Adaptive Evolution Identifies MHY1-Mediated Transcriptional Reprogramming for Polyphenol Tolerance in Yarrowia lipolytica.

Summary

Adaptive laboratory evolution in Yarrowia lipolytica uncovered MHY1 loss-of-function as a dominant, transferable mechanism for tolerance to diverse polyphenols, validated by gene deletion and point-mutation reconstructions. Alternative adaptations, including chromosome-scale copy-number variation, emerged in compound-specific contexts, and transcriptomics revealed a reprogrammed regulatory state with reduced stress-pathway activation.

Key Findings

• Adaptive evolution to curcumin, naringenin, and resveratrol selected recurrent MHY1 loss-of-function mutations and chromosome E duplications.
• Functional reconstructions (ΔMHY1, F240L, C153*) reproduced high-level tolerance across polyphenols, establishing causality.
• Resveratrol-tolerant lines achieved tolerance via chromosome-scale copy-number variation without MHY1 mutations.
• Transcriptomics showed a distinct regulatory state with reduced stress-pathway transcription and stabilized core metabolism.

Clinical Implications

No immediate change in clinical care; however, enabling safer, high-tolerance microbial production of polyphenol ingredients could improve supply-chain quality for topical and ingestible products, potentially reducing impurity-related adverse reactions.

Limitations

• Industrial-scale performance and product titers were not reported.
• Findings were in Y. lipolytica; generalizability to other production hosts requires validation.

Future Directions

Quantify tolerance-benefit tradeoffs on product yields at bioreactor scale; test MHY1 inactivation across hosts and pathways; combine with transporter engineering and genome stabilization for robust fermentations.