Rxivist logo

MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure

By Zhihao Wu, Ishaq Tantray, Junghyun Lim, Songjie Chen, Yu Li, Zoe Davis, Cole Sitron, Jason Dong, Suzana Gispert, Georg Auburger, Onn Brandman, Xiaolin Bi, Michael P. Snyder, Bingwei Lu

Posted 19 Feb 2019
bioRxiv DOI: 10.1101/554634 (published DOI: 10.1016/j.molcel.2019.06.031)

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 disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.

Download data

  • Downloaded 501 times
  • Download rankings, all-time:
    • Site-wide: 29,186 out of 84,050
    • In cell biology: 1,372 out of 4,278
  • Year to date:
    • Site-wide: 35,870 out of 84,050
  • Since beginning of last month:
    • Site-wide: 33,923 out of 84,050

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News