Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation.,The EMBO Journal

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Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-11-13 , DOI: 10.15252/embj.2019102155
Nicola Ferreira _{1,

2} , Kara L Perks _{1,

2} , Giulia Rossetti _{1,

2} , Danielle L Rudler _{1,

2} , Laetitia A Hughes _{1,

2} , Judith A Ermer _{1,

2} , Louis H Scott _{1,

2} , Irina Kuznetsova _{1,

2} , Tara R Richman _{1,

2} , Vinod K Narayana ₃ , Laila N Abudulai _{4,

5,

6} , Anne-Marie J Shearwood _{1,

2} , Henrietta Cserne Szappanos ₇ , Dedreia Tull ₃ , George C Yeoh ₁ , Livia C Hool _{7,

8} , Aleksandra Filipovska _{1,

2,

5} , Oliver Rackham _{1,

9,

10}

Affiliation

Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
The University of Western Australia Centre for Medical Research, Crawley, WA, Australia.
Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Vic., Australia.
Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, Perth, WA, Australia.
School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.
The School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia.
School of Human Sciences (Physiology), The University of Western Australia, Crawley, WA, Australia.
Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA, Australia.
Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.

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.

中文翻译：

应激信号传导和细胞增殖逆转线粒体误译的影响。

翻译保真度对于原核生物和真核生物核编码蛋白至关重要；然而，人们对线粒体误译的作用及其对新陈代谢的潜在影响知之甚少。我们生成了具有易错且超准确线粒体翻译的酵母和小鼠模型，并发现对于哺乳动物细胞功能而言，翻译率比翻译准确性更重要。具体来说，我们发现线粒体误译导致线粒体整体翻译和呼吸复合物组装率降低。在哺乳动物中，这种效应可以通过增加线粒体蛋白质稳定性和上调柠檬酸循环来补偿。此外，这还诱导线粒体应激信号传导，从而通过线粒体生物发生、端粒酶表达和细胞增殖恢复线粒体翻译，从而使新陈代谢正常化。相反，我们发现线粒体翻译保真度的提高会降低蛋白质合成速率，但不会引起线粒体应激反应。因此，翻译速度无法恢复，导致小鼠扩张型心肌病。总之，我们的研究结果揭示了哺乳动物特有的信号通路，这些信号通路对线粒体蛋白质合成保真度的变化做出反应并影响代谢。

更新日期：2019-12-17

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