Coenzyme Q Headgroup Intermediates Can Ameliorate a Mitochondrial Encephalopathy

Authors

Guangbin Shi
Claire Miller
Sota Kuno
Alejandro G Rey Hipolito
Salsabiel El Nagar
Giulietta M Riboldi
Megan Korn
Wyatt C Tran
Zixuan Wang
Lia Ficaro
Tao Lin
Quentin Spillier
Begoña Gamallo-Lana
Drew R Jones
Matija Snuderl
Soomin C Song
Adam C Mar
Alexandra L Joyner
Roy V Sillitoe
Robert S Banh
Michael E Pacold

Language

English

Publication Date

9-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09246-x

PMID

40634618

PMCID

PMC12422950

PubMedCentral® Posted Date

7-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ10 headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl−/− mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ9 and CoQ10 in the brains of Hpdl−/− mice. Oral treatment of Hpdl−/− pups with 4-HMA or 4-HB enabled 90–100% of Hpdl−/− mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ10 headgroup intermediates can restore CoQ10 synthesis in vivo.

Keywords

Animals, Ubiquinone, Mice, Mitochondrial Encephalomyopathies, Male, Disease Models, Animal, Brain, Female, Humans, Ataxia, Parabens, Muscle Weakness, Mitochondrial Diseases

Published Open-Access

yes

Recommended Citation

Shi, Guangbin; Miller, Claire; Kuno, Sota; et al., "Coenzyme Q Headgroup Intermediates Can Ameliorate a Mitochondrial Encephalopathy" (2025). Duncan NRI Faculty and Staff Publications. 176.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/176