Article | Published:

Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis

Nature Structural & Molecular Biology volume 23, pages 441449 (2016) | Download Citation

Abstract

Elongation factor 4 (EF4) is a key quality-control factor in translation. Despite its high conservation throughout evolution, EF4 deletion in various organisms has not yielded a distinct phenotype. Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility. Deletion of mtEF4 accelerated mitochondrial translation at the cost of producing unstable proteins. Somatic tissues overcame this defect by activating mechanistic (mammalian) target of rapamycin (mTOR), thereby increasing rates of cytoplasmic translation to match rates of mitochondrial translation. However, in spermatogenic cells, the mTOR pathway was downregulated as part of the developmental program, and the resulting inability to compensate for accelerated mitochondrial translation caused cell-cycle arrest and apoptosis. We detected the same phenotype and molecular defects in germline-specific mtEF4-knockout mice. Thus, our study demonstrates cross-talk between mtEF4-dependent quality control in mitochondria and cytoplasmic mTOR signaling.

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Acknowledgements

We are grateful to Y. Zhang, Q. Chen and X. Fu for help and discussions, X. Zhang for proteomics data analyses, L. Sun and Y. Jia for assistance with TEM, and T. Juelich for English editing. This work was supported by grants from the Major State Basic Research Development Program of China (2013CB531200 and 2012CB911000 to Y.Q.), the National Natural Science Foundation of China (31322015 and 31270847 to Y.Q.), the Institute of Biophysics 135 Goal-oriented Project, National Laboratory of Biomacromolecules (Institute of Biophysics, Chinese Academy of Sciences) to Y.Q., the Opening Project of the Zhejiang Provincial Top Key Discipline of Clinical Medicine (LKFJ009) to Y.Q. and the Shanghai Key Laboratory of Molecular Andrology, China to Y.Q. We thank F. Gao (Institute of Zoology, Beijing) for anti-GCNA1.

Author information

Author notes

    • Yanyan Gao
    •  & Xiufeng Bai

    These authors contributed equally to this work.

Affiliations

  1. Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

    • Yanyan Gao
    • , Xiufeng Bai
    • , Dejiu Zhang
    • , Wenbin Liu
    • , Xintao Cao
    • , Zilei Chen
    • , Fugen Shangguan
    •  & Yan Qin
  2. University of Chinese Academy of Sciences, Beijing, China.

    • Dejiu Zhang
    • , Chunsheng Han
    • , Xintao Cao
    • , Fei Gao
    •  & Yan Qin
  3. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

    • Chunsheng Han
    •  & Fei Gao
  4. Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.

    • Jing Yuan
  5. Key Laboratory of Food Nutrition and Safety, Ministry of Education, School of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, China.

    • Wenbin Liu
    •  & Zhenyuan Zhu

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Contributions

Y.Q. conceived the project and designed the experiments. Y.G. and X.B. performed most experiments and processed and analyzed the data. D.Z., C.H., J.Y., W.L., X.C., Z.C., F.S., Z.Z., and F.G. assisted with experiments. Y.Q. wrote the manuscript, which was edited by all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yan Qin.

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    Variation in cellular signaling pathways

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DOI

https://doi.org/10.1038/nsmb.3206

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