{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:09:41Z","timestamp":1789567781767,"version":"build-2803163510"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["MICIU\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MICIU\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006393","name":"Universidad de Granada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006393","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023561","name":"Ministerio de Universidades","doi-asserted-by":"publisher","award":["UCEPP2017-05"],"award-info":[{"award-number":["UCEPP2017-05"]}],"id":[{"id":"10.13039\/501100023561","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023561","name":"Ministerio de Universidades","doi-asserted-by":"publisher","award":["P31.24.02"],"award-info":[{"award-number":["P31.24.02"]}],"id":[{"id":"10.13039\/501100023561","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DI 1731\/2-3"],"award-info":[{"award-number":["DI 1731\/2-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["417919780"],"award-info":[{"award-number":["417919780"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u2018Elterninitiative Kinderkrebsklinik e.V.\u2019","award":["#701900167"],"award-info":[{"award-number":["#701900167"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Primary coenzyme Q (CoQ) deficiency is a mitochondrial disorder with variable clinical presentation and limited response to standard CoQ10 supplementation. Recent studies suggest that 4-hydroxybenzoic acid (4-HBA), a biosynthetic precursor of CoQ, may serve as a substrate enhancement treatment in cases caused by pathogenic variants in COQ2, a gene encoding a key enzyme in CoQ biosynthesis. However, it remains unclear whether 4-HBA is required throughout life to maintain health, whether it offers advantages over CoQ10 treatment, and whether these findings are translatable to humans.<\/jats:p>\n                  <jats:p>Here, we demonstrate that lifelong 4-HBA supplementation in a murine model carrying the pathogenic Coq2A252V variant is well tolerated and prevents the onset of mitochondrial encephalopathy. In contrast, withdrawal of 4-HBA leads to progressive neurological decline. Notably, while conventional CoQ10 supplementation transiently ameliorated cardiac dysfunction, it failed to prevent fatal neurological deterioration.<\/jats:p>\n                  <jats:p>Guided by these preclinical findings, we initiated a first-in-human individual therapeutic trial with 4-HBA in a 3-year-old boy with genetically confirmed primary CoQ10 deficiency due to compound heterozygous pathogenic COQ2 variants. The patient presented with a Leigh-like syndrome characterized by bilateral brain lesions, developmental delay, muscular hypotonia, failure to thrive, lactic acidosis and steroid-resistant nephrotic syndrome. Despite high-dose oral CoQ10 supplementation, clinical response had been minimal. Prior to clinical application, patient-derived fibroblasts were treated in vitro with 4-HBA, resulting in a marked increase in endogenous CoQ10 levels.<\/jats:p>\n                  <jats:p>Following the initiation of oral 4-HBA treatment, the patient experienced rapid and sustained remission of proteinuria, improved renal hyperfiltration and a gradual increase in serum CoQ10 concentrations. No adverse effects were observed during a 6-month follow-up. Clinically, the patient showed notable improvements in motor skills, language acquisition, cognitive alertness and overall development, accompanied by significant gains in growth and nutritional status. Clinical recovery was also reflected by improved scores on the Newcastle Paediatric Mitochondrial Disease Scale. These findings support 4-HBA as a promising targeted metabolic treatment for COQ2-related CoQ deficiency and highlight the need for further clinical investigation.<\/jats:p>","DOI":"10.1093\/brain\/awaf334","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T11:52:01Z","timestamp":1757505121000},"page":"1784-1797","source":"Crossref","is-referenced-by-count":5,"title":["Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-7848","authenticated-orcid":false,"given":"Felix","family":"Distelmaier","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"MetabERN: European Reference Network for Rare Hereditary Metabolic Disorders, Health Care Provider D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"West German Center for Child and Adolescent Health, Partner Site D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Corral-Sarasa","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Jim\u00e9nez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Elena","family":"D\u00edaz-Casado","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Rohmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Jena University Hospital , Jena 07747 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Seibt","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"West German Center for Child and Adolescent Health, Partner Site D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diran","family":"Herebian","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"West German Center for Child and Adolescent Health, Partner Site D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander H J","family":"Smits","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Center for Structural Studies, Heinrich-Heine-University , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"West German Center for Child and Adolescent Health, Partner Site D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ertan","family":"Mayatepek","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, Heinrich-Heine-University D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"MetabERN: European Reference Network for Rare Hereditary Metabolic Disorders, Health Care Provider D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]},{"name":"West German Center for Child and Adolescent Health, Partner Site D\u00fcsseldorf , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Breitkreutz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0798-6346","authenticated-orcid":false,"given":"Ralf A","family":"Husain","sequence":"additional","affiliation":[{"name":"Center for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital , Jena 07747 ,","place":["Germany"]},{"name":"Center for Rare Diseases, Jena University Hospital , Jena 07747 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"L\u00f3pez-Herrador","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Gonz\u00e1lez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3355-0298","authenticated-orcid":false,"given":"Luis C","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de Granada , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.Granada , Granada 18016 ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fragilidad y Envejecimiento Saludable (CIBERFES) , Granada 18016 ,","place":["Spain"]},{"name":"Instituto de Biotecnolog\u00eda, Centro de Investigaci\u00f3n Biom\u00e9dica, Universidad de Granada , Granada 18016 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2026050508310860500_awaf334-B1","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3390\/antiox10040520","article-title":"Metabolic targets of coenzyme Q10 in mitochondria","volume":"10","author":"Hidalgo-Guti\u00e9rrez","year":"2021","journal-title":"Antioxidants 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