Journal
AUTOPHAGY
Volume 17, Issue 3, Pages 672-689Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1728096
Keywords
Autophagy; huntingtin; Huntington disease; mitochondria; mitophagy
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Funding
- Instituto de Salud Carlos III [MSII15/00007]
- Spanish Ministry of Science and Innovation [JCI2012-13544]
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The study found that HTT protein plays a crucial role in mitophagy, and the expansion of its polyQ tract affects this process, ultimately leading to the accumulation of damaged mitochondria and an increase in oxidative stress, leading to negative effects on mitochondrial dysfunction and neurodegeneration in Huntington disease.
The precise degradation of dysfunctional mitochondria by mitophagy is essential for maintaining neuronal homeostasis. HTT (huntingtin) can interact with numerous other proteins and thereby perform multiple biological functions within the cell. In this study, we investigated the role of HTT during mitophagy and analyzed the impact of the expansion of its polyglutamine (polyQ) tract. HTT is involved in different mitophagy steps, promoting the physical proximity of different protein complexes during the initiation of mitophagy and recruiting mitophagy receptors essential for promoting the interaction between damaged mitochondria and the nascent autophagosome. The presence of the polyQ tract in mutant HTT affects the formation of these protein complexes and determines the negative consequences of mutant HTT on mitophagy, leading to the accumulation of damaged mitochondria and an increase in oxidative stress. These outcomes contribute to general mitochondrial dysfunction and neurodegeneration in Huntington disease.
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