title: Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress.
abstract: 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.
authors: Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors: Anna G
authors: AG
authors: Barsukova
authors: Dennis
authors: D
authors: Bourdette
authors: Michael
authors: M
authors: Forte
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D000255:Adenosine Triphosphate; D021983:Cyclophilins; D002118:Calcium