TY - JOUR
T1 - Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress
AU - Barsukova, Anna G.
AU - Bourdette, Dennis
AU - Forte, Michael
PY - 2011/8
Y1 - 2011/8
N2 - A proposed mechanism of neuronal death associated with a variety of neurodegenerative diseases is the response of neurons to oxidative stress and consequent cytosolic Ca 2+ overload. One hypothesis is that cytosolic Ca 2+ overload leads to mitochondrial Ca 2+ 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 Ca 2+ have been implicated. However, the effects of oxidative stress on the interplay between cytosolic and mitochondrial Ca 2+ 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 Ca 2+, as well as ATP levels, during oxidative stress. Our data demonstrate that during acute oxidative stress mitochondria contribute to neuronal Ca 2+ overload by release of their Ca 2+ stores. This result contrasts with the prevailing view of mitochondria as a buffer of cytosolic Ca 2+ under stress conditions. In addition, we show that CyPD deficiency reverses the release of mitochondrial Ca 2+, leading to lower of cytosolic Ca 2+ 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.
AB - A proposed mechanism of neuronal death associated with a variety of neurodegenerative diseases is the response of neurons to oxidative stress and consequent cytosolic Ca 2+ overload. One hypothesis is that cytosolic Ca 2+ overload leads to mitochondrial Ca 2+ 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 Ca 2+ have been implicated. However, the effects of oxidative stress on the interplay between cytosolic and mitochondrial Ca 2+ 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 Ca 2+, as well as ATP levels, during oxidative stress. Our data demonstrate that during acute oxidative stress mitochondria contribute to neuronal Ca 2+ overload by release of their Ca 2+ stores. This result contrasts with the prevailing view of mitochondria as a buffer of cytosolic Ca 2+ under stress conditions. In addition, we show that CyPD deficiency reverses the release of mitochondrial Ca 2+, leading to lower of cytosolic Ca 2+ 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.
KW - Calcium homeostasis
KW - Cortical neurons
KW - Mitochondria
KW - Mutant mice
KW - Neuroprotection
KW - Permeability transition pore
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U2 - 10.1111/j.1460-9568.2011.07760.x
DO - 10.1111/j.1460-9568.2011.07760.x
M3 - Article
C2 - 21722208
AN - SCOPUS:79960943442
SN - 0953-816X
VL - 34
SP - 437
EP - 447
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 3
ER -