Microcin J25 induces the opening of the mitochondrial transition pore and cytochrome <i>c</i> release through superoxide generation

Niklison-Chirou, Maria Victoria; Bellomio, Augusto; Dupuy, Fernando Gabriel; Arcuri, Beatriz F. de; Minahk, Carlos; Morero, Roberto D.

doi:10.1111/j.1742-4658.2008.06550.x

Cited by 25 publications

(10 citation statements)

References 41 publications

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“…All mice (4- and 25-months old) were maintained in the same housing with identical environmental conditions. Mitochondria were isolated as previous described 53 .…”

Section: Methodsmentioning

confidence: 99%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulation.

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“…All mice (4- and 25-months old) were maintained in the same housing with identical environmental conditions. Mitochondria were isolated as previous described 53 .…”

Section: Methodsmentioning

confidence: 99%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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“…These findings provide a starting point for the development of more potent inhibitors based on the respiratory chain target by strategic replacement of amino acids in the MccJ25 molecule or the development of an MccJ25 mutant with selective RNAP inhibition, free of the respiratory chain target action. The last possibility is important for possible clinical antibiotic applications because the pathogenic actions of MccJ25 on mammalian mitochondria under aerobic conditions would not be eliminated (Niklison Chirou et al , 2004, 2008).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine 9 is the key amino acid in microcin J25 superoxide overproduction

Chalon

Bellomio

Solbiati

et al. 2009

FEMS Microbiology Letters

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Escherichia coli microcin J25 (MccJ25) is a lasso-peptide antibiotic comprising 21 L-amino acid residues (G(1)-G-A-G-H(5)-V-P-E-Y-F(10)-V-G-I-G-T(15)-P-I-S-F-Y(20)-G). MccJ25 has two independent substrates: RNA-polymerase (RNAP) and the membrane respiratory chain. The latter is mediated by oxygen consumption inhibition together with an increase of superoxide production. In the present paper, the antibiotic MccJ25 was engineered by substituting Tyr(9) or Tyr(20) with phenylalanine. Both mutants were well transported into the cells and remained active on RNAP. Only the Y9F mutant lost the ability to overproduce superoxide and inhibit oxygen consumption. The last results confirm that the Tyr(9), and not Tyr(20), is involved in the MccJ25 action on the respiratory chain target.

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“…This leads to the suggestion that Capistruin-producing Burkholderia species either encode an immunity protein or feature some modification of the target. Capistruin and Microcin J25 biological activity is due to their ability to inhibit RNA polymerase (RNAP), although for Microcin J25, the over-production of reactive oxygen species (ROS) through a possible secondary target has also been suggested [37][38][39]. Microcin J25 and Capistruin share the RNAP secondary channel as their binding site.…”

Section: Capistruinmentioning

confidence: 99%

Do Global Regulators Hold the Key to Production of Bacterial Secondary Metabolites?

Thapa

Grove

2019

Antibiotics

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The emergence of multiple antibiotic resistant bacteria has pushed the available pool of antibiotics to the brink. Bacterial secondary metabolites have long been a valuable resource in the development of antibiotics, and the genus Burkholderia has recently emerged as a source of novel compounds with antibacterial, antifungal, and anti-cancer activities. Genome mining has contributed to the identification of biosynthetic gene clusters, which encode enzymes that are responsible for synthesis of such secondary metabolites. Unfortunately, these large gene clusters generally remain silent or cryptic under normal laboratory settings, which creates a hurdle in identification and isolation of these compounds. Various strategies, such as changes in growth conditions and antibiotic stress, have been applied to elicit the expression of these cryptic gene clusters. Although a number of compounds have been isolated from different Burkholderia species, the mechanisms by which the corresponding gene clusters are regulated remain poorly understood. This review summarizes the activity of well characterized secondary metabolites from Burkholderia species and the role of local regulators in their synthesis, and it highlights recent evidence for the role of global regulators in controlling production of secondary metabolites. We suggest that targeting global regulators holds great promise for the awakening of cryptic gene clusters and for developing better strategies for discovery of novel antibiotics.

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Microcin J25 induces the opening of the mitochondrial transition pore and cytochrome c release through superoxide generation

Cited by 25 publications

References 41 publications

FASN activity is important for the initial stages of the induction of senescence

FASN activity is important for the initial stages of the induction of senescence

Tyrosine 9 is the key amino acid in microcin J25 superoxide overproduction

Do Global Regulators Hold the Key to Production of Bacterial Secondary Metabolites?

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