科研之友
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摘要
A proposed mechanism of neuronal death associated with a variety of neurodegenerative diseases is the response of neurons to oxidative stress and consequent cytosolic Ca2+ overload. One hypothesis is that cytosolic Ca2+ overload leads to mitochondrial Ca2+ overload and prolonged opening of the permeability transition pore (PTP), resulting in mitochondrial dysfunction. Elimination of cyclophilin D (CyPD), a key regulator of the PTP, results in neuroprotection in a number of murine models of neurodegeneration in which oxidative stress and high cytosolic Ca2+ have been implicated. However, the effects of oxidative stress on the interplay between cytosolic and mitochondrial Ca2+ in adult neurons and the role of the CyPD-dependent PTP in these dynamic processes have not been examined. Here, using primary cultured cerebral cortical neurons from adult wild-type (WT) mice and mice missing cyclophilin D (CyPD-KO), we directly assess cytosolic and mitochondrial Ca2+, as well as ATP levels, during oxidative stress. Our data demonstrate that during acute oxidative stress mitochondria contribute to neuronal Ca2+ overload by release of their Ca2+ stores. This result contrasts with the prevailing view of mitochondria as a buffer of cytosolic Ca2+ under stress conditions. In addition, we show that CyPD deficiency reverses the release of mitochondrial Ca2+, leading to lower of cytosolic Ca2+ levels, attenuation of the decrease in cytosolic and mitochondrial ATP, and a significantly higher viability of adult CyPD-knockout neurons following exposure of neurons oxidative stress. The study offers a first insight into the mechanism underlying CyPD-dependent neuroprotection during oxidative stress.
- 出版日期2011-8
