Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Ferreira, Nicola and Perks, Kara L and Rossetti, Giulia and Rudler, Danielle L and Hughes, Laetitia A and Ermer, Judith A and Scott, Louis H and Kuznetsova, Irina and Richman, Tara R and Narayana, Vinod K and Abudulai, Laila N and Shearwood, Anne‐Marie J and Cserne Szappanos, Henrietta and Tull, Dedreia and Yeoh, George C and Hool, Livia C and Filipovska, Aleksandra and Rackham, Oliver (2019) Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation. The EMBO Journal. ISSN 0261-4189

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Link to published document: http://doi.org/10.15252/embj.2019102155

Abstract

Translation fidelity is crucial for prokaryotes and eukaryotic nuclear-encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error-prone and hyper-accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian-specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 19 Nov 2019 22:53
Last Modified: 19 Nov 2019 22:53
URI: https://eprints.victorchang.edu.au/id/eprint/874

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