The antimicrobial peptide LL-37 triggers release of apoptosis-inducing factor and shows direct effects on mitochondria |
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Authors: | Elisabeth Bankell Xiaoyan Liu Martin Lundqvist Daniel Svensson Karl Swärd Emma Sparr Bengt-Olof Nilsson |
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Institution: | 1. Department of Experimental Medical Science, Lund University, BMC D12, SE-22184, Lund, Sweden;2. Division of Physical Chemistry, Department of Chemistry, Lund University, SE-22100, Lund, Sweden;3. Division of Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-22100, Lund, Sweden |
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Abstract: | The human antimicrobial peptide LL-37 permeabilizes the plasma membrane of host cells, but LL-37-induced direct effects on mitochondrial membrane permeability and function has not been reported. Here, we demonstrate that LL-37 is rapidly (within 20 min) internalized by human osteoblast-like MG63 cells, and that the peptide co-localizes with MitoTracker arguing for accumulation in mitochondria. Subcellular fractionation and Western blot disclose that stimulation with LL-37 (8 μM) for 2 h triggers release of the mitochondrial protein apoptosis-inducing factor (AIF) to the cytosol, whereas LL-37 causes no release of cytochrome C oxidase subunit IV of the inner mitochondrial membrane, suggesting that LL-37 affects mitochondrial membrane permeability in a specific manner. Next, we investigated release of AIF and cytochrome C from isolated mitochondria by measuring immunoreactivity by dot blot. The media of mitochondria treated with LL-37 (8 μM) for 2 h contained 50% more AIF and three times more cytochrome C than that of control mitochondria, showing that LL-37 promotes release of both AIF and cytochrome C. Moreover, in vesicles reflecting mitochondrial membrane lipid composition, LL-37 stimulates membrane permeabilization and release of tracer molecules. We conclude that LL-37 is rapidly internalized by MG63 cells and accumulates in mitochondria, and that the peptide triggers release of pro-apoptotic AIF and directly affects mitochondrial membrane structural properties. |
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Keywords: | Apoptosis Cathelicidin Innate immunity Mitochondria Mitochondria model membranes |
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