Cellular Recharge: 8-Year-Old Boy Walks Again After Unprecedented Therapy Reactivates Cellular Energy

Researchers have discovered a new way to stimulate the body's natural production of CoQ10 using small molecules called 4-HMA and 4-HB, which are better absorbed than traditional supplements. This approach has shown promising results in mice and in a boy with paralysis caused by a genetic deficiency, helping to restore neurological function. The discovery paves the way for more effective therapies for mitochondrial and neurodegenerative diseases.

Coenzyme Q10 (CoQ10) is a natural substance essential for cellular energy production and also acts as a potent antioxidant. It is especially important for the proper functioning of the heart, brain, and muscles.

Over time, or as a result of chronic diseases such as diabetes, Alzheimer's, heart disease, and even the use of certain medications like statins, CoQ10 levels in the body can significantly decrease. This decline is associated with muscle symptoms, fatigue, and neurological changes.

Despite this, trying to reverse this deficiency with CoQ10 supplements is not always effective, as the substance has low absorption, especially in the brain, and therefore cannot adequately restore levels in the most affected tissues.

To overcome this limitation, researchers have been searching for alternatives that help the body produce its own CoQ10 more efficiently. A major breakthrough came with the discovery of a key step in the natural production of CoQ10 in mammals.

Scientists at NYU Langone identified that an enzyme called HPDL is responsible for converting a small molecule called 4-HMA into another called 4-HB. The latter, 4-HB, is the direct precursor of CoQ10, meaning it is the raw material that cells use to manufacture this vital coenzyme.

Interestingly, both 4-HMA and 4-HB are small molecules that the body easily absorbs, unlike CoQ10 itself.

This discovery paved the way for innovative treatments. In tests with mice genetically modified to simulate a rare and serious mitochondrial disease, researchers were able to extend the animals' lives and improve their neurological status by administering either 4-HMA or 4-HB.

These molecules were successfully incorporated into the production of CoQ10 in the brains of animals.

Inspired by these results, scientists tested the approach on a boy with a rare genetic condition linked to mutations in the HPDL gene, which had caused progressive paralysis. With emergency authorization, he began receiving 4-HB dissolved in water daily.

Within a few weeks, he already showed improvements in balance and physical endurance, and two months later, he was able to walk long distances with his family, something previously unthinkable.

Although the treatment did not completely reverse the symptoms, the case marked the first time that neurological symptoms associated with primary CoQ10 deficiency were stabilized or improved by precursors (such as 4-HB), rather than CoQ10 itself.

This figure shows the effects of 4-HMA treatment on mice genetically deficient in HPDL, an enzyme involved in the production of coenzyme Q10 (CoQ10), essential for cellular energy generation. Part (a) of the figure shows different gait parameters of the mice (such as step length, paw support time, ground contact intensity, limb symmetry, etc.), comparing normal mice (Hpdl+/+), those carrying one altered copy of the gene (Hpdl+/-), and mice with two altered copies treated with 4-HMA (Hpdl-/- + 4-HMA). The results show that, with treatment, the deficient mice can walk with parameters similar to those of normal mice, indicating that the supplement helped restore motor function. Part (b) shows brain magnetic resonance imaging (MRI) scans of a human patient with mutations in the HPDL gene, before and after 30 days of treatment with 4-HB (a CoQ10 precursor). The images show improvements in brain structure, suggesting that the treatment may also be beneficial in humans with this rare condition. These results indicate a promising advance in the use of metabolic precursors as an alternative to direct CoQ10 supplementation, especially in mitochondrial diseases.

According to the scientists, the use of precursors may represent a more effective way to restore coenzyme levels, especially in the brain, where direct supplementation fails. This is because these small molecules can more easily cross cellular barriers and are used by cells to naturally generate CoQ10.

The researchers also noted that there is a "critical period" in brain development when treatment with 4-HB or 4-HMA can make a difference. After this window closes, the damage caused by CoQ10 deficiency may be more difficult to reverse.

This reinforces the importance of early diagnosis, especially for rare genetic diseases, but may also have implications for more common aging-related diseases. Future studies will focus on identifying the best timing and optimal doses for this therapy.

This line of research represents a paradigm shift: instead of trying to directly correct the deficiency with high doses of CoQ10, which the body often cannot utilize, the new approach focuses on delivering the building blocks that cells can actually use to manufacture their own reserves.

Thus, this strategy with precursors such as 4-HB may prove to be a promising and accessible alternative not only for rare diseases, but also for neurodegenerative disorders and other conditions in which CoQ10 is depleted.

READ MORE:

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 

Nature, 9 July 2025

https://doi.org/10.1038/s41586-025-09246-x

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.