Michael Pacold, MD, PhD, is an Assistant Professor in Radiation Oncology at NYU Grossman School of Medicine. His lab develops chemical biology and metabolomics tools to study how tumors grow in nutrient- and oxygen-limited environments. Dr. Pacold also maintains a clinical practice in CNS Radiation Oncology.

At the heart of groundbreaking science is the ability to follow data wherever it leads, even when it takes research in an entirely new direction. Dr. Pacold’s work began with a focus on cancer metabolism, but an unexpected discovery has opened the door to a potential treatment for a devastating childhood neurological disease. With early support from the Pershing Square Sohn Cancer Research Prize and more recently the MIND Prize, Dr. Pacold is translating fundamental discoveries into real-world impact and is the second grantee to have won both awards.

In 2022, Dr. Pacold was awarded the Pershing Square Sohn Cancer Prize to investigate how cancer cells produce and utilize Coenzyme Q10 (CoQ10) to survive in low-oxygen conditions. Building on work published in Nature in 2021, his lab discovered that the enzyme HPDL is required to synthesize 4-HMA, a previously unknown intermediate in the CoQ10 biosynthetic pathway. This metabolite is ultimately converted into 4-HB, a direct precursor of CoQ10.

This discovery proved highly relevant to patients with HPDL gene variants, who suffer from a severe neurodegenerative disorder characterized by seizures, motor decline, and early death. Mice lacking HPDL exhibit similar symptoms. The Pacold lab found that treating these mice with CoQ10 precursor molecules dramatically improved symptoms, restored CoQ10 levels in the brain, and rescued survival.

Originally focused on cancer metabolism, Dr. Pacold pivoted his research following this discovery, with full encouragement from PSF. In the second year of his 2022 Prize, his team initiated treatment at NYU Langone for an 8-year-old boy with HPDL deficiency. The child, previously dependent on a wheelchair due to progressive paralysis, regained the ability to walk and even run following daily oral treatment with 4-HB. He has now celebrated two birthdays since starting treatment. Unlike CoQ10, which has limited brain penetration, these small-molecule precursors can cross the blood-brain barrier, restoring CoQ10 levels directly within the central nervous system.

This case was published in Nature in July 2025, marking the first report of clinical recovery from this fatal disease using metabolic precursor therapy.

To build upon this promising work, The Pershing Square Foundation awarded Dr. Pacold The MIND Prize in 2025. With $750,000 in additional support over three years, his lab will investigate whether promoting mitochondrial function through delivery of CoQ10 precursors can alter the trajectory of other neurodevelopmental and neurodegenerative diseases.

The brain relies on mitochondria to produce the energy required for cognition and survival. While mitochondrial dysfunction is common in neurodegeneration, it remains unclear whether it is a driver or a consequence of disease. In his MIND Prize project, Dr. Pacold will test whether improving the delivery of mitochondrial cofactors can restore function and slow or reverse disease in animal models, with the ultimate goal of translating these findings into therapies for patients.

“The Pershing Square Foundation's motto is, ‘Risk capital for philanthropy.’ And I think this fits exactly what you, as a young investigator, are trying to do. Young investigators are at a critical moment in their careers where they're working on their riskiest ideas, many of which will fail, but some of which might just change the world.”

From investigating cancer metabolism to uncovering a treatment for a rare, fatal childhood disease, Dr. Pacold embodies the spirit of scientific discovery and the impact of research funding that empowers scientists to pursue bold, transformative ideas. PSF is honored to support Dr. Pacold as he advances innovative research to improve the lives of patients.

• Shi G, Miller C, Kuno S, Rey Hipolito AG, El Nagar S, Riboldi GM, Korn M, Tran WC, Wang Z, Ficaro L, Lin T, Spillier Q, Gamallo-Lana B, Jones DR, Snuderl M, Song SC, Mar AC, Joyner AL, Sillitoe RV, Banh RS, Pacold ME. Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy. Nature. 2025 Jul 9, doi: 10.1038/s41586-025-09246-x. Epub ahead of print. PMID: 40634618.

• Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, Wang R, Jones DR, Papagiannakopoulos T, Pacold ME, Mar AC, Littman DR, Nudler E. Unravelling cysteine-deficiency-associated rapid weight loss. Nature. 2025 Jul;643(8072):776-784. doi: 10.1038/s41586-025-08996-y. PMID: 40399674.

• Lin NP, Johnson KR, Li Y, Jones Dr, Pacold ME, Narendra DP. DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy. EMBO J. 2024 Nov;43(22):5548-5585. doi: 10.1038/s44318-024-00242-x. PMCID: PMC11574132.

• Trolle J, McBee RM, Kaufman A, Pinglay S, Berger H, German S, Liu L, Shen MJ, Guo X, Martin JA, Pacold ME, Jones DR, Boeke JD, Wang HH. Resurrecting essential amino acid biosynthesis in mammalian cells. Elife. 2022,11. doi: 10.7554/eLife.72847. PMCID: PMC9560156.

• Banh RS, Kim ES, Spillier Q, Biancur DE, Yamamoto K, Sohn ASW, Shi G, Jones DR, Kimmelman AC, Pacold ME. The Polar Oxy-metabolome Reveals the 4-Hydroxymandelate CoQ10 Synthesis Pathway. Nature, 2021, 597 (7876): 420-425. PMCID: PMC8538427.

• Wu L, Hollinshead KER, Hao Y, Au C, Kroehling L, Ng C, Lin WY, Li D, Silva HM, Shin J, Lafaille JJ, Possemato R, Pacold ME, Papagiannakopoulos T, Kimmelman AC, Satija R, Littman DR. Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy. Cell 2020; 182; 641-654. PMCID: PMC7556360 Chantranupong L, Saulnier JL, Wang W, Jones DR, Pacold ME, Sabatini BL. Rapid Purification and Metabolomic Profiling of Synaptic Vesicles from Mammalian Brain. Elife 2020, 9: e59699. PMCID: PMC7575323.

• Ngo B, Kim E, Osorio-Vasquez V, Doll S, Bustraan S, Liang RJ, Luengo A, Davidson SM, Ali A, Ferraro GB, Fischer GM, Eskandari R, Kang DS, Ni J, Plasger A, Rajasekhar VK, Kastenhuber ER, Bacha S, Siriam RK, Stein BD, Bakhoum SF, Snuderl M, Cotzia P, Healey JH, Mainolfi N, Suri V, Friedman A, Manfredi M, Sabatini DM, Jones DR, Yu M, Zhao JJ, Jain RK, Davies MA, Vander Heiden MG, Hernando E, Mann M, Cantley LC*, Pacold ME*. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer Discov. 2020, 10 (9): 1352-1373. PMCID: PMC7483776.

• Banh RS, Biancur DE, Yamamoto K, Sohn ASW, Walters B, Kuljanin M, Gikandi A, Wang H, Mancias JD, Schneider RJ, Pacold ME, Kimmelman AC. Neurons release serine to support mRNA translation in pancreatic cancer. Cell, 2020, Oct 28. DOI: 10.1016/j.cell.2020.10.016. PMCID: PMC8100789.

• Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJYM, Possemato R, Fiske BP, Cho SW, Freinkman E, Birsoy K, Abu-Remaileh M, Shaul YD, Liu CM, Zhou M, Koh MJ, Chung HY, Davidson SM, Luengo A, Wang AQ, Xu X, Yasgar A, Rai G, Westover KD, Vander Heiden MG, Shen M, Gray NS, Boxer MB, Sabatini DM: A phosphoglycerate dehydrogenase inhibitor reveals coordination between serine synthesis and one-carbon unit utilization. Nat. Chem. Biol. 2016, 12 (6): 452-458. PMCID: PMC4871733