Anastrozole-mediated modulation of mitochondrial activity by inhibition of mitochondrial permeability transition pore opening: an initial perspective

Abstract

The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of aromatase inhibition on the mtPTP has been studied previously, the effect of anastrozole on the mtPTP has not been completely elucidated. The role of anastrozole in modulating the mtPTP was evaluated by docking, molecular dynamics and network-guided studies using human CypD data. The peripheral blood mononuclear cells (PBMCs) of patients with mitochondrial disorders and healthy controls were treated with anastrozole and evaluated for mitochondrial permeability transition pore (mtPTP) function and apoptosis using a flow cytometer. Spectrophotometry was employed for estimating total ATP levels. The anastrozole–CypD complex is more stable than cyclosporin A (CsA)–CypD. Anastrozole performed better than cyclosporine in inhibiting mtPTP. Additional effects included inducing mitochondrial membrane depolarization and a reduction in mitochondrial swelling and superoxide generation, intrinsic caspase-3 activity and cellular apoptosis, along with an increase in ATP levels. Anastrozole may serve as a potential therapeutic agent for mitochondrial disorders and ameliorate the clinical phenotype by regulating the activity of mtPTP. However, further studies are required to substantiate our preliminary findings.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anastrozole
• mitochondrial permeability transition pore
• mitochondrial disorders
• molecular docking
• MD simulation
• protein targets
• binding sites
• docking complexes
• structural modelling

Acknowledgments

In this section, you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments). This study was partially supported by grant projects of the Ministry of Health of the Czech Republic (FN HK 00179906) and of the Charles University in Prague, by the Cooperatio Program, research area NEUR. Also supported by Excelence project UHK 2216/2023-2024.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Institutional Review Board Statement

The study was carried out with the necessary approval from the Institutional Ethical Committee board and complied with the Declaration of Helsinki. The cross-sectional study adhered to the Ethical Principles for Medical Research Involving Human Subjects, World Medical Association Declaration of Helsinki.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient(s) to publish this paper.

Authors’ contributions

SoK: Conceptualization, experimental work, formal analysis, methodology, validation, investigation, data curation and writing—original draft, review and editing. NC: Experimental work, formal analysis, methodology, validation, investigation, data curation, software and writing—original draft. TS:- review, and editing. MF: Formal analysis, review, and editing of the manuscript. PKC: Formal analysis, review, and editing. AK: Experimental work, formal analysis, data curation, and writing—original draft, review, and editing. VS: Supervision, visualization, original draft preparation, review, and editing of the manuscript. RKS: Visualization, original draft preparation, review, and editing of the manuscript. HS: Experimental work, investigation, visualization, review, and editing of the manuscript. SJ: Investigation, visualization, review, and editing of the manuscript. MV: Review, and editing of the manuscript. KK: Supervision, visualization, original draft preparation, review, and editing of the manuscript. SkP: Supervision, visualization, original draft preparation, review, and editing of the manuscript. MK: Review, and editing of the manuscript. PnS: Supervision, visualization, original draft preparation, review, and editing of the manuscript. RS: Supervision, visualization, original draft preparation, review, and editing of the manuscript. SK: Conceptualization, supervision, visualization, original draft preparation, review, and editing of the manuscript.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

Additional information

Funding

It was supported by the UHK project VT2019-2021. This study was also partially supported by grants from the Ministry of Health of the Czech Republic (FN HK 00179906) and the Charles University in Prague, Czech Republic (PROGRES Q40).