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

Vinh G. Tran, Shih-I Tan, Hao Xu, Daniel R. Weilandt, Xi Li, Sarang S. Bhagwat, Zhixin Zhu, Jeremy S. Guest, Joshua D. Rabinowitz and Huimin Zhao ()
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Vinh G. Tran: University of Illinois Urbana-Champaign
Shih-I Tan: University of Illinois Urbana-Champaign
Hao Xu: University of Illinois Urbana-Champaign
Daniel R. Weilandt: Princeton University
Xi Li: Princeton University
Sarang S. Bhagwat: University of Illinois Urbana-Champaign
Zhixin Zhu: University of Illinois Urbana-Champaign
Jeremy S. Guest: University of Illinois Urbana-Champaign
Joshua D. Rabinowitz: Princeton University
Huimin Zhao: University of Illinois Urbana-Champaign

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62304-w

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