Engineering chronological lifespan toward a robust yeast cell factory

• 成果类型: Article
• 署名作者: Wu, Zulin; Gao, Jiaoqi; Gao, Ning; Zhao, Yunxian; Zhou, Yongjin J.
• 署名单位: Chinese Academy of Sciences; Dalian Institute of Chemical Physics, CAS; Jiujiang University; Chinese Academy of Sciences; Dalian Institute of Chemical Physics, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2515324122
• 发表日期: 2025-11-18
• 页码: e2515324122
• 关键词: chronological lifespan; bioproduction; yeast; sclareol; metabolic engineering; saccharomyces-cerevisiae; protein; longevity; tor; GROWTH; SCH9; extension; subunit; complex; kinase

摘要

Metabolic rewiring helps to construct efficient microbial cell factories; however, these cells suffer from metabolic stress during long-term fed-batch fermentation. Thus, the construction of robust cells is vital for industrial application of microbial cell factories at the laboratory scale. Here, we systematically characterized longevity factors and pathways for biosynthesis of the diterpenoid sclareol and found that weakening nutrient-sensing pathways and enhancing mitophagy synergistically improved sclareol production by 70.3% (20.1 g/L with a yield of 0.046 g/g glucose). Further enhancing central metabolism improved sclareol production to 25.9 g/L with a yield of 0.051 g/g glucose, the highest production achieved in microbes. Omics data demonstrated that the extension of chronological lifespan by upregulating the expression of lifespan-related genes automatically remodeled the cellular metabolism and improved overall cellular robustness for efficient chemical biosynthesis. We also showed that our strategy significantly improved the biosynthesis of other products such as sesquiterpene beta- elemene and phenolic acids. Therefore, this study may provide metabolic connections between cell aging and biosynthetic capacity. Significance It is challenging to associate the laboratory-scale shake-flask fermentation with industrial fed-batch production due to cell aging and the accumulation of toxic metabolites in long-term strain cultivation. Here, we comprehensively engineered cellular resistance and longevity to improve chemical production in yeast. This study established a clear connection between chronological lifespan and biosynthesis capacity for improving sclareol production, a precursor for Ambrox synthesis. Rather than classic metabolic engineering, this longevity engineering strategy could be applied in versatile microbial cell factories for sustainable and economical biomanufacturing.