Abstract
Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.
Highlights
We examined the morphological properties of mitochondria, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes using different organelle-specific fluorescence dyes
Other cell organelles were not significantly affected by ECH treatment (Fig. 1c, Supplementary Fig. 1a–e). This finding was further confirmed by transmission electron microscopy (TEM) analysis, which showed that ECH had a pronounced promoting effect on mitochondrial integrity (Fig. 1d)
The results revealed that ECH-mediated mitochondrial fusion was shown in Fig. 2e, ECH was found to covalently modify the peptide significantly blocked by CK2α′ siRNA
Summary
Mitochondria, which are subcellular organelles responsible for energy production, are considered to play a crucial role in ischemic stroke.[1,2,3] Mitochondrial impairment leads to excessive oxidative stress, mitochondrial membrane potential (MMP)decreases, and mitochondrial DNA (mtDNA) release; mitochondrial quality control is crucial for maintaining a healthy mitochondrial population and preserving proper cell function.[4,5] the current treatment options for modulating mitochondrial homeostasis during cerebral ischemia remain limited.Mitochondria are highly dynamic organelles that continuously undergo fusion and fission.[6,7] Mitochondrial fusion/fission balance is necessary for cell adaptation to changing environments.[8]Mechanistically, fusion contributes to restoring mitochondrial function by enabling mixing of the contents of partially damaged mitochondria as a form of complementation.[9]. Covalent docking analysis against the predicted active pocket containing K171 on CK2α′ further confirmed that ECH binds to CK2α′ by forming a covalent bond addition, transfection of CK2α′ plasmids, but not control vectors, into CK2α′−/− cells phenocopied the mitochondrial fusionpromoting effect of ECH on CK2α′+/+ cells ECH was found to increase the expression of to observe the conformational change of CK2α′ upon ECH mitochondrial fusion protein Mfn[2] with or without OGD/R insult; binding, we superposed our docking model to previously these effects were effectively reversed by CK2α′ siRNA
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