Liu Weidong, Sun Yin, Yue Sining, Kong Yi, Cong Qianqian, Lan Yufei, Zhao Mingwen, Shi Liang
Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture; Microbiology Department, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China.
Tai'an Academy of Agricultural Sciences, Tai'an, Shandong, 271000, China.
Microb Cell Fact. 2025 Mar 11;24(1):62. doi: 10.1186/s12934-025-02668-2.
Ganoderic acids (GAs), recognized as significant triterpenoid bioactive components in Ganoderma lucidum, exhibit a broad spectrum of pharmacological activities, including immunomodulation, anti-cancer, and anti-aging properties. Despite their significant pharmacological potential, the low yield of GAs from natural sources has emerged as a critical bottleneck hindering their broader application in the pharmaceutical and health care industries. Previous studies have suggested that environmental perturbations can influence energy metabolism, potentially impacting the biosynthesis of bioactive compounds. However, the specific influence of environmental changes on energy metabolism and subsequent effects on GAs synthesis in G. lucidum remains an understudied area.
We demonstrated that intracellular ATP deficiency significantly influences GAs accumulation induced by alterations in energy metabolism. Intracellular ATP deficiency was consistently observed under all four known conditions that induce GAs accumulation: heat stress (HS), nitrogen limitation, treatment with 50 µM methyl jasmonate (MeJA), and treatment with 200 µM salicylic acid (SA). Consistent with these findings, silencing the ATP synthase beta subunit (ATPsyn-beta) or treating with oligomycin (Oli), an ATP synthase inhibitor, increased GAs accumulation and induced intracellular ATP deficiency in G. lucidum. Our results revealed an increase in the GAs biosynthetic pathway and increased levels of the GAs precursor acetyl-CoA in mycelia with intracellular ATP deficiency. Enhanced fatty acid β-oxidation was identified as the primary source of additional acetyl-CoA, indicating that this process, induced by intracellular ATP deficiency, is crucial for GAs accumulation.
This study demonstrated that changes in intracellular ATP content respond to environmental perturbations and impact the biosynthesis of GAs, holding substantial implications for production practices. Modulating ATP levels could increase GAs yields, cater to market demands, and reduce costs. The research also furnishes a scientific foundation for optimizing cultivation conditions, employing genetic engineering to refine biosynthetic pathways, and leveraging environmental control to boost production efficiency.
灵芝酸（GAs）是灵芝中重要的三萜类生物活性成分，具有广泛的药理活性，包括免疫调节、抗癌和抗衰老特性。尽管它们具有显著的药理潜力，但天然来源的灵芝酸产量低已成为阻碍其在制药和医疗保健行业更广泛应用的关键瓶颈。先前的研究表明，环境扰动会影响能量代谢，可能影响生物活性化合物的生物合成。然而，环境变化对灵芝能量代谢的具体影响以及随后对灵芝酸合成的影响仍是一个研究不足的领域。
我们证明细胞内ATP缺乏显著影响能量代谢改变诱导的灵芝酸积累。在所有四种已知的诱导灵芝酸积累的条件下均持续观察到细胞内ATP缺乏：热应激（HS）、氮限制、用50 μM茉莉酸甲酯（MeJA）处理和用200 μM水杨酸（SA）处理。与这些发现一致，沉默ATP合酶β亚基（ATPsyn-β）或用ATP合酶抑制剂寡霉素（Oli）处理可增加灵芝酸积累并诱导灵芝细胞内ATP缺乏。我们的结果显示，细胞内ATP缺乏的菌丝体中灵芝酸生物合成途径增加，灵芝酸前体乙酰辅酶A水平升高。增强的脂肪酸β-氧化被确定为额外乙酰辅酶A的主要来源，表明由细胞内ATP缺乏诱导的这一过程对灵芝酸积累至关重要。
本研究表明细胞内ATP含量的变化对环境扰动做出反应并影响灵芝酸的生物合成，对生产实践具有重要意义。调节ATP水平可以提高灵芝酸产量，满足市场需求并降低成本。该研究还为优化培养条件、利用基因工程完善生物合成途径以及利用环境控制提高生产效率提供了科学依据。
