کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6017223 | 1580162 | 2015 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Regular ArticleTransient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells Regular ArticleTransient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells](/preview/png/6017223.png)
- Glutamate elevates cytosolic Ca2Â + in NSC34D cells mainly through Ca2Â + influx.
- Glutamate-induced mitochondrial Ca2Â + uptake through MCU.
- Mitochondrial Ca2Â + triggers transient permeability transition pore (tMPT) opening.
- tMPT is coupled to bursting superoxide production in NSC34D cells.
- Prolonged activation of tMPT leads to cell death in NSC34D motor neuron-like cells.
Excitotoxicity plays a critical role in neurodegenerative disease. Cytosolic calcium overload and mitochondrial dysfunction are among the major mediators of high level glutamate-induced neuron death. Here, we show that the transient opening of mitochondrial permeability transition pore (tMPT) bridges cytosolic calcium signaling and mitochondrial dysfunction and mediates glutamate-induced neuron death. Incubation of the differentiated motor neuron-like NSC34D cells with glutamate (1 mM) acutely induces cytosolic calcium transient (30% increase). Glutamate also stimulates tMPT opening, as reflected by a 2-fold increase in the frequency of superoxide flash, a bursting superoxide production event in individual mitochondria coupled to tMPT opening. The glutamate-induced tMPT opening is attenuated by suppressing cytosolic calcium influx and abolished by inhibiting mitochondrial calcium uniporter (MCU) with Ru360 (100 μM) or MCU shRNA. Further, increased cytosolic calcium is sufficient to induce tMPT in a mitochondrial calcium dependent manner. Finally, chronic glutamate incubation (24 h) persistently elevates the probability of tMPT opening, promotes oxidative stress and induces neuron death. Attenuating tMPT activity or inhibiting MCU protects NSC34D cells from glutamate-induced cell death. These results indicate that high level glutamate-induced neuron toxicity is mediated by tMPT, which connects increased cytosolic calcium signal to mitochondrial dysfunction.
Journal: Experimental Neurology - Volume 271, September 2015, Pages 122-130