Honokiol Induces Superoxide Production by Targeting Mitochondrial Respiratory Chain Complex I in Candida Albicans

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Aug 31

PMID 28854218

Citations 13

Authors

Lingmei Sun

Kai Liao

Dayong Wang

Affiliations

Soon will be listed here.

Abstract

Background: Honokiol, a compound extracted from Magnolia officinalis, has antifungal activities by inducing mitochondrial dysfunction and triggering apoptosis in Candida albicans. However, the mechanism of honokiol-induced oxidative stress is poorly understood. The present investigation was designed to determine the specific mitochondrial reactive oxygen species (ROS)-generation component.

Methods/results: We found that honokiol induced mitochondrial ROS accumulation, mainly superoxide anions (O2•-) measured by fluorescent staining method. The mitochondrial respiratory chain complex I (C I) inhibitor rotenone completely blocked O2•- production and provided the protection from the killing action of honokiol. Moreover, respiratory activity and the C I enzyme activity was significantly reduced after honokiol treatment. The differential gene-expression profile also showed that genes involved in oxidoreductase activity, electron transport, and oxidative phosphorylation were upregulated.

Conclusions: The present work shows that honokiol may bind to mitochondrial respiratory chain C I, leading to mitochondrial dysfunction, accompanied by increased cellular superoxide anion and oxidative stress.

General Significance: This work not only provides insights on the mechanism by which honokiol interferes with fungal cell, demonstrating previously unknown effects on mitochondrial physiology, but also raises a note of caution on the use of M. officinalis as a Chinese medicine due to the toxic for mitochondria and suggests the possibility of using honokiol as chemosensitizer.

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References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Jarvis W . Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. J Infect Dis. 1993; 167(5):1247-51. DOI: 10.1093/infdis/167.5.1247. View

She X, Khamooshi K, Gao Y, Shen Y, Lv Y, Calderone R . Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis. Cell Microbiol. 2015; 17(9):1350-64. PMC: 4677794. DOI: 10.1111/cmi.12438. View

She X, Zhang L, Chen H, Calderone R, Li D . Cell surface changes in the Candida albicans mitochondrial mutant goa1Δ are associated with reduced recognition by innate immune cells. Cell Microbiol. 2013; 15(9):1572-84. PMC: 3738057. DOI: 10.1111/cmi.12135. View

Scialo F, Sriram A, Fernandez-Ayala D, Gubina N, Lohmus M, Nelson G . Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan. Cell Metab. 2016; 23(4):725-34. PMC: 4835580. DOI: 10.1016/j.cmet.2016.03.009. View

Li D, She X, Calderone R . Functional diversity of complex I subunits in Candida albicans mitochondria. Curr Genet. 2015; 62(1):87-95. PMC: 4724564. DOI: 10.1007/s00294-015-0518-6. View

Bondaryk M, Kurzatkowski W, Staniszewska M . Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Postepy Dermatol Alergol. 2013; 30(5):293-301. PMC: 3858657. DOI: 10.5114/pdia.2013.38358. View

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View

Moreno-Sanchez R, Hernandez-Esquivel L, Rivero-Segura N, Marin-Hernandez A, Neuzil J, Ralph S . Reactive oxygen species are generated by the respiratory complex II--evidence for lack of contribution of the reverse electron flow in complex I. FEBS J. 2012; 280(3):927-38. DOI: 10.1111/febs.12086. View

10.

LEHAN P, FURCOLOW M, BRASHER C, LARSH H . Therapeutic trials with the newer antifungal agents. Antibiot Annu. 1956; :467-9. View

11.

Dikalov S, Losik T, Arbiser J . Honokiol is a potent scavenger of superoxide and peroxyl radicals. Biochem Pharmacol. 2008; 76(5):589-96. PMC: 2575413. DOI: 10.1016/j.bcp.2008.06.012. View

12.

Sun L, Liao K, Liang S, Yu P, Wang D . Synergistic activity of magnolol with azoles and its possible antifungal mechanism against Candida albicans. J Appl Microbiol. 2015; 118(4):826-38. DOI: 10.1111/jam.12737. View

13.

Orr A, Ashok D, Sarantos M, Shi T, Hughes R, Brand M . Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening. Free Radic Biol Med. 2013; 65:1047-1059. PMC: 4321955. DOI: 10.1016/j.freeradbiomed.2013.08.170. View

14.

Abrantes P, McArthur C, Africa C . Multi-drug resistant oral Candida species isolated from HIV-positive patients in South Africa and Cameroon. Diagn Microbiol Infect Dis. 2014; 79(2):222-7. DOI: 10.1016/j.diagmicrobio.2013.09.016. View

15.

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

16.

Jin J, Guo N, Zhang J, Ding Y, Tang X, Liang J . The synergy of honokiol and fluconazole against clinical isolates of azole-resistant Candida albicans. Lett Appl Microbiol. 2010; 51(3):351-7. DOI: 10.1111/j.1472-765X.2010.02900.x. View

17.

Alexander B, Perfect J . Antifungal resistance trends towards the year 2000. Implications for therapy and new approaches. Drugs. 1997; 54(5):657-78. DOI: 10.2165/00003495-199754050-00002. View

18.

Sun J, Fu X, Liu Y, Wang Y, Huo B, Guo Y . Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug Des Devel Ther. 2015; 9:6327-42. PMC: 4675651. DOI: 10.2147/DDDT.S92777. View

19.

Wang X, Wang Y, Gao W . Honokiol possesses potential anti-inflammatory effects on rheumatoid arthritis and GM-CSF can be a target for its treatment. Int J Clin Exp Pathol. 2015; 8(7):7929-36. PMC: 4555686. View

20.

Pan J, Lee Y, Wang Y, You M . Honokiol targets mitochondria to halt cancer progression and metastasis. Mol Nutr Food Res. 2016; 60(6):1383-95. DOI: 10.1002/mnfr.201501007. View