PT  - JOURNAL ARTICLE
AU  - Sandra Franco-Iborra
AU  - Ainhoa Plaza-Zabala
AU  - David Sebastian
AU  - Miquel Vila
AU  - Marta Martinez-Vicente
TI  - Impairment of neuronal mitophagy by mutant huntingtin
AID  - 10.1101/330001
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 330001
4099  - http://biorxiv.org/content/early/2018/05/24/330001.short
4100  - http://biorxiv.org/content/early/2018/05/24/330001.full
AB  - Neuronal homeostasis depends on the proper functioning of different quality control systems. The accurate degradation of dysfunctional mitochondria by mitophagy is essential for maintaining mitochondrial quality and quantity in neurons. Huntingting protein (Htt) can interact with numerous other proteins and thereby perform multiple biological functions in the cell. We investigated the role of Htt during neuronal mitophagy in post-mitotic differentiated striatal neurons avoiding artificial overexpression of mitophagy-related proteins. Our study shows that Htt promotes the physical proximity of different protein complexes during initiation of the mitophagy process. Htt is needed to promote the ULK1 complex activation, the recruitment of the essential receptors of mitophagy –optineurin and NDP52- and the interaction of these receptors with LC3-II. Mutant Htt also causes a gain of toxic function avoiding the formation of the Beclin1-Vps34 initiation complex. We report that the presence of the expanded polyQ tract can affect the efficiency of neuronal mitophagy and consequently promote the accumulation of damaged mitochondria and increase oxidative stress, leading to mitochondrial dysfunction and contributing to neurodegeneration in Huntington’s disease.