Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Hq, Xu; Sun, Yan; Zhang, Yun; Wang, Wei; Dan, Juhua; Yao, Jianting; Chen, Haibo; Tian, Fang; Sun, Xin; Guo, Shuyuan; Tian, Zhen; Tian, Ye

doi:10.1159/000366383

Cited by 28 publications

(33 citation statements)

References 49 publications

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“…photodynamic cell killing in a manner that does not agree with previous investigations [7,16,65,66,68,69]. Additional data (Fig.…”

Section: Discussioncontrasting

confidence: 58%

“…Compared to doxorubicin and vincristine resistant lines, parent LBR cells exhibited the lowest level of mitochondrial dysfunction posttreatment, despite generating the highest level of ROS. In contrast, the efficacy of PpIX-dependent photodynamic treatments has been shown to correlate with photo-generated ROS, oxidative damage and cell death when the cells concerned are phenotypically similar [68,69]. Under hyperoxia, cells expressed significantly higher levels of genes coding for proteins linked to maintaining cellular redox homeostasis, including several key antioxidants and the oxidative stress-activated transcription factor Nrf2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

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In vivo, mammalian cells reside in an environment of 0.5-10% O 2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O 2 ) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways.

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“…photodynamic cell killing in a manner that does not agree with previous investigations [7,16,65,66,68,69]. Additional data (Fig.…”

Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…These suppressors retained the intense cellular fluorescence arising from PPIX accumulation, indicating that the mode of suppression was not the elimination of PPIX that could generate harmful endogenous reactive oxygen species (Fig. 2B) (13). Three suppressor strains (S5, S19, and S23) were grown for analyses of CcO activity in purified mitochondria.…”

Section: Resultsmentioning

confidence: 99%

The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria

Kim

Jeong

Parnell

et al. 2016

Journal of Biological Chemistry

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The cellular transport of the cofactor heme and its biosynthetic intermediates such as protoporphyrin IX is a complex and highly coordinated process. To investigate the molecular details of this trafficking pathway, we created a synthetic lesion in the heme biosynthetic pathway by deleting the gene HEM15 encoding the enzyme ferrochelatase in S. cerevisiae and performed a genetic suppressor screen. Cells lacking Hem15 are respiratory-defective because of an inefficient heme delivery to the mitochondria. Thus, the biogenesis of mitochondrial cytochromes is negatively affected. The suppressor screen resulted in the isolation of respiratory-competent colonies containing two distinct missense mutations in Nce102, a protein that localizes to plasma membrane invaginations designated as eisosomes. The presence of the Nce102 mutant alleles enabled formation of the mitochondrial respiratory complexes and respiratory growth in hem15⌬ cells cultured in supplemental hemin. Respiratory function in hem15⌬ cells can also be restored by the presence of a heterologous plasma membrane heme permease (HRG-4), but the mode of suppression mediated by the Nce102 mutant is more efficient. Attenuation of the endocytic pathway through deletion of the gene END3 impaired the Nce102-mediated rescue, suggesting that the Nce102 mutants lead to suppression through the yeast endocytic pathway.Heme is an essential cofactor in eukaryotes and bacteria and functions in a myriad of pathways including oxygen transport, nitric oxide and carbon monoxide sensing, oxygenase reactions, and electron transport reactions (1-3). The heme biosynthetic pathway in eukaryotes, including the yeast Saccharomyces cerevisiae, is a complex process involving eight enzymes (see Fig. 1A) (4). The process starts in the mitochondrial matrix with the condensation of glycine with succinyl-CoA to produce ∂-aminolevulinic acid (ALA) 3 by the enzyme 5-aminolevulinate synthase (Hem1 is the yeast designation) (2, 4). ALA is translocated across the mitochondrial membranes to the cytosol, where the next four enzymes in the pathway convert two ALA molecules to form the intermediate pyrrole porphobilinogen and subsequent formation of coproporphyrinogen III, which is transported back into the mitochondria for conversion to protoporphyrin IX (PPIX). Ferrous iron is inserted into PPIX by ferrochelatase (Hem15), tethered to the inner membrane and facing the matrix, to form the heme cofactor. A defect in any of heme biosynthetic enzymes leads to one of the porphyric disorders in humans, each with a unique phenotype resulting from a buildup of toxic intermediates (3).The mechanism of heme transport between cellular compartments remains poorly understood (4). Nevertheless, significant inroads have been recently made utilizing the heme auxotroph Caenorhabditis elegans, resulting in the identification of heme and porphyrin transporters, including the HRG-1-related heme transporters (4, 5). These transporters have mammalian homologs with similar function and specificity. Additionally, the fel...

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“…2) result from Pb-induced MPTP opening. Moreover, mitochondrial injury can cause ROS production, while increased formation of ROS can induce the MPTP opening (Agudo-López et al 2011;Xu et al 2014). To further investigate the effect of MPTP opening on apoptosis in Pb-exposed rPT cells, translocation event of cyt-c from mitochondria to the cytosol was determined by western blot analysis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

et al. 2015

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Previous studies have already demonstrated that mitochondria play a key role in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells. To further clarify the underlying mechanism of Pb-induced mitochondrial apoptosis, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and its regulatory components in Pb-induced apoptosis in rPT cells. Mitochondrial permeability transition pore (MPTP) opening together with disruption of mitochondrial ultrastructure, translocation of cytochrome c from mitochondria to cytoplasm and subsequent caspase-3 activation were observed in this study, suggesting that MPT is involved in Pb-induced apoptosis in rPT cells. Simultaneously, Pb-induced caspase-3 activation and apoptosis can be significantly inhibited by three MPTP inhibitors (CsA, DIDS, BA), which target different regulatory components of MPTP (Cyp-D, VDAC, ANT), respectively, demonstrating that Cyp-D, VDAC and ANT participate in MPTP regulation during lead exposure. Moreover, decreased ATP levels and increased ADP/ATP ratio induced by lead treatment can be significantly reversed by BA, indicating that Pb-mediated ANT dysfunction resulted in ATP depletion. In addition, up-regulation of VDAC-1, ANT-1 together with down-regulation of Cyp-D, VDAC-2 and ANT-2 at both the levels of transcription and translation were revealed in rPT cells under lead exposure conditions. In conclusion, Pb-mediated mitochondrial apoptosis in rPT cells is dependent on MPTP opening. Different expression levels in each isoform of three regulatory components contribute to alteration in their functions, which may promote the MPTP opening.

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Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Cited by 28 publications

References 49 publications

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

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