2025年7月9日出版的《自然》杂志发表了美国科学家的一项最新研究成果。来自美国纽约大学的Michael E. Pacold小组的最新研究探明了辅酶Q头群中间体可以改善线粒体脑病。

为了测试补充4-HMA或4-HB是否能促进体内CoQ10头群的合成，研究小组给Hpdl^-/-老鼠服用4-HMA和4-HB，它模拟了一种极其罕见的，致命的人类线粒体脑病。4-HMA和4-HB在Hpdl^-/-小鼠脑内均被纳入CoQ₉和CoQ₁₀。用4-HMA或4-HB对Hpdl^-/-幼崽进行口服治疗，使90-100%的Hpdl^-/-小鼠能够活到成年。

此外，4-HB治疗稳定并改善了由双等位基因HPDL变异引起的进行性痉挛患者的神经系统症状。他们的研究表明，4-HMA和4-HB可以改变由HPDL变异体驱动的线粒体脑病的症状，并证明CoQ₁₀头群中间体可以在体内恢复CoQ₁₀的合成。

据了解，辅酶Q₁₀ （CoQ₁₀）是一种内源性合成的亲脂性抗氧化剂，脑内CoQ₁₀水平降低是原发性CoQ₁₀缺乏的脑病的基础，并与常见的神经退行性疾病和衰老过程相关。补充CoQ₁₀不会增加大脑或其他组织中的CoQ₁₀库。最近发现的哺乳动物CoQ₁₀头群合成途径，其中4-羟基苯基丙酮酸双加氧酶样蛋白（HPDL）使4-羟基酸酯（4-HMA）合成CoQ₁₀头群前体4-羟基苯甲酸酯（4-HB），为药理学上恢复CoQ₁₀合成和机制上治疗CoQ₁₀缺乏提供了机会。

附：英文原文

Title: Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy

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

Issue&Volume: 2025-07-09

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.

DOI: 10.1038/s41586-025-09246-x

Source: https://www.nature.com/articles/s41586-025-09246-x