ATP Deficiency Triggers Ganoderic Acids Accumulation Via Fatty Acid β-oxidation Pathway in Ganoderma Lucidum

Overview

Journal Microb Cell Fact

Publisher Biomed Central

Specialties Biotechnology
Microbiology

Date 2025 Mar 12

PMID 40069729

Authors

Weidong Liu

Yin Sun

Sining Yue

Yi Kong

Qianqian Cong

Yufei Lan

Mingwen Zhao

Liang Shi

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

References

Persson L, Ambati V, Brandman O . Cellular Control of Viscosity Counters Changes in Temperature and Energy Availability. Cell. 2020; 183(6):1572-1585.e16. PMC: 7736452. DOI: 10.1016/j.cell.2020.10.017. View

Araujo W, Ishizaki K, Nunes-Nesi A, Larson T, Tohge T, Krahnert I . Identification of the 2-hydroxyglutarate and isovaleryl-CoA dehydrogenases as alternative electron donors linking lysine catabolism to the electron transport chain of Arabidopsis mitochondria. Plant Cell. 2010; 22(5):1549-63. PMC: 2899879. DOI: 10.1105/tpc.110.075630. View

Shi L, Gong L, Zhang X, Ren A, Gao T, Zhao M . The regulation of methyl jasmonate on hyphal branching and GA biosynthesis in Ganoderma lucidum partly via ROS generated by NADPH oxidase. Fungal Genet Biol. 2014; 81:201-11. DOI: 10.1016/j.fgb.2014.12.002. View

Li T, Wang Q, Yang Y, Song D . The mechanism of polysaccharide synthesis of Sanghuangporus sanghuang based on multi-omic analyses and feedback inhibition. Carbohydr Polym. 2023; 321:121288. DOI: 10.1016/j.carbpol.2023.121288. View

Franchini A, Egli T . Global gene expression in Escherichia coli K-12 during short-term and long-term adaptation to glucose-limited continuous culture conditions. Microbiology (Reading). 2006; 152(Pt 7):2111-2127. DOI: 10.1099/mic.0.28939-0. View

Shi L, Yue S, Gao T, Zhu J, Ren A, Yu H . Nitrate reductase-dependent nitric oxide plays a key role on MeJA-induced ganoderic acid biosynthesis in Ganoderma lucidum. Appl Microbiol Biotechnol. 2020; 104(24):10737-10753. DOI: 10.1007/s00253-020-10951-y. View

Marin-Hernandez A, Rodriguez-Zavala J, Jasso-Chavez R, Saavedra E, Moreno-Sanchez R . Protein acetylation effects on enzyme activity and metabolic pathway fluxes. J Cell Biochem. 2021; 123(4):701-718. DOI: 10.1002/jcb.30197. View

Deng J, Wang P, Chen X, Cheng H, Liu J, Fushimi K . FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models. Proc Natl Acad Sci U S A. 2018; 115(41):E9678-E9686. PMC: 6187197. DOI: 10.1073/pnas.1806655115. View

Xia J, He X, Yang W, Song H, Yang J, Zhang G . Unveiling the distribution of chemical constituents at different body parts and maturity stages of Ganoderma lingzhi by combining metabolomics with desorption electrospray ionization mass spectrometry imaging (DESI). Food Chem. 2023; 436:137737. DOI: 10.1016/j.foodchem.2023.137737. View

10.

Abba S, Galetto L, Ripamonti M, Rossi M, Marzachi C . RNA interference of muscle actin and ATP synthase beta increases mortality of the phytoplasma vector Euscelidius variegatus. Pest Manag Sci. 2018; 75(5):1425-1434. DOI: 10.1002/ps.5263. View

11.

Guan S, Sheu M, Wu C, Chiang C, Liu S . ATP synthase subunit-β down-regulation aggravates diabetic nephropathy. Sci Rep. 2015; 5:14561. PMC: 4598833. DOI: 10.1038/srep14561. View

12.

Jiang A, Liu Y, Liu R, Ren A, Ma H, Shu L . Integrated Proteomics and Metabolomics Analysis Provides Insights into Ganoderic Acid Biosynthesis in Response to Methyl Jasmonate in . Int J Mol Sci. 2019; 20(24). PMC: 6941157. DOI: 10.3390/ijms20246116. View

13.

Lu Z, Jia X, Chen Y, Han X, Chen F, Tian S . Identification and Characterization of Key Charged Residues in the Cofilin Protein Involved in Azole Susceptibility, Apoptosis, and Virulence of Aspergillus fumigatus. Antimicrob Agents Chemother. 2018; 62(5). PMC: 5923094. DOI: 10.1128/AAC.01659-17. View

14.

Cui M, Zhao Y, Zhang X, Zhao W . Abscisic acid-mediated cytosolic Ca modulates triterpenoid accumulation of . J Zhejiang Univ Sci B. 2023; 24(12):1174-1179. PMC: 10710909. DOI: 10.1631/jzus.B2300279. View

15.

Cao P, Wu C, Dang Z, Shi L, Jiang A, Ren A . Effects of Exogenous Salicylic Acid on Ganoderic Acid Biosynthesis and the Expression of Key Genes in the Ganoderic Acid Biosynthesis Pathway in the Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes). Int J Med Mushrooms. 2017; 19(1):65-73. DOI: 10.1615/IntJMedMushrooms.v19.i1.70. View

16.

Fischer E, Sauer U . A novel metabolic cycle catalyzes glucose oxidation and anaplerosis in hungry Escherichia coli. J Biol Chem. 2003; 278(47):46446-51. DOI: 10.1074/jbc.M307968200. View

17.

Hou L, Guo S, Wang Y, Nie X, Yang P, Ding D . Neuropeptide ACP facilitates lipid oxidation and utilization during long-term flight in locusts. Elife. 2021; 10. PMC: 8324298. DOI: 10.7554/eLife.65279. View

18.

Olin-Sandoval V, Yu J, Miller-Fleming L, Alam M, Kamrad S, Correia-Melo C . Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism. Nature. 2019; 572(7768):249-253. PMC: 6774798. DOI: 10.1038/s41586-019-1442-6. View

19.

Li H, He Y, Zhang D, Yue T, Jiang L, Li N . Enhancement of ganoderic acid production by constitutively expressing Vitreoscilla hemoglobin gene in Ganoderma lucidum. J Biotechnol. 2016; 227:35-40. DOI: 10.1016/j.jbiotec.2016.04.017. View

20.

Guo B, Zhang F, Yin Y, Ning X, Zhang Z, Meng Q . Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease. iScience. 2024; 27(9):110633. PMC: 11367490. DOI: 10.1016/j.isci.2024.110633. View