Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy Journal Article


Authors: Shi, G.; Miller, C.; Kuno, S.; Rey Hipolito, A. G.; El Nagar, S.; Riboldi, G. M.; Korn, M.; Tran, W. C.; Wang, Z.; Ficaro, L.; Lin, T.; Spillier, Q.; Gamallo-Lana, B.; Jones, D. R.; Snuderl, M.; Song, S. C.; Mar, A. C.; Joyner, A. L.; Sillitoe, R. V.; Banh, R. S.; Pacold, M. E.
Article Title: Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy
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. © The Author(s) 2025.
Journal Title: Nature
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Publication status: Online ahead of print
Date Published: 2025-07-09
Online Publication Date: 2025-07-09
Language: English
DOI: 10.1038/s41586-025-09246-x
PROVIDER: scopus
PUBMED: 40634618
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus
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  1. Alexandra L Joyner
    99 Joyner