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This article is a preprint and has not been certified by peer review.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

References

Stacpoole, P. W. & McCall, C. E. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat. Mitochondrion 70, 59-102, doi:10.1016/j.mito.2023.02.007(2023).

Ganetzky, R., McCormick, E. M. & Falk, M. J. in GeneReviews((R)) (eds M. P. Adam et al.)(1993).

Ebertowska, A., Ludkiewicz, B., Klejbor, I., Melka, N. & Morys, J. Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment. Folia Morphol(Warsz) 79, 191-197, doi:10.5603/FM.a2020.0020(2020).

DeBrosse, S. D., Okajima, K., Zhang, S., Nakouzi, G., Schmotzer, C. L. et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex(PDC)deficiency: lack of correlation with genotype. Mol Genet Metab 107, 394-402,doi:10.1016/j.ymgme.2012.09.001(2012).

Verma, A., Lehman, A. N., Gokcan, H., Cropcho, L., Black, D. et al. Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism. Mol Genet Genomic Med 12,e2283, doi:10.1002/mgg3.2283(2024).

Jakkamsetti, V., Marin-Valencia, I., Ma, Q., Good, L. B., Terrill, T. et al. Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency. Sci Transl Med 11, doi:10.1126/scitranslmed.aan0457(2019).

Patel, M. S., Mahmood, S., Jung, J. & Rideout, T. C. Reprogramming of aerobic glycolysis in non-transformed mouse liver with pyruvate dehydrogenase complex deficiency. Physiol Rep 9,e14684, doi:10.14814/phy2.14684(2021).

Sidhu, S., Gangasani, A., Korotchkina, L. G., Suzuki, G., Fallavollita, J. A. et al. Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice. Am J Physiol Heart Circ Physiol 295, H946-H952,doi:10.1152/ajpheart.00363.2008(2008).

Gopal, K., Abdualkader, A. M., Li, X., Greenwell, A. A., Karwi, Q. G. et al. Loss of muscle PDH induces lactic acidosis and adaptive anaplerotic compensation via pyruvate-alanine cycling and glutaminolysis. J Biol Chem 299,105375, doi:10.1016/j.jbc.2023.105375(2023).

Taylor, M. R., Hurley, J. B., Van Epps, H. A. & Brockerhoff, S. E. A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet. Proc Natl Acad Sci U S A 101, 4584-4589, doi:10.1073/pnas.0307074101(2004).

Green, R., Allen, L. H., Bjorke-Monsen, A. L., Brito, A., Gueant, J. L. et al.Vitamin B(12) deficiency. Nat Rev Dis Primers 3, 17040, doi:10.1038/nrdp.2017.40(2017).

Qin, S., Wang, Y., Li, L., Liu, J., Xiao, C. et al.Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans. Cell Rep 40,111381, doi:10.1016/j.celrep.2022.111381(2022).

Carmel, R. Biomarkers of cobalamin(vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin,methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr 94, 348S-358S,doi:10.3945/ajcn.111.013441(2011).

Solomon, L. R. Functional cobalamin(vitamin B12) deficiency: role of advanced age and disorders associated with increased oxidative stress. Eur J Clin Nutr 69, 687-692,doi:10.1038/ejcn.2014.272(2015).

Zhu, S., Zhang, R., Yao, L., Lin, Z., Li, Y. et al.De novo NAD(+) synthesis is ineffective for NAD(+) supply in axenically cultured Caenorhabditis elegans. Commun Biol 8, 545,doi:10.1038/s42003-025-07984-2(2025).

Li, Y., Duan, D., Zhu, S., Liu, Z., Zhang, Q. et al. Genome-wide RNAi screening in C.elegans reveals OXPHOS and pyrimidine synthesis pathways as PKA regulators. Commun Biol 8, 1280, doi:10.1038/s42003-025-08718-0(2025).

Qin, C., Liu, Z., Duan, D. & Wu, L. Genome-wide RNAi analysis in adult Caenorhabditis elegans unveils genes controlling age-related fat accumulation. Mech Ageing Dev 226,112089, doi:10.1016/j.mad.2025.112089(2025).

Li, X., Zhang, H., Hodder, T., Wang, W., Myers, C. L. et al. Systems-level design principles of metabolic rewiring in an animal. Nature 640, 203-211, doi:10.1038/s41586-025-08636-5(2025).

Wei, W. & Ruvkun, G. Lysosomal activity regulates Caenorhabditis elegans mitochondrial dynamics through vitamin B12 metabolism. Proc Natl Acad Sci U S A 117,19970-19981, doi:10.1073/pnas.2008021117(2020).

Robinson, B. H.& MacKay, N. The biochemistry of PDHC deficiency. J Inherit Metab Dis 20, 300-307, doi:10.1023/a:1005323514130(1997).

Patel, K. P., O'Brien, T. W., Subramony, S. H., Shuster, J. & Stacpoole, P. W. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 105,34-43, doi:10.1016/j.ymgme.2011.09.032(2012).

Gray, R. G., Kumar, D., Whitfield, A. E.& Green, A. Antenatal and postnatal diagnosis of pyruvate dehydrogenase E1 alpha subunit deficiency. Prenat Diagn 20, 434-437(2000).

Watson, E., Olin-Sandoval, V., Hoy, M. J., Li, C. H., Louisse, T. et al. Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. Elife 5, doi:10.7554/eLife.17670(2016).

Bulcha, J. T., Giese, G. E., Ali, M. Z., Lee, Y. U., Walker, M. D. et al. A Persistence Detector for Metabolic Network Rewiring in an Animal. Cell Rep 26,460-468 e464,doi:10.1016/j.celrep.2018.12.064(2019).

Zhou, J., Duan, M., Wang, X., Zhang, F., Zhou, H. et al. A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology. Nat Cell Biol 24,526-537, doi:10.1038/s41556-022-00883-2(2022).

Na, H., Ponomarova, O., Giese, G. E.& Walhout, A. J. M. C. elegans MRP-5 Exports Vitamin B12 from Mother to Offspring to Support Embryonic Development. Cell Rep 22,3126-3133, doi:10.1016/j.celrep.2018.02.100(2018).

Watson, E., MacNeil, L. T., Ritter, A. D., Yilmaz, L. S., Rosebrock, A. P. et al. Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell 156,759-770, doi:10.1016/j.cell.2014.01.047(2014).

Vashi, P., Edwin, P., Popiel, B., Lammersfeld, C.& Gupta, D. Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer. PLoS One 11,e0147843, doi:10.1371/journal.pone.0147843(2016).

Hannibal, L., Lysne, V., Bjorke-Monsen, A. L., Behringer, S., Grunert, S. C. et al. Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency. Front Mol Biosci 3,27, doi:10.3389/fmolb.2016.00027(2016).

Yao, L., Wang, Y., Qin, S., Zhu, S.& Wu, L. The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA. Commun Biol 6,96, doi:10.1038/s42003-023-04475-0(2023).

Chen, J., Guccini, I., Di Mitri, D., Brina, D., Revandkar, A. et al. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.Nat Genet 50, 219-228, doi:10.1038/s41588-017-0026-3(2018).

Husseiny, M.& Nilsson, R. The role of B(12) deficiency and methionine synthase in methionine-dependent cancer cells. Cancer Metab 13, 34, doi:10.1186/s40170-025-00405-2(2025).

Goh, G. Y. S., Beigi, A., Yan, J., Doering, K. R. S.& Taubert, S. Mediator subunit MDT-15 promotes expression of propionic acid breakdown genes to prevent embryonic lethality in Caenorhabditis elegans. G3(Bethesda) 13, doi:10.1093/g3journal/jkad087(2023).

Shen, H., Campanello, G. C., Flicker, D., Grabarek, Z., Hu, J. et al. The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B(12). Cell 171, 771-782 e711,doi:10.1016/j.cell.2017.09.051(2017).

Clifton, B. E., Kaczmarski, J. A., Carr, P. D., Gerth, M. L., Tokuriki, N. et al. Evolution of cyclohexadienyl dehydratase from an ancestral solute-binding protein. Nat Chem Biol 14,542-547, doi:10.1038/s41589-018-0043-2(2018).

Ruetz, M., Campanello, G. C., Purchal, M., Shen, H., McDevitt, L. et al. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair.Science 366, 589-593, doi:10.1126/science.aay0934(2019).

Liu, S.& Locasale, J. W. Flux measurements of the tricarboxylic acid cycle in the tumors of mice. Life Metab 2, load020, doi:10.1093/lifemeta/load020(2023).

Chuang, M. H., Chiou, S. H., Huang, C. H., Yang, W. B.& Wong, C. H. The lifespan-promoting effect of acetic acid and Reishi polysaccharide. Bioorg Med Chem 17, 7831-7840, doi:10.1016/j.bmc.2009.09.002(2009).

Edwards, C., Canfield, J., Copes, N., Brito, A., Rehan, M. et al. Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet 16,8,doi:10.1186/s12863-015-0167-2(2015).

Yang, M.& Du, Z. Reaffirming the value of model organisms in training scientific minds. Nat Cell Biol 27, 1589-1591, doi:10.1038/s41556-025-01754-2(2025).

Stabler, S. P.& Allen, R. H. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 24, 299-326, doi:10.1146/annurev.nutr.24.012003.132440(2004).

Suliman, H. S., Sawyer, G. M., Appling, D. R.& Robertus, J. D. Purification and properties of cobalamin-independent methionine synthase from Candida albicans and Saccharomyces cerevisiae. Arch Biochem Biophys 441, 56-63,doi:10.1016/j.abb.2005.06.016(2005).

Young, D. B., Comas, I.& de Carvalho, L. P. Phylogenetic analysis of vitamin B12-related metabolism in Mycobacterium tuberculosis. Front Mol Biosci 2, 6,doi:10.3389/fmolb.2015.00006(2015).

Yang, F., Vought, B. W., Satterlee, J. S., Walker, A. K., Jim Sun, Z. Y. et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.Nature 442, 700-704, doi:10.1038/nature04942(2006).

Goh, G. Y., Martelli, K. L., Parhar, K. S., Kwong, A. W., Wong, M. A. et al. The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans. Aging Cell 13,70-79, doi:10.1111/acel.12154(2014).

Zhang, Y., Shen, X., Shen, Y., Wang, C., Yu, C. et al. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy. Nature 649,1022-1031, doi:10.1038/s41586-025-09745-x(2026).

Avula, S., Parikh, S., Demarest, S., Kurz, J.& Gropman, A. Treatment of mitochondrial disorders. Curr Treat Options Neurol 16, 292, doi:10.1007/s11940-014-0292-7(2014).

Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71-94,doi:10.1093/genetics/77.1.71(1974).

Samuel, T. K., Sinclair, J. W., Pinter, K. L.& Hamza, I. Culturing Caenorhabditis elegans in axenic liquid media and creation of transgenic worms by microparticle bombardment. J Vis Exp, e51796, doi:10.3791/51796(2014).

Booher, K., Lin, D. W., Borrego, S. L.& Kaiser, P. Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells. Cell Cycle 11,4414-4423, doi:10.4161/cc.22767(2012).

Zhang, R., Fang, J., Qi, T., Zhu, S., Yao, L. et al. Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria. Cell Res 33, 821-834,doi:10.1038/s41422-023-00854-8(2023).

Wu, L., Zhou, B., Oshiro-Rapley, N., Li, M., Paulo, J. A. et al. An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell 167, 1705-1718 e1713, doi:10.1016/j.cell.2016.11.055(2016).

Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P.& Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10, 935-945, doi:10.1038/ncb1753(2008).

Kolberg, L., Raudvere, U., Kuzmin, I., Adler, P., Vilo, J. et al. g:Profiler-interoperable web service for functional enrichment analysis and gene identifier mapping(2023 update). Nucleic Acids Res 51, W207-W212, doi:10.1093/nar/gkad347(2023).

Falk, M. J., Rao, M., Ostrovsky, J., Daikhin, E., Nissim, I. et al. Stable isotopic profiling of intermediary metabolic flux in developing and adult stage Caenorhabditis elegans.J Vis Exp, doi:10.3791/2288(2011).

Zhu, Y., Tong, X., Xue, J., Qiu, H., Zhang, D. et al. Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity. Nat Chem Biol 21, 35-46,doi:10.1038/s41589-024-01689-z(2025).

Ye, C., Sutter, B. M., Wang, Y., Kuang, Z.& Tu, B. P. A Metabolic Function for Phospholipid and Histone Methylation. Mol Cell 66, 180-193 e188,doi:10.1016/j.molcel.2017.02.026(2017).

Ye, C., Sutter, B. M., Wang, Y., Kuang, Z., Zhao, X. et al. Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink. Mol Cell 73, 1115-1126 e1116, doi:10.1016/j.molcel.2019.01.012(2019).

Liu, S., Liu, X.& Locasale, J. W. Quantitation of metabolic activity from isotope tracing data using automated methodology. Nat Metab 6, 2207-2209, doi:10.1038/s42255-024-01144-2(2024).

Kraft, D. A software package for sequential quadratic programming. Forschungsbericht-Deutsche Forschungs- und Versuchsanstalt fur Luft- und Raumfahrt(1988).

Antoniewicz, M. R., Kelleher, J. K.& Stephanopoulos, G. Elementary metabolite units(EMU): a novel framework for modeling isotopic distributions. Metab Eng 9, 68-86,doi:10.1016/j.ymben.2006.09.001(2007).

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

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2026-03-15

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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

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