RT Journal Article
SR Electronic
T1 Impairment of neuronal mitophagy by mutant huntingtin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 330001
DO 10.1101/330001
A1 Sandra Franco-Iborra
A1 Ainhoa Plaza-Zabala
A1 David Sebastian
A1 Miquel Vila
A1 Marta Martinez-Vicente
YR 2018
UL http://biorxiv.org/content/early/2018/05/24/330001.abstract
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.