A zebrafish <i>tufm</i> mutant model for the COXPD4 syndrome of aberrant mitochondrial function

Ting Li; Tursunjan Aziz; Guangyuan Li; Lin Zhang; Jihua Yao; Shunji Jia

doi:10.1016/j.jgg.2024.05.009

Volume 51 Issue 9

Sep. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(9): 922-933

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A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function

doi: 10.1016/j.jgg.2024.05.009

a. School of Life Sciences, Fudan University, Shanghai 200438, China;
b. State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
c. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

Funds:

This work was financially supported by the National Natural Science Foundation of China (#92254302 and #32293202 to S. J.) and National Key Research and Development Project (#2019YFA0801403 to S. J.).

Received Date: 2024-04-08
Accepted Date: 2024-05-25
Rev Recd Date: 2024-05-23

Available Online: 2025-06-06

Publish Date: 2024-05-31

Abstract

Abstract

Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy. Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4 (COXPD4), a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain (MRC) complexes. The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management. In this study, we construct a zebrafish tufm^-/- mutant that closely resembles the COXPD4 syndrome, exhibiting compromised mitochondrial protein translation, dysfunctional mitochondria with oxidative phosphorylation defects, and significant metabolic suppression of the tricarboxylic acid cycle. Leveraging this COXPD4 zebrafish model, we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4. Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.
- Tufm,
- Mitochondria,
- COXPD4,
- Disease model,
- Zebrafish

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References(42)

References

Aldossary, A.M., Tawfik, E.A., Alomary, M.N., Alsudir, S.A., Alfahad, A.J., Alshehri, A.A., Almughem, F.A., Mohammed, R.Y., Alzaydi, M.M., 2022. Recent advances in mitochondrial diseases: From molecular insights to therapeutic perspectives. Saudi. Pharm. J. 30, 1065-1078.

Antonicka, H., Ostergaard, E., Sasarman, F., Weraarpachai, W., Wibrand, F., Pedersen, A.M., Rodenburg, R.J., van der Knaap, M.S., Smeitink, J.A., Chrzanowska-Lightowlers, Z.M., et al., 2010. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am. J. Hum. Genet. 87, 115-122.

Antonicka, H., Sasarman, F., Kennaway, N.G., Shoubridge, E.A., 2006. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum. Mol. Genet. 15, 1835-1846.

Baden, K.N., Murray, J., Capaldi, R.A., Guillemin, K., 2007. Early developmental pathology due to cytochrome c oxidase deficiency is revealed by a new zebrafish model. J. Biol. Chem. 282, 34839-34849.

Byrnes, J., Ganetzky, R., Lightfoot, R., Tzeng, M., Nakamaru-Ogiso, E., Seiler, C., Falk, M.J., 2018. Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish. Neurochem. Int. 117, 23-34.

Chen, Z., Bordieanu, B., Kesavan, R., Lesner, N.P., Venigalla, S.S.K., Shelton, S.D., DeBerardinis, R.J., Mishra, P., 2023. Lactate metabolism is essential in early-onset mitochondrial myopathy. Sci. Adv. 9, eadd3216.

Choi, C.Y., Vo, M.T., Nicholas, J., Choi, Y.B., 2022. Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis. Cell Death Differ. 29, 451-464.

Coenen, M.J., Antonicka, H., Ugalde, C., Sasarman, F., Rossi, R., Heister, J.G., Newbold, R.F., Trijbels, F.J., van den Heuvel, L.P., Shoubridge, E.A., et al., 2004. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N. Engl. J. Med .351, 2080-2086.

Di Nottia, M., Montanari, A., Verrigni, D., Oliva, R., Torraco, A., Fernandez-Vizarra, E., Diodato, D., Rizza, T., Bianchi, M., Catteruccia, M., et al., 2017. Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 961-967.

Glasgow, R.I.C., Thompson, K., Barbosa, I.A., He, L., Alston, C.L., Deshpande, C., Simpson, M.A., Morris, A.A.M., Neu, A., Lobel, U., et al., 2017. Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits. Neurogenetics 18, 227-235.

Gorman, G.S., Chinnery, P.F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D.R., Zeviani, M., Turnbull, D.M., 2016. Mitochondrial diseases. Nat. Rev. Dis. Primers 2, 16080.

Gustafsson, C.M., Falkenberg, M., Larsson, N.G., 2016. Maintenance and Expression of Mammalian Mitochondrial DNA. Annu. Rev. Biochem. 85, 133-160.

He, K., Guo, X., Liu, Y., Li, J., Hu, Y., Wang, D., Song, J., 2016. TUFM downregulation induces epithelial-mesenchymal transition and invasion in lung cancer cells via a mechanism involving AMPK-GSK3beta signaling. Cell. Mol. Life Sci. 73, 2105-2121.

Hershkovitz, T., Kurolap, A., Gonzaga-Jauregui, C., Paperna, T., Mory, A., Wolf, S.E., Regeneron Genetics, C., Overton, J.D., Shuldiner, A.R., Saada, A., et al., 2019. A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4. J. Hum. Genet. 64, 589-595.

Kemp, J.P., Smith, P.M., Pyle, A., Neeve, V.C., Tuppen, H.A., Schara, U., Talim, B., Topaloglu, H., Holinski-Feder, E., Abicht, A., et al., 2011. Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency. Brain. 134, 183-195.

Kim, D., Hwang, H.Y., Ji, E.S., Kim, J.Y., Yoo, J.S., Kwon, H.J., 2021. Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction. Commun. Biol. 4, 1.

Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., et al., 2016. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS. Genet. 12, e1005679.

Kummer, E., Ban, N., 2021. Mechanisms and regulation of protein synthesis in mitochondria. Nat. Rev. Mol. Cell Biol. 22, 307-325.

Kuo, S.M., Chen, C.J., Chang, S.C., Liu, T.J., Chen, Y.H., Huang, S.Y., Shih, S.R., 2017. Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy. mBio. 8, 00481-17.

Lei, Y., Kansy, B.A., Li, J., Cong, L., Liu, Y., Trivedi, S., Wen, H., Ting, J.P., Ouyang, H., Ferris, R.L., 2016. EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. Oncogene 35, 4698-4707.

Lei, Y., Wen, H., Yu, Y., Taxman, D.J., Zhang, L., Widman, D.G., Swanson, K.V., Wen, K.W., Damania, B., Moore, C.B., et al., 2012. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36, 933-946.

Lin, J., Chen, K., Chen, W., Yao, Y., Ni, S., Ye, M., Zhuang, G., Hu, M., Gao, J., Gao, C., et al., 2020. Paradoxical Mitophagy Regulation by PINK1 and TUFm. Mol. Cell 80, 607-620.

Mayr, J.A., Haack, T.B., Freisinger, P., Karall, D., Makowski, C., Koch, J., Feichtinger, R.G., Zimmermann, F.A., Rolinski, B., Ahting, U., et al., 2015. Spectrum of combined respiratory chain defects. J. Inherit. Metab. Dis. 38, 629-640.

Molina-Berenguer, M., Vila-Julia, F., Perez-Ramos, S., Salcedo-Allende, M.T., Camara, Y., Torres-Torronteras, J., Marti, R., 2022. Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations. FASEB J. 36, e22091.

Ng, Y.S., Bindoff, L.A., Gorman, G.S., Klopstock, T., Kornblum, C., Mancuso, M., McFarland, R., Sue, C.M., Suomalainen, A., Taylor, R.W., et al., 2021. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. 20, 573-584.

Perez-Martinez, X., Funes, S., Camacho-Villasana, Y., Marjavaara, S., Tavares-Carreon, F., Shingu-Vazquez, M., 2008. Protein synthesis and assembly in mitochondrial disorders. Curr. Top. Med. Chem. 8, 1335-1350.

Reinecke, F., Smeitink, J.A., van der Westhuizen, F.H., 2009. OXPHOS gene expression and control in mitochondrial disorders. Biochim. Biophys. Acta 1792, 1113-1121.

Russell, O.M., Gorman, G.S., Lightowlers, R.N., Turnbull, D.M., 2020. Mitochondrial Diseases: Hope for the Future. Cell 18, 168-188.

Schlieben, L.D., Prokisch, H., 2020. The Dimensions of Primary Mitochondrial Disorders. Front. Cell Dev. Biol. 8, 600079.

Smeitink, J.A., Elpeleg, O., Antonicka, H., Diepstra, H., Saada, A., Smits, P., Sasarman, F., Vriend, G., Jacob-Hirsch, J., Shaag, A., et al., 2006. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am. J. Hum. Genet. 79, 869-877.

Smits, P., Smeitink, J., van den Heuvel, L., 2010. Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J. Biomed Biotechnol. 2010, 737385.

Steele, S.L., Prykhozhij, S.V., Berman, J.N., 2014. Zebrafish as a model system for mitochondrial biology and diseases. Transl. Res. 163, 79-98.

Suomalainen, A., Battersby, B.J., 2018. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77-92.

Taylor, R.W., Pyle, A., Griffin, H., Blakely, E.L., Duff, J., He, L., Smertenko, T., Alston, C.L., Neeve, V.C., Best, A., et al., 2014. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 312, 68-77.

Thompson, K., Collier, J.J., Glasgow, R.I.C., Robertson, F.M., Pyle, A., Blakely, E.L., Alston, C.L., Olahova, M., McFarland, R., Taylor, R.W., 2020. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J. Inherit. Metab. Dis. 4, 36-50.

Valente, L., Shigi, N., Suzuki, T., Zeviani, M., 2009. The R336Q mutation in human mitochondrial EFTu prevents the formation of an active mt-EFTu.GTP.aa-tRNA ternary complex. Biochim. Biophys. Acta 1792, 791-795.

Valente, L., Tiranti, V., Marsano, R.M., Malfatti, E., Fernandez-Vizarra, E., Donnini, C., Mereghetti, P., De Gioia, L., Burlina, A., Castellan, C., et al., 2007. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am. J. Hum. Genet. 80, 44-58.

Wang, F., Zhang, D., Zhang, D., Li, P., Gao, Y., 2021a. Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease. Front. Cell Dev. Biol. 9, 675465.

Wang, X., Shen, X., Yan, Y., Li, H., 2021b. Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications. Biosci. Rep. 41, 4402.

Weraarpachai, W., Antonicka, H., Sasarman, F., Seeger, J., Schrank, B., Kolesar, J.E., Lochmuller, H., Chevrette, M., Kaufman, B.A., Horvath, R., et al., 2009. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat. Genet. 41, 833-837.

Zhang, X., Xiang, F., Li, D., Yang, F., Yu, S., Wang, X., 2024. Adult-onset combined oxidative phosphorylation deficiency type 14 manifests as epileptic status: a new phenotype and literature review. BMC. Neurol. 24, 15.

Zhu, C.L., Yao, R.Q., Li, L.X., Li, P., Xie, J., Wang, J.F., Deng, X.M., 2021. Mechanism of Mitophagy and Its Role in Sepsis Induced Organ Dysfunction: A Review. Front. Cell Dev. Biol. 9, 664896.

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