Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress

Anna G. Barsukova, Dennis Bourdette, Michael Forte

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)437-447
Number of pages11
JournalEuropean Journal of Neuroscience
Volume34
Issue number3
DOIs
StatePublished - Aug 2011

Keywords

  • Calcium homeostasis
  • Cortical neurons
  • Mitochondria
  • Mutant mice
  • Neuroprotection
  • Permeability transition pore

ASJC Scopus subject areas

  • Neuroscience(all)

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