Preprint / Version 1

Pyruvate dehydrogenase deficiency hijacks B12 to sustain energy production

This article is a preprint and has not been certified by peer review.

Authors

    Duo Duan,   Chunxia Qin,  
    Chunxia Qin
    Jie Chen,   Shiyu Liu,  
    Shiyu Liu
    Shihao Zhu,  
    Shihao Zhu
    Zicheng Liu,  
    Zicheng Liu
    Hai-Lin Dong,   Bingbing Wu,  
    Bingbing Wu
    Ting Zhang,   Zhi-Ying Wu,   Shengnan Wu,   Wei Lu,   Xinwen Huang,   Lianfeng Wu
    Lianfeng Wu
Categories
Physiology & Pathology
Keywords
Pyruvate dehydrogenase complex; vitamin B12; metabolic rewiring; propionate metabolism; energy production

Abstract

The pyruvate dehydrogenase complex (PDC) serves as the crucial gate between cytosolic and mitochondrial metabolism1. In humans, PDC deficiency (PDCD) leads to a severe mitochondrial disorder without effective treatment2,3,4. Beyond its known enzymatic defect, the broader metabolic consequences of PDCD remain unclear. Using cross-species approaches spanning Caenorhabditis elegans, mouse primary hepatocytes, human cell lines, and patient blood samples, we reveal a conserved and obligatory metabolic trade-off in PDCD: functional depletion of vitamin B12. This loss is driven by compensatory rewiring via an MDT-15/MED15-NHR-68/HNF4 pathway, diverting carbon flux from B12-dependent propionate metabolism to sustain acetyl-CoA synthesis and mitochondrial function. Thus, PDCD triggers an acquired B12 deficiency as a survival strategy. Therapeutically, this vulnerability is targetable, as acetate supplementation restores acetyl-CoA levels and rescues B12 function. Our work reveals a fundamental adaptive principle where a vital vitamin-dependent pathway is sacrificed to maintain core energy production, unveiling novel therapeutic avenues.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.03.15.000158

Submission ID:

158

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Posted

2026-03-15

How to Cite

Duan, D., Qin, C., Chen, J., Liu, S., Zhu, S., Liu, Z., Dong, H.-L., Wu, B., Zhang, T., Wu, Z.-Y., Wu, S., Lu, W., Huang, X., & Wu, L. (2026). Pyruvate dehydrogenase deficiency hijacks B12 to sustain energy production. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.03.15.000158

Declaration of Competing Interests

The authors declare no competing interests to disclose.

Copyright

The copyright holder for this preprint is the author/funder.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.