Neurotoxic nitric oxide rapidly depolarizes and permeabilizes mitochondria by dynamically opening the mitochondrial transition pore⋆

Kindler, Dean D.; Thiffault, Christine; Solenski, Nina J.; Dennis, Jameel; Kostecki, Vanessa; Jenkins, Russell W.; Keeney, Paula M.; Bennett, James P.

doi:10.1016/s1044-7431(03)00074-5

Cited by 31 publications

(18 citation statements)

References 60 publications

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“…32 To assess the relative importance of mitochondrial stress in response to DHA, we performed experiments employing CsA, an inhibitor of the mitochondrial transition pore. 33,34 CsA inhibited DHA-induced mitochondrial depolarization and subsequent neuroblastoma cell death (Figs. 3b and 3c).…”

Section: Discussionmentioning

confidence: 93%

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Lindskog

Gleissman

Ponthan

et al. 2006

Intl Journal of Cancer

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Docosahexaenoic acid (DHA) is an x-3 polyunsaturated fatty acid vital for the developing nervous system and significantly decreased in neuroblastoma cells compared to nontransformed nervous tissue. We investigated whether supplementation of DHA affects the susceptibility of neuroblastoma cells to oxidative stress generated endogenously and in response to cytotoxic therapy. DHA, but not the monounsaturated oleic acid (OA), induced dose-and timedependent neuroblastoma cell death. DHA supplementation was associated with depolarization of the mitochondrial membrane potential, production of reactive oxygen species (ROS) and accumulation of DNA in sub-G1 phase of the cell cycle. The antioxidant, vitamin E, inhibited mitochondrial depolarization and subsequent cell death induced by DHA, whereas, the mitochondrial pore inhibitor, cyclosporin A, partly inhibited DHA-induced neuroblastoma cell death. Depletion of glutathione by L-buthioninesulfoximine significantly enhanced the cytotoxic effects of DHA. Nontransformed fibroblasts were not substantially affected by DHA. DHA, but not OA, significantly enhanced the cytotoxicity of cisplatin, doxorubicin and irinotecan both in chemosensitive and in multidrug-resistant neuroblastoma cells. DHA potently sensitized neuroblastoma cells to a clinically relevant concentration (1 lM) of arsenic trioxide (As 2 O 3 ) and enhanced the effect of the nonsteroidal antiinflammatory drug (NSAID), diclofenac. These findings provide experimental evidence that the x-3 fatty acid, DHA, is cytotoxic to drug-resistant neuroblastoma. The potent action of DHA with arsenic trioxide, NSAID and chemotherapeutic agents suggests clinical testing of this therapeutic concept in children with neuroblastoma. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 93%

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Lindskog

Gleissman

Ponthan

et al. 2006

Intl Journal of Cancer

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“…If the pore closes, DY should be restored, Ca 2+ taken up and ATP synthesis should resume. This may be what underlies the phenomena of flickering, i.e., transient depolarization and Ca 2+ loss followed by restoration of DY and, presumably, internal Ca 2+ [26,28,[55][56][57]. As we will see, this may be an important distinction between iMPT and oMPT, since uptake of cytochrome c and AIF may not be possible even if oMPT is reversed.…”

Section: Reversibility Of Imptmentioning

confidence: 87%

Intersection between Mitochondrial Permeability Pores and Mitochondrial Fusion/Fission

Gazaryan

Brown

2007

Neurochem Res

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The goal of this review is to highlight recent developments in the field of mitochondrial membrane processes, which provide new insights into the relation between mitochondrial fission/fusion events and the mitochondrial permeability transition (MPT). First, we distinguish between pore opening events at the inner and outer mitochondrial membranes. Inner membrane pore opening, or iMPT, leads to membrane depolarization, release of low molecular weight compounds, cristae reorganization and matrix swelling. Outer membrane pore opening, or oMPT, allows partial release of apoptotic proteins, while complete release requires additional remodeling of inner membrane cristae. Second, we summarize recent data that supports a similar temporal and physical separation between inner and outer mitochondrial membrane fusion events. Finally, we focus on cristae remodeling, which may be the intersection between oMPT and iMPT events. Interestingly, components of fusion machinery, such as mitofusin 2 and OPA1, appear to play a role in cristae remodeling as well.

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“…The concentrations of NO donors used were determined based on dose-response experiments and were in the range of those used by others (Badorff et al, 2000;Chen et al, 2001;Kim et al, 2000;Reynaert et al, 2004). However, in cell cultures, the concentration of NO to which the cells are exposed is much smaller than that of the NO donor added to the culture and is likely to be even smaller in the cytoplasm when NO reaches its intracellular targets (Beltran et al, 2000;Kindler et al, 2003).…”

Section: Nitric Oxide Donorsmentioning

confidence: 99%

Nitric Oxide Inhibits Caspase Activation and Apoptotic Morphology but Does Not Rescue Neuronal Death

Zhou

Qian

Iadecola

2005

J Cereb Blood Flow Metab

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Nitric oxide (NO) has been shown to inhibit apoptotic cell death by S-nitrosylation of the catalyticsite cysteine residue of caspases. However, it is not clear whether in neurons NO-mediated caspase inactivation leads to improved cell survival. To address this issue, we studied the effect of NO donors on caspase activity and cell survival in cortical neuronal culture treated with the apoptosis inducer staurosporine (STS) and camptothecin. In parallel, cell viability was assessed by the MTS assay and MAP2 staining. We found that NO donors ((7)-S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, and NONOates) dose-dependently inhibited caspase-3 and -9 activity induced by STS and camptothecin. The reduction in caspase-3 activity was, in large part, because of the blockage of the proteolytic conversion of pro-caspase-3 to active caspase-3. NO donors also inhibited the appearance of the classical apoptotic nuclear morphology. However, inhibition of both caspase activity and apoptotic morphology was not associated with enhancement of cell viability. Thus, inhibition of caspase and apoptotic morphology by NO donors does not improve neuronal survival. The data suggest that inhibition of caspase by NO unmasks a caspase-independent form of cell death. A better understanding of this form of cell death may provide new strategies for neuroprotection in neuropathologies, such as ischemic brain injury, associated with apoptosis.

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Neurotoxic nitric oxide rapidly depolarizes and permeabilizes mitochondria by dynamically opening the mitochondrial transition pore⋆

Cited by 31 publications

References 60 publications

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Intersection between Mitochondrial Permeability Pores and Mitochondrial Fusion/Fission

Nitric Oxide Inhibits Caspase Activation and Apoptotic Morphology but Does Not Rescue Neuronal Death

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