The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

Pavlyuchenkova, Anastasia N.; Chelombitko, Maria A.; Fedorov, Artem V.; Kuznetsova, Maria K.; Zinovkin, Roman A.; Razin, Ehud

doi:10.3390/ijms24021471

Open AccessArticle

The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

by

Anastasia N. Pavlyuchenkova

^1,2,†

,

Maria A. Chelombitko

^2,3,†

,

Artem V. Fedorov

⁴,

Maria K. Kuznetsova

¹,

Roman A. Zinovkin

^2,3,*

and

Ehud Razin

⁵

¹

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

²

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

³

The “Russian Clinical Research Center for Gerontology”, Ministry of Healthcare of the Russian Federation, Pirogov Russian National Research Medical University, 129226 Moscow, Russia

⁴

Department of Cell Biology and Histology, Biology Faculty, Lomonosov Moscow State University, 119234 Moscow, Russia

⁵

Department of Biochemistry and Molecular Biology, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2023, 24(2), 1471; https://doi.org/10.3390/ijms24021471

Submission received: 30 November 2022 / Revised: 8 January 2023 / Accepted: 10 January 2023 / Published: 12 January 2023

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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Abstract

There is accumulating evidence that mitochondria and mitochondrial STAT3 are involved in the activation of mast cells. The mitochondria-targeted curcuminoids Mitocur-1 and Mitocur-3 have been suggested to reduce antigen-dependent mast cell activation by inhibiting mitochondrial STAT3. The aim of the current work was to investigate the mechanisms of action of these mitocurcuminoids on mast cells and mitochondrial functions. The pretreatment of rat basophilic leukemia cells RBL-2H3 with Mitocur-1 and Mitocur-3 decreased antigen-dependent degranulation but did not affect spontaneous degranulation. Both compounds caused mitochondrial fragmentation and increased mitochondrial ROS. Inhibition of Drp1 prevented mitochondrial fragmentation induced by Mitocur-3 but not by Mitocur-1. The antioxidant N-acetylcysteine inhibited mitochondrial fission induced by Mitocur-1 but not Mitocur-3. Mitochondrial fragmentation caused by Mitocur-3 but not Mitocur-1 was accompanied by activation of Drp1 and AMPK. These data suggest a distinct mechanism of action of mitocurcuminoids on the mitochondria of RBL-2H3 cells: Mitocur-3 stimulated AMPK and caused Drp1-dependent mitochondrial fragmentation, while Mitocur-1-induced mitochondrial fission was ROS-dependent. This difference may contribute to the higher toxicity of Mitocur-3 compared to Mitocur-1. The findings contribute to further drug development for inflammatory and allergic diseases.

Keywords: mast cell; RBL-2H3 cells; mitochondria; mitochondria-targeted curcuminoids; Mitocur-1; Mitocur-3

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MDPI and ACS Style

Pavlyuchenkova, A.N.; Chelombitko, M.A.; Fedorov, A.V.; Kuznetsova, M.K.; Zinovkin, R.A.; Razin, E. The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions. Int. J. Mol. Sci. 2023, 24, 1471. https://doi.org/10.3390/ijms24021471

AMA Style

Pavlyuchenkova AN, Chelombitko MA, Fedorov AV, Kuznetsova MK, Zinovkin RA, Razin E. The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions. International Journal of Molecular Sciences. 2023; 24(2):1471. https://doi.org/10.3390/ijms24021471

Chicago/Turabian Style

Pavlyuchenkova, Anastasia N., Maria A. Chelombitko, Artem V. Fedorov, Maria K. Kuznetsova, Roman A. Zinovkin, and Ehud Razin. 2023. "The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions" International Journal of Molecular Sciences 24, no. 2: 1471. https://doi.org/10.3390/ijms24021471

APA Style

Pavlyuchenkova, A. N., Chelombitko, M. A., Fedorov, A. V., Kuznetsova, M. K., Zinovkin, R. A., & Razin, E. (2023). The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions. International Journal of Molecular Sciences, 24(2), 1471. https://doi.org/10.3390/ijms24021471

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The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

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