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Toxic vs Therapeutic: The Dose-Dependent Effects of β-Resorcylic Acid Depend on Mitochondrial Metabolism
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  • Agustín Hidalgo-Gutiérrez,
  • Elena Díaz-Casado,
  • Eliana Barriocanal-Casado,
  • Pilar González-García,
  • Mohammed Bakkali,
  • Riccardo Chiozzi,
  • Marcos Martínez-Ruíz,
  • Dario Ancuna-Castroviejo,
  • Luis López
Agustín Hidalgo-Gutiérrez
University of Granada
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Elena Díaz-Casado
University of Granada
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Eliana Barriocanal-Casado
University of Granada
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Pilar González-García
University of Granada
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Mohammed Bakkali
University of Granada
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Riccardo Chiozzi
Utrecht University
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Marcos Martínez-Ruíz
University of Granada
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Dario Ancuna-Castroviejo
University of Granada
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Luis López
Universidad de Granada
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Abstract

Background and Purpose: Recent preclinical studies have shown that β-resorcylic acid (β-RA) is an hydroxybenzoic acid derivative (HBA) potentially useful for the treatment of Coenzyme Q (CoQ) deficiencies, but the therapeutic mechanisms seem to be diverged in the different mouse models tested. Also, the use of high doses of HBAs in the clinic should be rigorously evaluated since some HBAs have reported toxicity. Experimental approach: We used biased and unbiased approaches to evaluate the effect of a high dose of β-RA, previously used for the preclinical treatment of CoQ deficiency, in wild-type animals, and to test the therapeutic potential of a lower dose of β-RA in both wild-type and an unique mouse model (Coq9R239X) of mitochondrial encephalopathy caused by CoQ deficiency. Key results: The high dose of β-RA induces hepatic, renal and cerebral toxicity in wild-type animals. That toxicity is caused by mitochondrial complex I disruption, upregulation of mitoribosome components, downregulation of fatty acids oxidation and induction of apoptosis and ER Stress, and depends of the metabolic use of β-RA in the CoQ biosynthetic pathway. The low dose of β-RA dramatically decreases the toxicity in wild-type animals, while preserving its therapeutic potential in Coq9R239X mice. Importantly, our approach of combining β-RA with 4-hydroxybenzoic acid further demonstrates that the therapeutic mechanism of β-RA depends in its capability to modulate CoQ metabolism. Conclusions & Implications: Our results highlight novel toxic and therapeutic mechanisms of HBAs and provide a safe translational perspective for the use of β-RA in the treatment of CoQ deficiencies.