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The antimicrobial peptide LL-37 triggers release of apoptosis-inducing factor and shows direct effects on mitochondria

Bankell, Elisabeth LU ; Liu, Xiaoyan LU ; Lundqvist, Martin LU ; Svensson, Daniel LU ; Swärd, Karl LU ; Sparr, Emma LU and Nilsson, Bengt Olof LU orcid (2022) In Biochemistry and Biophysics Reports 29.
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... (More)

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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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apoptosis, Cathelicidin, Innate immunity, Mitochondria, Mitochondria model membranes
in
Biochemistry and Biophysics Reports
volume
29
article number
101192
publisher
Elsevier
external identifiers
  • pmid:34988298
  • scopus:85121378636
ISSN
2405-5808
DOI
10.1016/j.bbrep.2021.101192
language
English
LU publication?
yes
id
e77538b3-ff03-4fa4-a58b-2411139cbbe8
date added to LUP
2022-01-25 14:25:50
date last changed
2024-03-23 17:33:40
@article{e77538b3-ff03-4fa4-a58b-2411139cbbe8,
  abstract     = {{<p>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.</p>}},
  author       = {{Bankell, Elisabeth and Liu, Xiaoyan and Lundqvist, Martin and Svensson, Daniel and Swärd, Karl and Sparr, Emma and Nilsson, Bengt Olof}},
  issn         = {{2405-5808}},
  keywords     = {{Apoptosis; Cathelicidin; Innate immunity; Mitochondria; Mitochondria model membranes}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Biochemistry and Biophysics Reports}},
  title        = {{The antimicrobial peptide LL-37 triggers release of apoptosis-inducing factor and shows direct effects on mitochondria}},
  url          = {{http://dx.doi.org/10.1016/j.bbrep.2021.101192}},
  doi          = {{10.1016/j.bbrep.2021.101192}},
  volume       = {{29}},
  year         = {{2022}},
}