RT Journal Article
SR Electronic
T1 MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 554634
DO 10.1101/554634
A1 Zhihao Wu
A1 Ishaq Tantray
A1 Junghyun Lim
A1 Songjie Chen
A1 Yu Li
A1 Zoe Davis
A1 Cole Sitron
A1 Jason Dong
A1 Suzana Gispert
A1 Georg Auburger
A1 Onn Brandman
A1 Xiaolin Bi
A1 Michael Snyder
A1 Bingwei Lu
YR 2019
UL http://biorxiv.org/content/early/2019/02/19/554634.abstract
AB Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here we describe a phenomenon termed MISTERMINATE (mitochondrial stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs including complex-I 30kD subunit (C-I30) mRNA, occurring on mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C-terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally-extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson’s disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.