Leveraging Stress Tolerance Property to Enhance Succinic Acid Production and Cell Metabolic Activity of <i>Yarrowia lipolytica</i>

Succinic acid (SA) is a promising platform chemical used in versatile fields, including biodegradable materials, food, agriculture, and medicine. Enhancing the yeast stress tolerance to SA toxicity is desirable for efficient SA production. However, efficient SA production through the manipulation of yeast SA stress tolerance remains limitedly explored. Here, through comparative transcriptome analysis under SA treatment, we identified that the gene YALI0_A07997g, whose function is yet unknown, is critical for SA tolerance in Yarrowia lipolytica. We further developed an efficient SA producer strain Y. lipolytica ΔSDH5-A11 by overexpressing YALI0_A07997g and disruption of the succinate dehydrogenase subunit gene SDH5. Subsequently, fed-batch fermentation was performed, and under the optimized conditions, the recombinant strain achieved a SA concentration of 88.5 g/L with a high productivity of 1.23 g/L/h. Online respiratory quotient (RQ) analysis revealed that the engineered yeast strain exhibited a lower RQ compared with the parent strain, suggesting higher metabolic activities toward SA production. Comparative transcriptomic analyses identified changes in gene expression related to improved stress tolerance of the recombinant yeast during the fed-batch fermentation. Our findings provide a novel strategy to employ genes related to yeast stress tolerance for efficient organic acid bioproduction.