@misc{10481/56472,
year = {2019},
month = {3},
url = {http://hdl.handle.net/10481/56472},
abstract = {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.},
organization = {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).},
publisher = {Elsevier B. V.},
keywords = {CoQ deficiency},
keywords = {Mitochondrial encephalopathy},
keywords = {Mitochondrial diseases},
keywords = {mTORC1},
keywords = {Mouse model},
title = {Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease},
doi = {https://doi.org/10.1016/j.ebiom.2019.03.025},
author = {Barriocanal Casado, Eliana and Hidalgo Gutiérrez, Agustín and Raimundo, Nuno and González García, Pilar and Acuña Castroviejo, Darío and Escames Rosa, Germaine and López García, Luis Carlos},
}