β-RA Reduces DMQ/CoQ Ratio and Rescues the Encephalopathic Phenotype in Mice

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2018 Nov 29

PMID 30482867

Citations 24

Authors

Agustin Hidalgo-Gutierrez

Eliana Barriocanal-Casado

Mohammed Bakkali

M Elena Diaz-Casado

Laura Sanchez-Maldonado

Miguel Romero

Ramy K Sayed

Cornelia Prehn

Germaine Escames

Juan Duarte

Dario Acuna-Castroviejo

Luis C Lopez

Affiliations

Soon will be listed here.

Abstract

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β-resorcylic acid (β-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. β-RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone-9 (DMQ) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down-regulation of astrocytes-related neuroinflammatory genes. Because the therapeutic outcomes of β-RA administration were superior to those after CoQ supplementation, its use in the clinic should be considered in CoQ deficiencies.

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References

Garcia-Corzo L, Luna-Sanchez M, Doerrier C, Ortiz F, Escames G, Acuna-Castroviejo D . Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency. Biochim Biophys Acta. 2014; 1842(7):893-901. DOI: 10.1016/j.bbadis.2014.02.008. View

Gigante M, Diella S, Santangelo L, Trevisson E, Acosta M, Amatruda M . Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants. Clin Genet. 2017; 92(2):224-226. DOI: 10.1111/cge.12960. View

Wang Y, Smith C, Parboosingh J, Khan A, Innes M, Hekimi S . Pathogenicity of two COQ7 mutations and responses to 2,4-dihydroxybenzoate bypass treatment. J Cell Mol Med. 2017; 21(10):2329-2343. PMC: 5618687. DOI: 10.1111/jcmm.13154. View

Pierrel F . Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency. Front Physiol. 2017; 8:436. PMC: 5479927. DOI: 10.3389/fphys.2017.00436. View

Herebian D, Seibt A, Smits S, Rodenburg R, Mayatepek E, Distelmaier F . 4-Hydroxybenzoic acid restores CoQ biosynthesis in human COQ2 deficiency. Ann Clin Transl Neurol. 2018; 4(12):902-908. PMC: 5740244. DOI: 10.1002/acn3.486. View

Duncan A, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves I, Lopez L . A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet. 2009; 84(5):558-66. PMC: 2681001. DOI: 10.1016/j.ajhg.2009.03.018. View

Ignatenko O, Chilov D, Paetau I, de Miguel E, Jackson C, Capin G . Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy. Nat Commun. 2018; 9(1):70. PMC: 5754366. DOI: 10.1038/s41467-017-01859-9. View

Linden D, Furne J, Stoltz G, Abdel-Rehim M, Levitt M, Szurszewski J . Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS. Br J Pharmacol. 2011; 165(7):2178-90. PMC: 3413855. DOI: 10.1111/j.1476-5381.2011.01681.x. View

Kuhl I, Miranda M, Atanassov I, Kuznetsova I, Hinze Y, Mourier A . Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals. Elife. 2017; 6. PMC: 5703644. DOI: 10.7554/eLife.30952. View

10.

Reichmann F, Hassan A, Farzi A, Jain P, Schuligoi R, Holzer P . Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice. Sci Rep. 2015; 5:9970. PMC: 4464346. DOI: 10.1038/srep09970. View

11.

DiMauro S, Schon E, Carelli V, Hirano M . The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013; 9(8):429-44. PMC: 3959773. DOI: 10.1038/nrneurol.2013.126. View

12.

Pagliarini D, Calvo S, Chang B, Sheth S, Vafai S, Ong S . A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008; 134(1):112-23. PMC: 2778844. DOI: 10.1016/j.cell.2008.06.016. View

13.

Butterworth R . Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. J Clin Exp Hepatol. 2015; 5(Suppl 1):S96-S103. PMC: 4442857. DOI: 10.1016/j.jceh.2014.02.004. View

14.

Tanji K, Bonilla E . Light microscopic methods to visualize mitochondria on tissue sections. Methods. 2008; 46(4):274-80. DOI: 10.1016/j.ymeth.2008.09.027. View

15.

Johnson S, Yanos M, Kayser E, Quintana A, Sangesland M, Castanza A . mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013; 342(6165):1524-8. PMC: 4055856. DOI: 10.1126/science.1244360. View

16.

Smith A, Ito Y, Ahmed A, Schwartzentruber J, Beaulieu C, Aberg E . A family segregating lethal neonatal coenzyme Q deficiency caused by mutations in COQ9. J Inherit Metab Dis. 2018; 41(4):719-729. DOI: 10.1007/s10545-017-0122-7. View

17.

Wang W, Karamanlidis G, Tian R . Novel targets for mitochondrial medicine. Sci Transl Med. 2016; 8(326):326rv3. PMC: 4819426. DOI: 10.1126/scitranslmed.aac7410. View

18.

Freyer C, Stranneheim H, Naess K, Mourier A, Felser A, Maffezzini C . Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid. J Med Genet. 2015; 52(11):779-83. PMC: 4680133. DOI: 10.1136/jmedgenet-2015-102986. View

19.

Brzywczy J, Sienko M, Kucharska A, Paszewski A . Sulphur amino acid synthesis in Schizosaccharomyces pombe represents a specific variant of sulphur metabolism in fungi. Yeast. 2002; 19(1):29-35. DOI: 10.1002/yea.798. View

20.

Bhagavan H, Chopra R . Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion. 2007; 7 Suppl:S78-88. DOI: 10.1016/j.mito.2007.03.003. View