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Multi-parameter Measurement of the Permeability Transition Pore Opening in Isolated Mouse Heart Mitochondria
Published on: September 7, 2012
Nanomolar LL-37 induces permeability of a biomimetic mitochondrial membrane
Xin Jiang1, Chenguang Yang2,3, Jie Qiu1
1Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China. yuanbing@sslab.org.cn.
Abstract:
LL-37, the only human host cathelicidin peptide, is proposed to be able to induce host cell apoptosis through mitochondrial membrane permeabilization (MMP). Detailed pathways of the LL-37-triggered MMP are however still disputed. It is generally believed that cationic peptides permeate a membrane mostly in conditions of micromolar peptide concentrations and negatively charged membranes, which are not usually satisfied in the mitochondrial circumstance. Herein, using a variety of single-molecule techniques, we show that nanomolar LL-37 specifically induces permeability of a phosphoethanolamine (PE)-rich biomimetic mitochondrial membrane in a protein-independent manner. The insertion dynamics of single LL-37 molecules exhibit different metastable states in bilayers composed of different lipids. Moreover, the PE lipids significantly facilitate adsorption and accumulation of LL-37 on the PE-rich bilayer, and produce deeper insertion of peptide oligomers, especially tetramers, into the bilayer. This work offers an alternative pathway of the LL-37-triggered MMP and apoptosis.
Insights
The human antimicrobial peptide LL-37 (cathelicidin) can induce apoptosis by permeabilizing mitochondrial membranes. This study reveals LL-37, at nanomolar concentrations, specifically targets phosphoethanolamine-rich membranes, offering a new apoptosis pathway.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biophysics
Background:
- LL-37, the sole human cathelicidin peptide, is implicated in inducing host cell apoptosis via mitochondrial membrane permeabilization (MMP).
- The precise mechanisms of LL-37-induced MMP remain unclear, particularly given that mitochondrial membranes typically lack the high negative charge and micromolar peptide concentrations often considered necessary for cationic peptide permeation.
Purpose of the Study:
- To investigate the specific conditions and mechanisms by which LL-37 induces mitochondrial membrane permeabilization (MMP).
- To explore the role of lipid composition in LL-37's interaction with biomimetic mitochondrial membranes.
- To elucidate an alternative pathway for LL-37-triggered apoptosis.
Main Methods:
- Utilized a suite of single-molecule techniques to observe LL-37 behavior.
- Employed biomimetic mitochondrial membranes enriched with phosphoethanolamine (PE) lipids.
- Analyzed LL-37 insertion dynamics and oligomerization within lipid bilayers.
Main Results:
- Demonstrated that nanomolar concentrations of LL-37 specifically induce permeability in PE-rich biomimetic mitochondrial membranes, independent of other proteins.
- Observed distinct metastable states for single LL-37 molecule insertion depending on lipid composition.
- Found that PE lipids significantly enhance LL-37 adsorption, accumulation, and deeper insertion of peptide oligomers (especially tetramers) into the membrane.
Conclusions:
- Proposed a novel pathway for LL-37-induced mitochondrial membrane permeabilization (MMP) and apoptosis.
- Highlighted the critical role of phosphoethanolamine (PE) lipids in facilitating LL-37 interaction with mitochondrial membranes at physiologically relevant nanomolar concentrations.
- Provided new insights into the biophysical mechanisms underlying antimicrobial peptide-induced cell death.
