Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan,Aging Cell

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Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Aging Cell ( IF 8.0 ) Pub Date : 2021-06-07 , DOI: 10.1111/acel.13408
Tara R Richman _{1,

2,

3} , Judith A Ermer _{1,

2,

3} , Stefan J Siira _{1,

2,

3} , Irina Kuznetsova _{1,

2,

3} , Christopher A Brosnan ₄ , Giulia Rossetti _{1,

2,

3,

5} , Jessica Baker _{1,

2,

3,

5} , Kara L Perks _{1,

2,

3,

5,

6} , Henrietta Cserne Szappanos ₇ , Helena M Viola ₇ , Nicola Gray ₈ , Mark Larance ₉ , Livia C Hool _{7,

10} , Steven Zuryn ₄ , Oliver Rackham _{1,

2,

3,

5,

6,

11} , Aleksandra Filipovska _{1,

2,

3,

5,

10,

12}

Affiliation

Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.
ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA, Australia.
Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Nedlands, WA, Australia.
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia.
Telethon Kids Institute, Perth Children's Hospital, Nedlands, WA, Australia.
School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA, Australia.
School of Human Sciences, The University of Western Australia, Nedlands, WA, Australia.
Australian National Phenome Centre, Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia.
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia.

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12^ep^/^ep) or hyper-accurate (Mrps12^ha^/^ha) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12^ep^/^ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12^ha^/^ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging.

中文翻译：

代谢压力调节的线粒体误译导致心血管疾病和寿命缩短

线粒体蛋白质合成速率和保真度的变化会影响线粒体的代谢和生理作用。在这里，我们探讨了高脂饮食形式的环境压力如何调节线粒体翻译并影响容易出错（Mrps12 ^ep^/^ep）或超精确（Mrps12 ^ha^/^{ha ）的突变小鼠的寿命}) 线粒体核糖体。有趣的是，尽管这两种突变在降低体重、降低循环胰岛素和增加高脂饮食期间的葡萄糖耐量方面在代谢上是有益的，但它们以组织特异性方式表现出不同的（有害或有益的）结果。在通常受代谢疾病影响的两个不同器官中，心脏和肝脏，Mrps12 ^ep^/^ep小鼠免受心脏缺陷的影响，但对肝脏中的脂质积累敏感，激活参与类固醇和氨基酸代谢的基因。相比之下，提高了Mrps12 ^ha^/^{ha的平移准确性}小鼠通过激活肝脏增殖程序保护肝脏免受高脂肪饮食的影响，但促进了严重肥厚性心肌病的发展并导致寿命缩短。这些发现反映了有丝分裂后（心脏）和高度增殖（肝脏）组织之间不同的复杂转录和细胞信号传导反应。我们展示了线粒体蛋白质合成的速率和保真度之间的权衡决定了由于经常遇到的压力环境条件或老化而导致的组织特异性结果。

更新日期：2021-07-16

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