Kalina V Boytcheva, Victoria E Cotton, Natalie Allcock, Ezio Rosato, Charalambos KyriacouCharalambos Kyriacou, Flaviano Giorgini
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.

History

Author affiliation

College of Life Sciences/Genetics & Genome Biology

Version

  • VoR (Version of Record)

Published in

Neurobiology of Disease

Volume

185

Pagination

106236

Publisher

Elsevier BV

issn

0969-9961

eissn

1095-953X

Copyright date

2023

Available date

2024-05-09

Spatial coverage

United States

Language

en

Deposited by

Professor Charalambos Kyriacou

Deposit date

2024-04-25

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