文献类型：期刊文献

英文题名：Physiological Response of Penicillium chrysogenum to Mimicked Local and Global Perturbations of Substrate and Dissolved Oxygen Gradients at Industrial-Scale

作者：Chen, Yining[1];Haringa, Cees[2];Wang, Zejian[1];Zhuang, Yingping[1,3];Wang, Guan[1,3]

机构：[1]East China Univ Sci & Technol ECUST, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]Delft Univ Technol, Dept Biotechnol, Delft, Netherlands;[3]East China Univ Sci & Technol, Qingdao Innovat Inst, Shanghai, Peoples R China

年份：2025

卷号：122

期号：6

起止页码：1402

外文期刊名：BIOTECHNOLOGY AND BIOENGINEERING

收录：;EI(收录号：20251118038216);WOS:【SCI-EXPANDED(收录号:WOS:001469489400001)】；

基金：This research was funded by the National Key R&D Program of China (Grant no. 2021YFC2101000), National Natural Science Foundation of China (Grant no. 31900073, 21978085), Shanghai Rising-Star Program (Grant no. 21QA1402400), Natural Science Foundation of Shanghai (Grant no. 19ZR1413600), and the Fundamental Research Funds for the Central Universities (Grant No. JKF01241708).

语种：英文

外文关键词：dissolved oxygen gradients; industrial-scale fermentation; metabolomics; Penicillium chrysogenum; scale-down; substrate gradients

摘要：Industrial-scale microbial fermentation processes often face limitations in mixing and mass transfer, leading to the formation of environmental gradients within the bioreactor. These gradients expose microbes to heterogeneous conditions over time and space. In this study, we evaluated the effects of combined substrate and dissolved oxygen (DO) gradients on the metabolic response of Penicillium chrysogenum at an industrial scale. Three representative heterogeneous environments were simulated in scale-down systems: (1) feed inlet (high glucose, low oxygen (HGLO): C-S > 20 mM, DO < 0.012 mM), (2) aeration inlet (high oxygen, low glucose (HOLG): C-S < 0.8 mM, DO > 0.2 mM), and (3) global environment (periodic 360 s fluctuation cycle with 45 s of HGLO and 75 s of HOLG conditions). Results showed that prolonged exposure to feed inlet conditions led to a complete loss of penicillin production capacity, accompanied by significant excretion of intracellular metabolites, and this effect was largely irreversible. While, cells randomly walking under the top impeller zone did not lose production capacity but showed signs of premature degeneration due to increased energy demand. When exposed to the global environment, cells finely tuned their metabolism in a periodical manner, with nearly a 50% loss of penicillin productivity. In summary, substrate gradients alone did not cause irreversible effects, but large substrate gradients contributed to reduced productivity. Oxygen gradients, however, not only reduced production but also caused irreversible cellular damage. These findings provide valuable insights for developing scale-up criteria and strain engineering strategies aimed at improving large-scale culture performance.