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Article

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

by
Paula Cilleros-Holgado
1,
David Gómez-Fernández
1,
Rocío Piñero-Pérez
1,
José Manuel Romero Domínguez
1,
Marta Talaverón-Rey
1,
Diana Reche-López
1,
Juan Miguel Suárez-Rivero
1,
Mónica Álvarez-Córdoba
1,
Ana Romero-González
1,
Alejandra López-Cabrera
1,
Marta Castro De Oliveira
2,3,
Andrés Rodríguez-Sacristan
4,5 and
José Antonio Sánchez-Alcázar
1,*
1
Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain
2
Neuropediatria, Neurolinkia, C. Jardín de la Isla, 8, Local 4 y 5, 41014 Sevilla, Spain
3
FEA Pediatría, Centro Universitario Hospitalar de Faro, R. Leão Penedo, 8000-386 Faro, Portugal
4
Neuropediatría, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain
5
Departamento de Farmacología, Radiología y Pediatría, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(5), 598; https://doi.org/10.3390/biom14050598
Submission received: 15 April 2024 / Revised: 13 May 2024 / Accepted: 16 May 2024 / Published: 18 May 2024
(This article belongs to the Special Issue Mitochondrial Quality Control in Aging and Neurodegeneration)
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Abstract

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.
Keywords: mitochondrial diseases; GFM1; EF-G1; fibroblasts; direct reprogramming; induced neurons; mitochondria; mtUPR; treatment mitochondrial diseases; GFM1; EF-G1; fibroblasts; direct reprogramming; induced neurons; mitochondria; mtUPR; treatment

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MDPI and ACS Style

Cilleros-Holgado, P.; Gómez-Fernández, D.; Piñero-Pérez, R.; Romero Domínguez, J.M.; Talaverón-Rey, M.; Reche-López, D.; Suárez-Rivero, J.M.; Álvarez-Córdoba, M.; Romero-González, A.; López-Cabrera, A.; et al. Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation. Biomolecules 2024, 14, 598. https://doi.org/10.3390/biom14050598

AMA Style

Cilleros-Holgado P, Gómez-Fernández D, Piñero-Pérez R, Romero Domínguez JM, Talaverón-Rey M, Reche-López D, Suárez-Rivero JM, Álvarez-Córdoba M, Romero-González A, López-Cabrera A, et al. Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation. Biomolecules. 2024; 14(5):598. https://doi.org/10.3390/biom14050598

Chicago/Turabian Style

Cilleros-Holgado, Paula, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero Domínguez, Marta Talaverón-Rey, Diana Reche-López, Juan Miguel Suárez-Rivero, Mónica Álvarez-Córdoba, Ana Romero-González, Alejandra López-Cabrera, and et al. 2024. "Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation" Biomolecules 14, no. 5: 598. https://doi.org/10.3390/biom14050598

APA Style

Cilleros-Holgado, P., Gómez-Fernández, D., Piñero-Pérez, R., Romero Domínguez, J. M., Talaverón-Rey, M., Reche-López, D., Suárez-Rivero, J. M., Álvarez-Córdoba, M., Romero-González, A., López-Cabrera, A., Oliveira, M. C. D., Rodríguez-Sacristan, A., & Sánchez-Alcázar, J. A. (2024). Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation. Biomolecules, 14(5), 598. https://doi.org/10.3390/biom14050598

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