Inhibition of the Mitochondrial Permeability Transition by the Nonimmunosuppressive Cyclosporin Derivative NIM811

Waldmeier, P. C.; Feldtrauer, Jean-Jacques; Qian, Ting; Lemasters, John J.

doi:10.1124/mol.62.1.22

Cited by 263 publications

(181 citation statements)

References 36 publications

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“…However, protection by CsA was lost after 16 hours. NIM811 (2 mol/L), a non-immunosuppressive CsA analog, 26 similarly decreased acetaminophen-induced hepatocyte killing after 6 hours but did not protect after 16 hours (Fig. 1B).…”

Section: Resultsmentioning

confidence: 98%

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. After administration of 10 mmol/L acetaminophen, necrotic killing increased to more than 49% and 74%, respectively, after 6 and 16 hours. MPT inhibitors, cyclosporin A (CsA), and NIM811 temporarily decreased necrotic killing after 6 hours to 26%, but cytoprotection was lost after 16 hours. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization approximately 4.5 hours after acetaminophen administration. CsA delayed these changes, indicative of the MPT, to approximately 11 hours after acetaminophen administration. Apoptosis indicated by nuclear changes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase-3 activation also increased after acetaminophen administration. Fructose (20 mmol/L, an adenosine triphosphategenerating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis from 37% to 59% after 16 hours. In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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Section: Resultsmentioning

confidence: 98%

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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“…Both NIM811 and CsA prevent depolarization of the mitochondrial inner membrane and inhibit mPT induced by Ca 2+ overload in mitochondria isolated from rat hepatocytes. However, NIM811 protects against tumor necrosis factor-α-induced apoptosis, spanning a much wider concentration range compared to CsA [113]. The cytoprotective properties of NIM811 against apoptotic stimuli have also been reported in other cell types [113,114,121,122].…”

Section: Targeting the Mptp In Acute Scimentioning

confidence: 86%

“…However, NIM811 protects against tumor necrosis factor-α-induced apoptosis, spanning a much wider concentration range compared to CsA [113]. The cytoprotective properties of NIM811 against apoptotic stimuli have also been reported in other cell types [113,114,121,122]. Therefore, the unique properties of NIM811 allows for testing of a broader dose range relative to CsA.…”

Section: Targeting the Mptp In Acute Scimentioning

confidence: 97%

“…NIM811 (N-methyl-isoleucine-cyclosporin) is a cyclosporin analog that also binds to Cyp-D and blocks mPT at nanomolar concentrations in brain mitochondria [112][113][114]. NIM811 was originally developed to be a less toxic alternative to CsA, but the modifications made to the cyclosporin structure eliminated the immunosuppressive properties mediated by calcineurin inhibition.…”

Section: Targeting the Mptp In Acute Scimentioning

confidence: 99%

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Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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“…Moreover, there is accumulating evidence that cyclosporin A can induce apoptosis in certain cells [124][125][126][127]. In fact, the clinical use of CsA is still limited by its potential toxicity [128,129] and a specific inhibition of the PT-pore as observed with cypD [120,122] would be therapeutically of high interest. Hence, it is important to determine how overexpressed cypD induces or inhibits cell death.…”

Section: Overexpression Studies On Cypdmentioning

confidence: 99%

The permeability transition pore in cell death

2007

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The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. The role of the PT-pore in apoptosisThe permeability transitionThe permeability transition (PT) is a sudden and sustained increase of the permeability of the inner mitochondrial membrane for solutes smaller than 1.5 kD. This has catastrophic consequences for this organelle. The mitochondrial membrane potential m , which relies on the im-permeability of the inner membrane for protons, breaks down and with it the ability of the cell to synthesize ATP. The ensuing blockade of the respiratory chain leads to the generation of reactive oxygen intermediates (ROIs), most likely via the direct transfer of electrons to molecular oxygen. Also, the high concentration of solutes in the mitochondrial matrix generates an osmotic pressure, which drives the influx of water molecules and the expansion of the extensively folded inner membrane and eventually disrupts the outer membrane leading to the release of factors that execute the suicide programme of apoptosis. Thus, the self-destruction of mitochondria via the PT is followed by the demise of the cell as a whole. This process of mitochondrial destruction was first observed in vitro but was dismissed at the time as an artefact because, among other reasons, it was inconceivable why mitochondria should dispose of a process to dismantle themselves. This changed, however, when it was shown that the PT is mediated by a protein complex, the so-called permeability transition pore (PT-pore), and that various physiological and pharmacological reagents can act on this pore and modify the deadly response of mitochondria. Finally, the realisation that cells can mount an active suicide response that is mediated in large part by mitochondria placed the PT-pore firmly on the map of researchers. In particular, the use of cyclosporine A (CsA) that can inhibit the PT-pore subunit cyc...

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Inhibition of the Mitochondrial Permeability Transition by the Nonimmunosuppressive Cyclosporin Derivative NIM811

Cited by 263 publications

References 36 publications

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

The permeability transition pore in cell death

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