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Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis

Author

Listed:
  • Vinh G. Tran

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Shih-I Tan

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Hao Xu

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Daniel R. Weilandt

    (Princeton University)

  • Xi Li

    (Princeton University)

  • Sarang S. Bhagwat

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Zhixin Zhu

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Jeremy S. Guest

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Joshua D. Rabinowitz

    (Princeton University)

  • Huimin Zhao

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

Abstract

Microbial production of chemicals may suffer from inadequate cofactor provision, a challenge further exacerbated in yeasts due to compartmentalized cofactor metabolism. Here, we perform cofactor engineering through the decompartmentalization of mitochondrial metabolism to improve succinic acid (SA) production in Issatchenkia orientalis. We localize the reducing equivalents of mitochondrial NADH to the cytosol through cytosolic expression of its pyruvate dehydrogenase (PDH) complex and couple a reductive tricarboxylic acid pathway with a glyoxylate shunt, partially bypassing an NADH-dependent malate dehydrogenase to conserve NADH. Cytosolic SA production reaches a titer of 104 g/L and a yield of 0.85 g/g glucose, surpassing the yield of 0.66 g/g glucose constrained by cytosolic NADH availability. Additionally, expressing cytosolic PDH, we expand our I. orientalis platform to enhance acetyl-CoA-derived citramalic acid and triacetic acid lactone production by 1.22- and 4.35-fold, respectively. Our work establishes I. orientalis as a versatile platform to produce markedly reduced and acetyl-CoA-derived chemicals.

Suggested Citation

  • Vinh G. Tran & Shih-I Tan & Hao Xu & Daniel R. Weilandt & Xi Li & Sarang S. Bhagwat & Zhixin Zhu & Jeremy S. Guest & Joshua D. Rabinowitz & Huimin Zhao, 2025. "Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62304-w
    DOI: 10.1038/s41467-025-62304-w
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    References listed on IDEAS

    as
    1. William C. DeLoache & Zachary N. Russ & John E. Dueber, 2016. "Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    2. Liang Sun & Jae Won Lee & Sangdo Yook & Stephan Lane & Ziqiao Sun & Soo Rin Kim & Yong-Su Jin, 2021. "Complete and efficient conversion of plant cell wall hemicellulose into high-value bioproducts by engineered yeast," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    3. Jana Škerlová & Jens Berndtsson & Hendrik Nolte & Martin Ott & Pål Stenmark, 2021. "Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Vinh G. Tran & Somesh Mishra & Sarang S. Bhagwat & Saman Shafaei & Yihui Shen & Jayne L. Allen & Benjamin A. Crosly & Shih-I Tan & Zia Fatma & Joshua D. Rabinowitz & Jeremy S. Guest & Vijay Singh & Hu, 2023. "An end-to-end pipeline for succinic acid production at an industrially relevant scale using Issatchenkia orientalis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Erika M. Palmieri & Ronald Holewinski & Christopher L. McGinity & Ciro L. Pierri & Nunziata Maio & Jonathan M. Weiss & Vincenzo Tragni & Katrina M. Miranda & Tracey A. Rouault & Thorkell Andresson & D, 2023. "Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
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