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Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress
Author(s) -
Barsukova Anna G.,
Bourdette Dennis,
Forte Michael
Publication year - 2011
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2011.07760.x
Subject(s) - neurodegeneration , oxidative stress , cytosol , mitochondrion , mitochondrial permeability transition pore , neuroprotection , microbiology and biotechnology , oxidative phosphorylation , biology , chemistry , biochemistry , neuroscience , programmed cell death , medicine , apoptosis , disease , enzyme
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.