Distinct Alterations in Mitochondrial Mass and Function Characterize Different Models of Apoptosis

Camilleri-Broët, Sophie; Vanderwerff, Holly; Caldwell, Elizabeth; Hockenbery, David M.

doi:10.1006/excr.1997.3899

Cited by 61 publications

(36 citation statements)

References 40 publications

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“…5C). Global mitochondrial swelling of this extent has been considered a trigger for cell death and a terminal event in several cell types (24,25,40,41), but we found that 1-3 h after brief (2 min) activation of P2X 7 receptors, the majority of mitochondria were no longer swollen and had recovered their original filamentous morphology (Fig. 5C).…”

Section: Rapid and Reversible Mitochondrial Changes: Depolarization Amentioning

confidence: 80%

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Mackenzie

Young

Adinolfi

et al. 2005

Journal of Biological Chemistry

155

160

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P2X 7 receptors are ATP-gated ion channels primarily expressed on antigen-presenting immune cells where they play a role in the acute inflammatory response. These ion channels couple not only to influx of cations, including calcium, but also to rapid alterations in cell morphology (membrane blebbing, phosphatidylserine exposure, microvesicle shedding). These features resemble the extranuclear events associated with end stages of apoptosis but cell death does not occur if receptor activation is brief. Here we delineate two signaling pathways underlying these apoptotic-like processes. Loss of membrane asymmetry occurs within seconds, which directly triggers cytoskeletal disruption and zeiotic membrane blebbing; this is readily reversible and requires both calcium influx through P2X 7 channels and mitochondrial calcium increase but is not associated with cytochrome c release. A slower, calcium-independent, ROCK-1-dependent cascade that does not involve rapid loss of membrane asymmetry but is associated with cytochrome c release is secondarily activated. The ROCK-1 pathway appears largely responsible for cell death, which occurs after prolonged stimulation of P2X 7 receptors. We suggest that the former mechanism underlies the reversible pseudoapoptotic events induced by brief activation of P2X 7 receptors.

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Section: Rapid and Reversible Mitochondrial Changes: Depolarization Amentioning

confidence: 80%

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Mackenzie

Young

Adinolfi

et al. 2005

Journal of Biological Chemistry

155

160

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show abstract

“…However, we still observed a significant inhibition of TCR-dependent events, including mitochondrial mass, even at 50 mM, whereas no significant increase in apoptosis was evident. Early apoptosis exerts little effect upon mitochondrial content/mass with no change of MTG expression, whereas membrane potential is reduced (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Iken

Liu²,

Liu³

et al. 2012

Am J Respir Cell Mol Biol

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The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan into kynurenine metabolites that suppress effector T-cell function. In this study, we investigated IDO and its metabolite, 3-hydroxyanthranilic acid (3HAA), in regulating lung allograft rejection, using a murine orthotopic lung transplant model with a major mismatch (BALB/c donor and C57BL6 recipient). IDO was overexpressed in murine donor lungs, using an established nonviral (polyethylenimine carrier)-based gene transfer approach, whereas 3HAA was delivered daily via intraperitoneal injection. Increased IDO expression or its metabolite, 3HAA, resulted in a remarkable therapeutic effect with near normal lung function and little acute rejection, approximately A1, compared with A3 in untreated allografts (grading based on International Society for Heart and Lung Transplantation guidelines). We found that a high IDO environment for 7 days in lung allografts resulted in impaired T-cell activation, the production of multiple effector cytokines (IL-2, IL-4, IL-5, IL-6, IFN-g, TNF-a, IL-12, and IL-13), and the generation of effector memory T cells (CD62L lo CD44 hi phenotype). In isolated murine splenocytes, we observed that IDO/3HAA impaired T-cell receptor (TCR)-mediated T-cell activation, and more importantly, a decrease of intracellular calcium, phospholipase C-g1 phosphorylation, and mitochondrial mass was evident. This work further illustrates the potential role of a high IDO environment in lung transplantation, and that the high IDO environment directly impairs TCR activation via the disruption of calcium signaling.Keywords: 3-hydroxyanthranilic acid; lung allograft rejection; nonviral gene transfer Lung transplantation is a well-accepted therapy for patients with endstage lung disease that is not amenable to other medical or surgical therapies. Unfortunately, acute cellular rejection (ACR) is a common complication in lung transplant recipients, despite current immunosuppressive protocols (1). ACR is problematic because it is the major risk factor for the development of bronchiolitis obliterans, believed to be the manifestation of chronic rejection, and ACR necessitates the augmentation of immune suppression, leading to increased mortality and morbidity (2). The difficulties with bronchiolitis obliterans and frequent rejections result in relatively poor outcomes for lung transplantation, compared with the transplants of other solid organs (1).Indoleamine 2,3-dioxygenase (IDO) is an inducible enzyme that promotes tryptophan (Trp) catabolism, and has been shown to involve immune modulating activities (3). By increasing IDO activity, an environment is generated with reduced Trp and an increase in its metabolic products, resulting in the modification of dendritic cell function and the inhibition of T-cell activation and proliferation. Consistent with this concept, our laboratory previously showed that an increase in IDO within rat lung allografts resulted in less rejection, transplant-mediated injury, and impaired CD8 cell function (4-6).In the pre...

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“…After two washes with extraction buffer, anti-rabbit FITClabeled IgG (Sigma) was added and the mitochondria was incubated for 15 min on ice, washed again, and immediately analyzed by flow cytometry on a FACScan flow cytometer by using CELLQUEST acquisition and analysis software (Becton Dickinson). Mitochondrial mass (28) or ⌬⌿ m (26) were analyzed in intact cells with nonyl acridine orange (NAO) and rhodamine 123 (rh123) (Molecular Probes) as follows. For NAO staining, treated cells were washed twice in ice-cold PBS, fixed with 80% ethanol at Ϫ20°C overnight, then incubated with 10 M NAO for 15 min at room temperature and analyzed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Neisseria meningitidisporin PorB interacts with mitochondria and protects cells from apoptosis

Massi

Ho²,

Wetzler³

2000

Proc. Natl. Acad. Sci. U.S.A.

155

141

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Neisserial porins are strong immune adjuvants and B cell activators. The effect of neisserial porin PorB on activation-induced cell death was investigated, as a potential additional mechanism of the porin's immunopotentiating ability. Neisserial porins interact with target cells to localize intracellularly in the mitochondrial compartment without negatively affecting cellular survival. Pretreatment with Neisseria meningitidis PorB porin decreased or abrogated the mitochondrial damage induced by apoptotic stimuli. In addition, end stage determinants of apoptosis, including DNA breakdown, were diminished by PorB. Immunoprecipitation experiments revealed that PorB interacts with the mitochondrial porin VDAC (voltage-dependent anion channel). The mechanism of the antiapoptotic effect of neisserial porins could be explained by the proteinprotein interaction of PorB with VDAC, similar to the interaction of VDAC with antiapoptotic Bcl-2 proteins, resulting in an enhancement of cell survival and continued activation of B cells.cell death ͉ voltage-dependent anion channel (VDAC) ͉ membrane potential ͉ staurosporine N eisserial porins, meningococcal PorA (class 1 protein) or PorB (class 2 or 3 proteins) or gonococcal protein IA or protein IB, are the major outer membrane protein of the pathogenic Neisseriaceae (1). They act as pores and are essential for organism survival. Interestingly, we and other investigators have demonstrated that these proteins act as immune stimulants and adjuvants (2-4) and can induce a T cell-dependent immune response against cell independent antigens (5-8). The mechanism of the adjuvant activity of neisserial porins recently has been elucidated, correlating with the porins' ability to upregulate the expression of the costimulatory molecule, B7-2, on the surface of B cells (and possibly other antigen-presenting cells) (6,8). Moreover, neisserial porins are potent B cell mitogens and act synergistically with CD40 or B cell receptor ligation to induce B cell proliferation and Ig secretion (6, 9). † Stimulation of immune cells normally increases their susceptibility to activation-induced cell death or apoptosis (10). Neisserial porins activate B cells as a probable mechanism of their adjuvant activity. If the porins also increased the susceptibility of B cells to apoptosis, this obviously would attenuate their immunopotentiating ability. Therefore, we investigated the ability of neisserial porins to affect the susceptibility of various cell types to apoptosis to determine whether another mechanism of the porins' adjuvant activity is to prevent B cell (and͞or antigen-presenting cell) apoptosis.If neisserial porins decreased the susceptibility of immune cells to apoptosis, what could be the possible mechanisms? It has been demonstrated that mitochondria and mitochondrial factors are intimately connected to the process of apoptosis (11). The mechanism of action of certain apoptotic stimuli, such as Fas receptor ligation or drugs like staurosporine (STS), involves opening of the mitochondrial permeabil...

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Distinct Alterations in Mitochondrial Mass and Function Characterize Different Models of Apoptosis

Cited by 61 publications

References 40 publications

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Neisseria meningitidisporin PorB interacts with mitochondria and protects cells from apoptosis

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