Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy

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 and Michael E. Pacold ()
Additional contact information
Guangbin Shi: NYU Grossman School of Medicine
Claire Miller: NYU Grossman School of Medicine
Sota Kuno: NYU Grossman School of Medicine
Alejandro G. Rey Hipolito: Texas Children’s Hospital
Salsabiel El Nagar: Memorial Sloan Kettering Cancer Center
Giulietta M. Riboldi: NYU Grossman School of Medicine
Megan Korn: NYU Langone Health
Wyatt C. Tran: NYU Langone Health
Zixuan Wang: NYU Grossman School of Medicine
Lia Ficaro: NYU Grossman School of Medicine
Tao Lin: Texas Children’s Hospital
Quentin Spillier: NYU Grossman School of Medicine
Begoña Gamallo-Lana: NYU Grossman School of Medicine
Drew R. Jones: NYU Grossman School of Medicine
Matija Snuderl: NYU Grossman School of Medicine
Soomin C. Song: NYU Langone Health
Adam C. Mar: NYU Grossman School of Medicine
Alexandra L. Joyner: Memorial Sloan Kettering Cancer Center
Roy V. Sillitoe: Texas Children’s Hospital
Robert S. Banh: NYU Langone Health
Michael E. Pacold: NYU Grossman School of Medicine

Nature, 2025, vol. 645, issue 8080, 466-474

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09246-x

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