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Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis

Nature Structural & Molecular Biology volume 23, pages 441–449 (2016)Cite this article

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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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Figure 1: Male infertility is the only observed phenotype of mtEF4 knockout mice, as verified in germline-specific-knockout mice.
Figure 2: mtEF4 is abundant in spermatocytes and round spermatids, and its ablation induces spermatogenesis arrest.
Figure 3: Spermatogenesis is inhibited by mitochondrial abnormalities.
Figure 4: mtEF4 ablation leads to deficiency in mtDNA-encoded OXPHOS subunits.
Figure 5: Deletion of mtEF4 induces upregulation of mitochondrial translation in both somatic and sperm cells but causes opposing responses in mTOR signaling.
Figure 6: Deletion of mtEF4 induces upregulation of cytoplasmic translation in somatic cells but downregulation in sperm cells.
Figure 7: Working model of the retrograde response after mtEF4 deletion in somatic and sperm cells.

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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.

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  1. Yanyan Gao and Xiufeng Bai: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Yan Qin.

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Integrated supplementary information

Supplementary Figure 1 Generation and validation of mtEF4-knockout mice.

(a) Alignment of EF4 (E. coli) with mouse, yeast and human EF4. (b) Domain structures of mouse mtEF4 compared to those of EF4 (E. coli). (c) mtEF4 is ubiquitous in mice tissues and organs. (d) Schematic strategy for the generation of mtEF4 KO mouse. (e) Southern blot verification of a single introduction of the targeting construct in the homologous recombined embryonic stem (ES) cell clones. C: control, 129 ES cells. 1-3: positive clones. 5’-: 5’-primer. 3’-: 3’-primer. (f) PCR-based genotyping of KO and gKO mice. (g) qPCR of mtEF4 transcripts from various tissues of WT and KO mice (mean ± s.d., n = 12 mice). (h) Western blotting (WB) of mtEF4 protein from total WT (+/+) and KO (−/−) mice, and gKO mice.

Supplementary Figure 2 Morphology of mitochondria-rich tissues and hormones from WT and total-KO male mice.

(a, b) Macrograph (a) and Hematoxylin and eosin (H&E) staining (b) of the heart. Scale bar: 200 μm (c) H&E staining of the liver, muscle and cerebrum. Scale bar: 200 μm (d) Quantification of the seminiferous tubule diameters (mean ± s.d., n = 5 mice, **P < 0.01). (e-g) Hormone changes upon mtEF4 ablation. Comparison of WT, KO and gKO mice serum follicle-stimulating hormone (FSH) (e), luteinizing hormone (LH) (f) and testosterone (T) (g) (mean ± s.d., n = 5 mice, *P < 0.05, **P < 0.01).

Supplementary Figure 3 Morphology of mitochondria-rich tissues from WT and gKO male mice.

(a-c) H&E staining of the heart, liver, muscle, cerebrum (a), testis (b) and epididymis (epi) (c) from WT and gKO mice. Scale bar: 200 μm. Red frame: zoom-in, scale bar: 50 μm. Red circle: immature spermatogenic cells. (d) The concentration of the spermatozoa in the epididymis. (e) Morphology of the sperms. Hoechst33258 (blue) and mitotracker (red) staining indicates nuclei and mitochondria, respectively. Abnormal mitochondrial sheaths are indicated by white arrows. Scale bar: 50 μm. (f, g) The mobility of the sperms. (h) Computer-assisted sperm analysis (CASA) parameter of the sperms. Average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), amplitude of lateral head displacement (ALH), beat cross frequency (BCF) (mean ± s.d., n = 10 mice, ***P < 0.001). (i, j) EF4 is co-localized with the ribosome in the mitochondria of mouse testicular tissue. (k, l) Transmission electron microscope (TEM) photographs of gKO testis (k) and the sperms (l). Mt: mitochondria, Nu: nucleus, scale bar: 1 μm. Red frame: zoom-in. Scale bar: 1 μm.

Supplementary Figure 4 Qualitative and quantitative analysis of OXPHOS subunits from mitochondria-rich tissues of WT and KO male mice.

(a) Blue native gels (BNG) of heart, liver, muscle and cerebrum mitochondria. (b) In-gel activity (IGA) of complex I and IV. (c) Quantification of IGA from complex I (left) and complex IV (right) (mean ± s.d., n = 4 mice). (d) WB of nuclear and mitochondrial DNA encoded OXPHOS complex subunits. (e) Relative amount (%) of arbitrary units from samples in (d). Tom20: internal control, mean ± s.d., n = 5 mice.

Supplementary Figure 5 Qualitative and quantitative analysis of OXPHOS complexes and subunits from mitochondria-rich tissues of WT and gKO male mice.

(a, b) BNG (a) and IGA (b) of heart, liver, muscle and cerebrum mitochondria show similar amount of OXPHOS complexes in WT and gKO mice. (c) Quantification of IGA from complex I (left) and complex IV (right) (mean ± s.d., n = 4 mice). (d) IGA of OXPHOS complexes from WT and gKO heart, testis and epididymis. (e, f) WB of nDNA (e) and mtDNA (f) encoded OXPHOS complex subunits in the samples as in (d). (g, h) Relative amount (%) of arbitrary units from samples in (e) and (f), respectively. H: heart, T: tesits, E: epididymis, Tom20: internal control, mean ± s.d., n = 5 mice, **P < 0.01, ***P < 0.001.

Supplementary Figure 6 Quantification of mtDNA, mRNA of OXPHOS subunits, and mitochondrial ribosomes.

(a) Relative mtDNA content (mean ± s.d., n = 10 mice, *P < 0.05). (b) Relative quantification of nDNA (blue) and mtDNA (red) encoded OXPHOS subunits. The ratio was defined as the qPCR value of each tested transcript from KO sample versus from WT sample. Actin: internal control, mean ± s.d., n = 10 mice. (c) Quantification of the expression of mitochondrial transcription factor TFAM (mean ± s.d., n = 5 mice, *P < 0.05). (d) Quantification of the expression of mitochondrial small and large ribosomal subunit protein, MRPS18 and MRPL11, respectively. Tom20: internal control, mean ± s.d., n = 3 mice.

Supplementary Figure 7 [35S]methionine pulse-chase-labeling and protein synthesis of isolated mitochondria from WT and gKO testes.

Purified mitochondria were pulse labeled with [35S]-Met for 1 h and subsequently chased by the addition of an excess of unlabeled Met with 3 h and 5 h incubation in the presence (a) or absence (c) of protease inhibitor. The thirteen mitochondrial translation products are indicated. (b, d) The quantification of (a) and (c), respectively. Internal control: Tom20, mean ± s.d., n = 3 mice, ***P < 0.001.

Supplementary Figure 8 mTOR inhibition in the heart results in OXPHOS defects, and deletion of mtEF4 induces downregulation of cytoplasmic translation in sperm cells.

(a) Wet weight of the hearts from male mice treated with DMSO or rapamycin (mean ± s.d., n = 5 mice, **P < 0.01). (b) Quantification of the OXPHOS subunits of the DMSO/rapamycin treated mice. The quantitative value of the sample WT heart treated with DMSO was defined as 100%. Tom20: internal control, mean ± s.d., n = 3 mice, *P < 0.05, **P < 0.01. (c, d) Cytoplasmic polysome patterns of WT (blue) and gKO (red) tissues. On the right, the monosomes (80S) versus polysomes ratio was quantified (mean ± s.d., n = 3 mice, *P<0.05). (e, f) Distribution of ATP5D mRNAs across the density gradients from (c, d) was determined by RT-sqPCR. Red square, increased subunits and monosomes in gKO testis than in WT testis.

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Variation in cellular signaling pathways (XLSX 661 kb)

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Gao, Y., Bai, X., Zhang, D. et al. Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis. Nat Struct Mol Biol 23, 441–449 (2016). https://doi.org/10.1038/nsmb.3206

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