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

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.

STAT3modulatesCD4+T mitochondrial dynamics and function in aging

“…CD45RO + CD27 − cells are effector cells that display high antigen recall response whereas CD45RO + CD27 + cells are intermediate memory population that lacks high antigen recall response. To understand the physiological relevance of mitoSTAT3 on T cell function, we utilized Mtcur‐1(Mtcur), a mitochondria‐targeted curcuminoid which is known to limit mitoSTAT3 in other cell types (Erlich et al, 2018) (Erlich et al, 2014; Pavlyuchenkova et al, 2023) and in immune cells (Conway et al, 2022). Stimulation of T cells from O adults in the presence of Mtcur for 40 h significantly reduced mitochondrial localization of p‐STAT3 Ser 727 (Figure 1d representative images & e quantification), compared to stimulation in the absence of Mtcur.…”

Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment

“…The release of intracellular and extrace an impact on immunocompetent cells, inc [31,[86][87][88]. It is known that, depending on R effect on cell macromolecules and, along wi the regulation of cell growth and differentia 94].…”

“…There are multiple sources of ROS presented in MC mitochondria, which include the electron transport chain, dehydrogenases in the matrix, intermembrane space proteins, monoamine oxidases in the outer membrane, etc. [31,105] [23,101]. Conditions that promote the formation of ROS in MCs can lead to MC activation by calcium signaling, including hypoxia, allergy, and exposure to aryl hydrocarbon receptor ligands [27,106,107].…”

“…ROS have the potential to modify and activate MC secretory activity is well known [22][23][24][25][26][27][28][29][30][31][32]. Under oxidative stress, MCs become an essential structural and functional component, and the regulation of this component can affect the integral state of the local tissue microenvironment and its resistance to various challenges.…”

Mast Cells in Human Health and Diseases

“…Mitochondria have been reported to be involved in MC activation. In article [ 1 ], the authors demonstrated that mitocurcuminoids cause mitochondrial fragmentation, do not affect spontaneous cell degranulation and inhibit antigen-dependent degranulation. Mitochondrial fragmentation inducers can cause mitochondria to malfunction so that they are unable to perform their functions during antigen-dependent activation of MCs.…”