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Wu, Z., Tantray, I., Lim, J., Chen, S., Li, Y., Davis, Z., Sitron, C., Dong, J., Gispert, S., Auburger, G., Brandman, O., Bi, X., Snyder, M., Lu, B. (2019). MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.  Mol. Cell 75(4): 835--848.e8.
FlyBase ID
FBrf0243318
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC7362879 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Mol. Cell
    Title
    Molecular Cell
    Publication Year
    1997-
    ISBN/ISSN
    1097-2765 1097-4164
    Data From Reference
    Alleles (59)
    Genes (38)
    Human Disease Models (2)
    Physical Interactions (1)
    Natural transposons (1)
    Insertions (7)
    Experimental Tools (1)
    Transgenic Constructs (47)