Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ebiom.2019.03.025.Background: The vastmajority ofmitochondrial disorders have limited the clinicalmanagement to palliative care. Rapamycin has emerged as a potential therapeutic drug formitochondrial diseases since it has shown therapeutic benefits in a fewmousemodels ofmitochondrial disorders. However, the underlying therapeutic mechanism is unclear, theminimal effective dose needs to be defined and whether this therapy can be generally used is unknown. Methods: Wehave evaluatedwhether lowand high doses of rapamycin administration may result in therapeutic effects in a mousemodel (Coq9R239X) ofmitochondrial 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 ofmicrogliosis-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.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)