Microcin J25 triggers cytochrome c release through irreversible damage of mitochondrial proteins and lipids

Niklison-Chirou, Maria Victoria; Dupuy, Fernando Gabriel; Pena, Liliana B.; Gallego, Susana M.; Barreiro-Arcos, Maria Laura; Ávila, César L.; Torres-Bugeau, Clarisa M.; Arcuri, Beatriz Eugenia F. de; Bellomio, Augusto; Minahk, Carlos; Morero, Roberto D.

doi:10.1016/j.biocel.2009.11.002

Cited by 19 publications

(9 citation statements)

References 48 publications

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“…Mitochondria are protagonists of cell death and potential targets of AMPs. 22 Thus, alterations in mitochondrial transmembrane potential (Ψ mit ) and morphology induced by Gm were monitored. Cell staining with MitoTracker Green showed mitochondrial disruption after 20 μM Gm treatment ( Figure 4A).…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload

Paredes‐Gamero¹,

Casaes-Rodrigues²,

Moura³

et al. 2012

Mol. Pharmaceutics

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In recent years, the antitumoral activity of antimicrobial peptides (AMPs) has been the goal of many research studies. Among AMPs, gomesin (Gm) displays antitumor activity by unknown mechanisms. Herein, we studied the cytotoxicity of Gm in the Chinese hamster ovary (CHO) cell line. Furthermore, we investigated the temporal ordering of organelle changes and the dynamics of Ca 2+ signaling during Gm-induced cell death. The results indicated that Gm binds to the plasma membrane and rapidly translocates into the cytoplasm. Moreover, 20 μM Gm increases the cytosolic Ca 2+ and induces membrane permeabilization after 30 min of treatment. Direct Ca 2+ measurements in CHO cells transfected with the genetically encoded D1-cameleon to the endoplasmic reticulum (ER) revealed that Gm induces ER Ca 2+ depletion, which in turn resulted in oscillatory mitochondrial Ca 2+ signal, as measured in cells expressing the genetically encoded probe to the mitochondrial matrix mit Pericam. This leads to mitochondria disruption, loss of mitochondrial membrane potential and increased reactive oxygen species prior to membrane permeabilization. Gm-induced membrane permeabilization by a Ca 2+ -dependent pathway involving Gm translocation into the cell, ER Ca 2+ depletion and disruption, mitochondrial Ca 2+ overload and oxidative stress.

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Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload

Paredes‐Gamero¹,

Casaes-Rodrigues²,

Moura³

et al. 2012

Mol. Pharmaceutics

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“…The biological activity of microcin J25 ranges from the antimicrobial action against Gram negative bacteria [6,8,16], the anti-mitochondrial effects [44,45] and apoptosis of COS-7 cells [45]. Also, the minimal inhibitory concentration necessary for bactericidal activity varies from 10 nM in sensitive Salmonella strains [16,46] to the micromolar range in E. coli laboratory strains [6,8,15], clinical isolates and also Salmonella strains [46].…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial peptide microcin J25 stabilizes the gel phase of bacterial model membranes

Rintoul

Morero

Dupuy

2015

Colloids and Surfaces B: Biointerfaces

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“…It inhibits bacterial transcription by blocking the nucleotide uptake channel of bacterial RNA polymerase [100,101], and has also been shown to increase superoxide production in bacteria. Microcin J25 also acts as a mitochondrial uncoupler and stimulates cytochrome C release from isolated, intact mammalian mitochondria [102,103], although it has minimal apoptotic activity in human cells in culture. In this remarkable structure, the "tail" portion of microcin J25 is threaded through and sterically trapped within the ring, forming a lasso topology [104,105].…”

Section: Cyclic Peptides Of Mixed Polaritymentioning

confidence: 99%

Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective

Bockus¹,

McEwen²,

Lokey³

2013

CTMC

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The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occurring cyclic peptides, in particular, exhibit a wide variety of unusual and potent biological activities. Many of these compounds penetrate cells by passive diffusion and some, like the clinically important drug cyclosporine A, are orally bioavailable. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of "drug-likeness". Because of their size and complexity, cyclic peptides occupy a chemical "middle space" in drug discovery that may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. However, the relationship between structure and pharmacokinetic (PK) behavior, especially cell permeability and metabolic clearance, in cyclic peptides has not been studied systematically, and the generality of cyclic peptides as orally bioavailable scaffolds remains an open question. This review focuses on cyclic peptide natural products from a "structure-PK" perspective, outlining what we know and don't know about their properties in the hope of uncovering trends that might be useful in the design of novel "rule-breaking" molecules.

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Microcin J25 triggers cytochrome c release through irreversible damage of mitochondrial proteins and lipids

Cited by 19 publications

References 48 publications

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload

The antimicrobial peptide microcin J25 stabilizes the gel phase of bacterial model membranes

Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective

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Microcin J25 triggers cytochrome c release through irreversible damage of mitochondrial proteins and lipids

Cited by 19 publications

References 48 publications

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca2+ Overload

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca2+ Overload

The antimicrobial peptide microcin J25 stabilizes the gel phase of bacterial model membranes

Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective

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Product

Resources

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Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload

Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca²⁺ Overload