Bypass Treatments for Primary Coenzyme Q10 Deficiency: An Update

Mantle, D, Cufflin, N and Hargreaves, IP ORCID: 0000-0002-2760-5603 (2026) Bypass Treatments for Primary Coenzyme Q10 Deficiency: An Update. International Journal of Molecular Sciences, 27 (8). ISSN 1661-6596

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Abstract

Primary coenzyme Q10 (CoQ10) deficiency results from mutations in genes involved in the CoQ10 biosynthetic pathway. In humans, at least 10 genes (PDSS1, PDSS2 to COQ10) are required for the biosynthesis of functional CoQ10, a mutation in any one of which can result in a deficit in CoQ10 status and present as primary CoQ10 deficiency. Furthermore, the genes NDUFA9 and HPDL, whilst not part of the PDSS1, PDSS2 to COQ10 gene sequence, have also been shown to have a crucial role in CoQ10 biosynthesis. A major problem in treating primary CoQ10 deficiencies is the poor bioavailability of supplemental CoQ10, both in terms of lack of absorption from the digestive tract and inability to cross the human blood–brain barrier. Bypass strategies aim to circumvent this problem by using more bioavailable precursor analogues that can enter the cell and be incorporated into the CoQ10 synthesis pathway downstream of the affected enzyme, examples being 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid or vanillic acid, which, in contrast to CoQ10, are small, water-soluble molecules. In this article, we have, therefore, reviewed potential bypass mechanisms for primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10, together with NDUFA9 and HPDL, using such precursors. Most of the published data relating to the bypass therapy of primary CoQ10 deficiency is derived from cell lines or animal models, and few human studies have so far been undertaken. In addition, further research is required to investigate the potential mechanisms by which bypass compounds such as 4-HB may access the human blood–brain barrier (BBB), for example, using in vitro co-culture BBB model systems incorporating CoQ10-deficient neurons. Overall, the objective of this article is, therefore, to systematically review the available data for each of the primary CoQ10 deficiencies, PDSS1, PDSS2 to COQ10 together with NDUFA9 and HPDL, in particular to identify the clinical potential of such studies.

Item Type:	Article
Uncontrolled Keywords:	3107 Microbiology; 3101 Biochemistry and Cell Biology; 31 Biological Sciences; Dietary Supplements; Nutrition; Complementary and Integrative Health; Neurosciences; 2.1 Biological and endogenous factors; 0399 Other Chemical Sciences; 0604 Genetics; 0699 Other Biological Sciences; Chemical Physics; 3101 Biochemistry and cell biology; 3107 Microbiology; 3404 Medicinal and biomolecular chemistry
Subjects:	R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	MDPI
Date of acceptance:	12 April 2026
Date of first compliant Open Access:	28 April 2026
Date Deposited:	28 Apr 2026 13:47
Last Modified:	28 Apr 2026 13:47
DOI or ID number:	10.3390/ijms27083526
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28486

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