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. 2019 Dec 16;38(24):e102155.
doi: 10.15252/embj.2019102155. Epub 2019 Nov 13.

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

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
Affiliations

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Nicola Ferreira et al. EMBO J. .

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.

Keywords: metabolism; mitochondria; mitochondrial ribosome; protein synthesis; stress response.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure EV1
Figure EV1. Conservation of ribosomal protein S12 and construction and testing of yeast MRPS12 mutants

  1. Sequence alignment of S12 proteins from Escherichia coli, yeast mitochondria, and mouse mitochondria. Identical residues are highlighted in purple, and structurally similar residues are highlighted in blue. Sequences were obtained from NCBI (accession numbers are as follows: E. coli KXH02983.1, mouse NP_001347179.1, Saccharomyces cerevisiae NP_014434.1).

  2. Schematic representation of the construction of the error‐prone (CK MRPS12‐K72I, ep), hyper‐accurate (CK MRPS12‐K71T, ha), and control (CK MRPS12‐WT) yeast models.

  3. Yeast survival assay to test growth on different carbon sources. Undiluted (N) and serial 1:10 dilutions of wild‐type (CK MRPS12‐WT) and mutant (CK MRPS12‐K72I, ep, and CK MRPS12‐K71T, ha) yeast strains were inoculated as standing droplets on YP agar plates containing either 2% glucose, 3% acetate, 2% lactose, and 0.1% glucose, 2% lactose, 2% glycerol, or 2% ethanol as carbon sources.

  4. De novo protein synthesis in mitochondria isolated from CK MRPS12‐WT, CK MRPS12‐K72I (ep), and CK MRPS12‐K71T (ha) yeast strains was measured by pulse incorporation of 35S‐labeled methionine and cysteine. Equal amounts of mitochondrial protein were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

Data information: In (C, D), images are representative of results obtained from six independent biological replicates.
Figure 1
Figure 1. Models of error‐prone and hyper‐accurate mitochondrial translation

  1. Structural comparison of the Escherichia coli, yeast mitochondrial, and mammalian mitochondrial ribosomes.

  2. Schematic representation of the generation of the error‐prone (Mrps12 ep/ep) and hyper‐accurate (Mrps12 ha/ha) mouse models.

  3. MRPS12 protein levels were determined in mitochondria isolated from livers and hearts from Mrps12 +/+, Mrps12 ep/ep, and Mrps12 ha/ha 10‐week‐old mice by immunoblotting. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

Data information: In (C), data are presented as mean ± SD. The data are representative of results obtained from six mice from each genotype.
Figure 2
Figure 2. Error‐prone mitochondrial translation reduces the rate of translation and the abundance of mitochondrial mRNAs and proteins but is rescued with age
  1. A

    De novo protein synthesis in mitochondria isolated from the livers of young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine. Mitochondrial proteins were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

  2. B

    The steady‐state levels of mature mitochondrial mRNAs, tRNAs, and rRNAs in liver of young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were analyzed by northern blotting. 18S rRNA was used as a loading control. Relative abundance of RNA was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  3. C

    De novo protein synthesis in mitochondria isolated from the livers of aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine, as described in (A).

  4. D

    The steady‐state levels of mature mitochondrial mRNAs, tRNAs, and rRNAs in liver of aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were analyzed by northern blotting, as described in (B).

  5. E, F

    Mitochondria isolated from livers of young (10‐week‐old, E) and aged (30‐week‐old, F) Mrps12 +/+ and Mrps12 ep/ep mice were examined by immunoblotting using antibodies to investigate the steady‐state levels of nuclear‐ and mitochondria‐encoded OXPHOS polypeptides. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

Data information: In (A, C), autoradiographs and stained gels are representative of results obtained from six mice from each genotype. In (B, D, E, F), data are presented as mean ± SD. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (two‐tailed paired Student's t‐test). These data are representative of results obtained from eight mice from each genotype.
Figure EV2
Figure EV2. Error‐prone mitochondrial translation reduces the rate of translation in the heart

  1. De novo protein synthesis in mitochondria isolated from the hearts of young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine. Mitochondrial proteins were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

  2. The steady‐state levels of mature mitochondrial mRNAs, tRNAs, and rRNAs in hearts of young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were analyzed by northern blotting. 18S rRNA was used as a loading control. Relative abundance of RNA was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  3. De novo protein synthesis in mitochondria isolated from the hearts of aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine, as described in (A).

  4. The steady‐state levels of mature mitochondrial mRNAs, tRNAs, and rRNAs in hearts of aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were analyzed by northern blotting, as described in (B).

  5. Mitochondrial proteins from the hearts of young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐ and mitochondria‐encoded OXPHOS polypeptides. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  6. The steady‐state levels of nuclear‐ and mitochondria‐encoded OXPHOS polypeptides in mitochondria isolated from the hearts of aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were measured as described in (E).

Data information: In (A, C), autoradiographs and stained gels are representative of results obtained from six mice from each genotype. In (B, D, E, F), data are presented as mean ± SD. *P ≤ 0.05 (two‐tailed paired Student's t‐test). The data are representative of results obtained from six mice from each genotype.
Figure EV3
Figure EV3. Error‐prone mitochondrial translation does not alter the abundance of mitoribosomal proteins or the profile of translating ribosomes

  1. Proteins from liver and heart mitochondria from young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐encoded proteins of the small and large subunit of the mitochondrial ribosome. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  2. A continuous 10–30% sucrose gradient was used to determine the distribution of the small and large ribosomal subunit and the monosomes in liver mitochondria from young (10‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice. Mitochondrial ribosomal protein markers of the small (MRPS16) and large (MRPL44) ribosomal subunits were detected by immunoblotting with specific antibodies.

  3. Immunoblotting was used to investigate the steady‐state levels of nuclear‐encoded mitochondrial translation factors in mitochondria from young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice, as described in (A).

  4. De novo protein synthesis in mitochondria isolated from the livers of young (10‐week‐old) Mrps12 +/+, Mrps12 ep/ep , and Mrps12 ha/ha mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine in the presence and absence of gentamicin. Mitochondrial proteins were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

Data information: In (A–C), data are presented as mean ± SD. *P ≤ 0.05 (Student's t‐test). In (A–D), immunoblots, autoradiographs, and stained gels are representative of results obtained from six mice from each genotype.
Figure 3
Figure 3. Error‐prone mitochondrial translation reduces the rate of respiratory complex assembly and respiration but does not alter the levels of proteins involved in proteolysis

  1. Non‐phosphorylating (state 4), phosphorylating (state 3), and uncoupled respiration in the presence of 2 μM FCCP was measured in liver mitochondria isolated from Mrps12 +/+ and Mrps12 ep/ep mice using an OROBOROS oxygen electrode using either pyruvate, glutamate, and malate as substrates or with succinate in the presence of rotenone at 10 weeks or 30 weeks of age.

  2. Isolated liver mitochondria were resolved by BN–PAGE and immunoblotted using the blue native OXPHOS antibody cocktail. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to Complex II.

  3. The rates of respiratory complex assembly were measured by pulse incorporation of 35S‐labeled methionine and cysteine. Equal amounts of mitochondrial protein were separated by BN–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

  4. Proteins from liver mitochondria of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐encoded proteases. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

Data information: In (A), data are presented as mean ± SD. *P ≤ 0.05 (Student's t‐test). The data are representative of results obtained from eight mice from each genotype. In (B, D), data are presented as mean ± SD. **P ≤ 0.01 (Student's t‐test). The data are representative of results obtained from six mice from each genotype. In (C), the autoradiograph and stained gel are representative of results obtained from six mice from each genotype.
Figure EV4
Figure EV4. Error‐prone mitochondrial translation has little effect on the heart

  1. Non‐phosphorylating (state 4), phosphorylating (state 3), and uncoupled respiration in the presence of 2 μM FCCP was measured in heart mitochondria isolated from Mrps12 +/+ and Mrps12 ep/ep mice using an OROBOROS oxygen electrode using either pyruvate, glutamate, and malate as substrates or with succinate in the presence of rotenone at 10 weeks or 30 weeks of age.

  2. Isolated heart mitochondria from 10‐week‐ or 30‐week‐old mice were resolved by BN–PAGE and immunoblotted using the with the blue native OXPHOS antibody cocktail. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to Complex II.

  3. Proteins from heart mitochondria of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐encoded proteases. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  4. Heart sections cut to 5‐μm thickness were stained with hematoxylin and eosin (H & E) from young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ (n = 4) and Mrps12 ep/ep (n = 4) mice and visualized at 20× magnification. Scale bar is 100 μm.

  5. Heart proteins from 30‐week‐old Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted using antibodies to investigate the steady‐state levels of S6, AKT, and their phosphorylated forms. GAPDH was used as a loading control, and the relative abundance of phosphorylated proteins was measured using Li‐Cor Odyssey Classic software normalized to total protein, relative to the loading control.

Data information: In (A–C, E), data are presented as mean ± SD of results obtained from six mice from each genotype. **P ≤ 0.01 (Student's t‐test). In (D), images are representative of results obtained from six mice from each genotype.
Figure 4
Figure 4. Error‐prone mitochondrial translation stimulates liver proliferation via a transcriptional response that induces telomerase expression and mitochondrial biogenesis

  1. The body, heart, and liver weights of Mrps12 +/+ and Mrps12 ep/ep mice at 5, 10, 15, and 30 weeks of age.

  2. Liver sections from young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ep/ep mice were stained with hematoxylin and eosin (H & E) or Gomori's trichrome and visualized at 20× magnification. Scale bar is 100 μm.

  3. Liver sections from 30‐week‐old Mrps12 +/+ and Mrps12 ep/ep mice were stained with Hoechst 33342 dye or against an antibody to Ki67 and visualized using fluorescence microscopy at 20× magnification; the scale bar is 100 μm. Merged images were taken at 40× magnification, and the scale bar is 20 μm. Normal liver and tumor sections were used as negative and positive controls, respectively. Percent of fluorescent positive area within sections was calculated using NIS Elements AR software (Nikon).

  4. Cellular proteins from the livers of 30‐week‐old Mrps12 +/+ and Mrps12 ep/ep mice were immunoblotted to investigate the steady‐state levels of SAPK, AKT, and mTOR signaling proteins and their phosphorylated forms. GAPDH was used as a loading control, and the relative abundance of phosphorylated proteins was measured using Li‐Cor Odyssey Classic software normalized to total protein, relative to the loading control.

  5. Quantitative RT–PCR was used to measure the abundance of mRNAs encoding proteins involved in liver proliferation, the catalytic subunit of telomerase (Tert), transcription factors that regulate Tert expression, and proteins that regulate mitochondrial biogenesis (Tfam, Atf4, Chop). The data were normalized to 18S rRNA.

  6. Mitochondrial DNA (mtDNA) was measured using quantitative PCR, and values were normalized to the β‐2‐microglobulin (B2m) gene.

Data information: In (A), data are presented as mean ± SD of results obtained from 10 mice from each genotype. In (B, C), images are representative of results obtained from six mice from each genotype. In (C–F), data are presented as mean ± SD of results obtained from six mice of each genotype. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (two‐tailed paired Student's t‐test).
Figure 5
Figure 5. Citric acid cycle metabolites and enzymes are altered in response to mitochondrial mistranslation

  1. Metabolite profiling revealed alterations in the citric acid cycle that normalizes with age.

  2. Proteomic analyses of samples from 10‐ and 30‐week‐old Mrps12 +/+ and Mrps12 ep/ep mice revealed an enrichment in proteins that are involved in citric acid cycle‐related biological processes, by gene ontology analyses. Detailed CirGO graphs (Kuznetsova et al, 2019) of enriched biological processes are provided in Appendix Figures S1 and S2.

  3. Respiratory chain subunit proteins and citric acid cycle enzymes that were altered in abundance are labeled in green and black, respectively, within a heatmap of all significantly altered proteins within the proteomic dataset.

Data information: In (A), data are presented as box plots of the fold change (x‐axis) of metabolites; horizontal middle lines represent the mean, and the box ranges are the upper and lower quartiles, with the whiskers showing the highest and lowest observations of results obtained from five to six mice from each genotype. Only metabolites whose abundance was significantly changed between Mrps12 +/+ and Mrps12 ep/ep mice, after Benjamini–Hochberg correction (FDR 0.01), are graphed. Samples were normalized according to median signal intensity. In (B, C), data are results obtained from five mice of each genotype, with averages presented in (C).
Figure 6
Figure 6. Hyper‐accurate mitochondrial mistranslation reduces mitochondrial respiration and results in a progressive dilated cardiomyopathy

  1. De novo protein synthesis in mitochondria isolated from the hearts of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine. Mitochondrial proteins were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

  2. Mitochondrial proteins from the hearts of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐ and mitochondria‐encoded OXPHOS polypeptides. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  3. Non‐phosphorylating (state 4), phosphorylating (state 3), and uncoupled respiration in the presence of 2 μM FCCP was measured in heart mitochondria isolated from Mrps12 +/+ and Mrps12 ha/ha mice using an OROBOROS oxygen electrode using succinate in the presence of rotenone at 30 weeks of age.

  4. Differences in heart weight between Mrps12 +/+ (n = 10) and Mrps12 ha/ha (n = 10) mice at 10 and 30 weeks of age. Values are also shown relative to tibia length.

  5. Images of representative hearts from Mrps12 +/+ and Mrps12 ha/ha mice at 10 and 30 weeks of age.

  6. Histology of hematoxylin and eosin (H & E) stained heart cross‐sections from young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice, visualized at 10× magnification, and individual images were assembled using Adobe Photoshop.

  7. Echocardiographic parameters for Mrps12 +/+ (n = 8) and Mrps12 ha/ha 10‐week‐old and 30‐week‐old mice. LVEDD, left ventricular end‐diastolic diameter; LVESD, left ventricular end‐systolic diameter; FS, fractional shortening; LVDPW, left ventricular posterior wall in diastole; LVSPW, left ventricular posterior wall in systole; IVDS, intraventricular septum in diastole; IVSS, intraventricular septum in systole; HR, heart rate.

  8. Heart sections cut to 5‐μm thickness were stained with H & E from young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice and visualized at 20× magnification. Scale bar is 100 μm.

Data information: In (A), autoradiographs and stained gels are representative of results obtained from six mice from each genotype. In (B, C), data are presented as mean ± SD of results obtained from six mice from each genotype. In (D), data are presented as mean ± SD of results obtained from 10 mice from each genotype. In (E, F, H), images are representative of results obtained from six mice from each genotype. In (G), data are presented as mean ± SD of results obtained from eight mice of each genotype. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (two‐tailed paired Student's t‐test).
Figure EV5
Figure EV5. The role of hyper‐accurate mitochondrial mistranslation in the liver and cell signaling

  1. De novo protein synthesis in mitochondria isolated from the livers of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice was measured by pulse and chase incorporation of 35S‐labeled methionine and cysteine. Mitochondrial proteins were separated by SDS–PAGE, stained using Coomassie Brilliant Blue to show equal loading, and visualized by autoradiography.

  2. Mitochondrial proteins from the livers of young (10‐week‐old) and aged (30‐week‐old) Mrps12 +/+ and Mrps12 ha/ha mice were immunoblotted using antibodies to investigate the steady‐state levels of nuclear‐ and mitochondria‐encoded OXPHOS polypeptides. Porin was used as a loading control. Relative abundance of proteins was measured using Li‐Cor Odyssey Classic software normalized to the loading control.

  3. Non‐phosphorylating (state 4), phosphorylating (state 3), and uncoupled respiration in the presence of 2 μM FCCP was measured in liver mitochondria isolated from Mrps12 +/+ and Mrps12 ha/ha mice using an OROBOROS oxygen electrode using succinate in the presence of rotenone at 30 weeks of age.

  4. Liver weights of Mrps12 +/+ and Mrps12 ha/ha mice at 30 weeks of age.

  5. Body weights of Mrps12 +/+ and Mrps12 ha/ha mice at 5, 10, 15, and 30 weeks of age.

  6. Proteins from the hearts and livers of 30‐week‐old Mrps12 +/+ and Mrps12 ha/ha mice were immunoblotted using antibodies to investigate the steady‐state levels of S6, AKT, and their phosphorylated forms. GAPDH was used as a loading control, and the relative abundance of phosphorylated proteins was measured using Li‐Cor Odyssey Classic software normalized to total protein, relative to the loading control.

  7. Quantitative RT–PCR was used to measure the abundance of mRNAs encoding transcription factors that regulate mitochondrial biogenesis. The data were normalized to 18S rRNA.

  8. Mitochondrial DNA (mtDNA) was measured using quantitative PCR, and values were normalized to the β‐2‐microglobulin (B2m) gene.

  9. Proteomic analyses of samples from 30‐week‐old Mrps12 +/+ and Mrps12 ha/ha mice revealed an enrichment in proteins with significantly changed levels that are involved in cardiac and mitochondrial metabolic processes, by gene ontology analyses. Detailed CirGO graphs (Kuznetsova et al, 2019) of enriched biological processes are provided in Appendix Figure S3.

  10. Respiratory chain subunit proteins that were significantly changed in abundance are labeled in green within a heatmap of all significantly altered proteins within the proteomic dataset.

Data information: In (A), autoradiographs and stained gels are representative of results obtained from six mice from each genotype. In (B, C), data are presented as mean ± SD of results obtained from five to six mice from each genotype. In (D, E), data are presented as mean ± SD of results obtained from 10 mice from each genotype. In (F–H), data are presented as mean ± SD of results obtained from six mice from each genotype. *P ≤ 0.05, ***P ≤ 0.001 (two‐tailed paired Student's t‐test). In (I, J), data are results obtained from five mice of each genotype, with averages presented in (J).
Figure 7
Figure 7. Mitochondrial stress signaling and cellular proliferation rescue mitochondrial mistranslation
A model illustrating how a transcriptional response to low‐level mitochondrial stress can mitigate the effects of mitochondrial mistranslation by activating cell proliferation and mitochondrial biogenesis.
See this image and copyright information in PMC

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