Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial diseaseResearch in context
Eliana Barriocanal-Casado,
Agustín Hidalgo-Gutiérrez,
Nuno Raimundo,
Pilar González-García,
Darío Acuña-Castroviejo,
Germaine Escames,
Luis C. López
Affiliations
Eliana Barriocanal-Casado
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain
Agustín Hidalgo-Gutiérrez
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain
Darío Acuña-Castroviejo
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Spain
Germaine Escames
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Spain
Luis C. López
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, 18016 Granada, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Spain; Corresponding author at: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, lab 131. Av. del Conocimiento s/n, 18016, Granada, Spain.
Background: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. Methods: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. Findings: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. Interpretation: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. Fund: Supported by the grants from “Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares – Federación FEDER” (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327). Keywords: CoQ deficiency, Mitochondrial encephalopathy, Mitochondrial diseases, mTORC1, Mouse model