%0 Journal Article
%T MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.
%A Wu Z
%A Tantray I
%A Lim J
%A Chen S
%A Li Y
%A Davis Z
%A Sitron C
%A Dong J
%A Gispert S
%A Auburger G
%A Brandman O
%A Bi X
%A Snyder M
%A Lu B
%J Mol Cell
%V 75
%N 4
%D 08 2019 22
%M 31378462
%F 19.328
%R 10.1016/j.molcel.2019.06.031
%X 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 the 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.