预印本 / 版本 1

Pyruvate dehydrogenase deficiency hijacks B12 to sustain energy production

本文是预印本，尚未经过同行评审认证。

作者

    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
分类
生理学与病理学
关键词
Pyruvate dehydrogenase complex; vitamin B12; metabolic rewiring; propionate metabolism; energy production

摘要

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.

指标

查看次数: 18
下载次数: 1

DOI：

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

Submission ID：

158

下载次数

已发布

2026-03-15

如何引用

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. 浪淘沙预印本平台. https://doi.org/10.65215/LTSpreprints.2026.03.15.000158

利益冲突声明

作者声明无任何需要披露的利益冲突。

Copyright

本预印本的版权持有者为作者/资助方。

Creative Commons License

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