PANK2-mediated de novo CoA synthesis is required for metabolic switching to fatty acid oxidation

Nordlie, S. M.; Schafer, R.; Rauckhorst, A.; Santos-Exposito, A. M.; Prieto-Rodriguez, A.; Wilson, B. A.; Evans, I. A.; Hadziamehtovic, U.; Nowlen, F.; Santos-Ocana, C.; Taylor, E. B.; Kruer, M. C.; Padilla Lopez, S.

doi:10.1101/2025.10.07.680981

bioRxiv · 10.1101/2025.10.07.680981

PANK2-mediated de novo CoA synthesis is required for metabolic switching to fatty acid oxidation

Nordlie, S. M.·Schafer, R.·Rauckhorst, A.·Santos-Exposito, A. M.·Prieto-Rodriguez, A.·Wilson, B. A.·Evans, I. A.·Hadziamehtovic, U.·Nowlen, F.·Santos-Ocana, C.·Taylor, E. B.·Kruer, M. C.·Padilla Lopez, S.

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Abstract

Humans have 3 different PANK enzymes (PANK1-3) that catalyze the first step in the de novo synthesis of Coenzyme A (CoA). All PANKs are feedback inhibited by acyl-CoAs but only PANK2 can overcome this inhibition by binding palmitoyl-carnitine. Previous studies, conducted under glucose-replete conditions, have failed to detect a PANK2-mediated contribution to CoA synthesis. We found that exposure to BSA-conjugated palmitate (PAL-BSA) led to activation of fatty acid oxidation (FAO) and the accumulation of both palmitoyl-carnitine and palmitoyl-CoA in HEK293T cells, suggesting that PANK2 is active under these conditions. Isotope tracing experiments with 13C15N-pantothenate showed that PANK2 uniquely sustains de novo CoA synthesis and high production of Acetyl-CoA in the presence of long-chain fatty acids, indicating that FAO is limited by CoA availability in these conditions. Consistent with this mechanism, fibroblasts from PKAN patients exhibited impaired oxidation of palmitoyl-carnitine, confirming the functional relevance of our results in a disease context.

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Nordlie, S. M., Schafer, R., Rauckhorst, A., Santos-Exposito, A. M., Prieto-Rodriguez, A., Wilson, B. A., Evans, I. A., Hadziamehtovic, U., Nowlen, F., Santos-Ocana, C., Taylor, E. B., Kruer, M. C., Padilla Lopez, S.. 2025-10-07. PANK2-mediated de novo CoA synthesis is required for metabolic switching to fatty acid oxidation. https://doi.org/10.1101/2025.10.07.680981

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