Preclinical study for the treatment of mitochondrial encephalopathy associated with Coenzyme Q deficiency

Abstract

Conclusions: 1. β‐RA is a powerful therapeutic agent for the mitochondrial encephalopathy due to Coq9 mutation, with better results than those obtained by the conventional oral CoQ supplementation. 2. The therapeutic effect of β‐RA is mainly due to a decrease of the DMQ/CoQ ratio. Therefore, β‐RA should be preferentially considered for the treatment of human CoQ10 deficiency with accumulation of DMQ10, as it has been reported in patients with mutations in COQ9, COQ7, or COQ4, but also in cells under siRNA knockdown of COQ3, COQ5 and COQ6. 3. A high dose of b-RA is toxic for the kidneys, liver and brain of wildtype animals, leading to premature death. However, a third of that dose is safe for wild-type animals, while preserving the therapeutics effects in Coq9R239X mice. These dose-dependent effects of b-RA depend on CoQ metabolism. 4. An accurate and early genetic diagnosis is required to initiate the treatment with b-RA in patients with CoQ deficiency and, the monitorization of renal and hepatic blood markers is highly recommended in the patients that initiate the treatment. 5. The sulfide metabolism influences the levels of glutathione, independently of the sulfur amino acids availability. 6. The modulation of sulfur amino acids availability does not produce therapeutic effects on Coq9R239X mice.