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bioRxiv · 10.1101/554634

MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure

Wu, Z.·Tantray, I.·Lim, J.·Chen, S.·Li, Y.·Davis, Z.·Citron, C.·Dong, J.·Gispert, S.·Auburger, G.·Brandman, O.·Bi, X.·Snyder, M.·Lu, B.
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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 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 Parkinsons disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.

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Wu, Z., Tantray, I., Lim, J., Chen, S., Li, Y., Davis, Z., Citron, C., Dong, J., Gispert, S., Auburger, G., Brandman, O., Bi, X., Snyder, M., Lu, B.. 2019-02-19. MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure. https://doi.org/10.1101/554634

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