Inactivation of aconitase during the apoptosis of mouse cerebellar granule neurons induced by a deprivation of membrane depolarization

Akiko Tabuchi, Kouhei Funaji, Jun Nakatsubo, Mamoru Fukuchi, Tomofusa Tsuchiya, Masaaki Tsuda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

During the excitotoxic neuronal cell death which accompanies an overflow of extracellular Ca2+ into neurons, aconitase, an oxidative stress-sensitive enzyme of the tricarboxylic acid (TCA)-cycle in mitochondria, is inactivated due to the generation of oxidative stress (Patel et al. [1996] Neuron 16:345-355). In this study, we investigated whether aconitase could be inactivated during the apoptosis of mouse cerebellar granule cells (CGCs), which was caused by a deprivation of membrane depolarization followed by a stoppage of Ca2+ influx into CGCs. Upon lowering the potassium (K+) concentration in medium from 25 to 5 mM (low K+), aconitase was inactivated in accordance with the decrease in methylthiazoletetrazolium (MTT)-reducing activity although its mRNA expression did not change. The blockade of Ca2+ influx into CGCs mediated by nicardipine at 25 mM KCI also caused the inactivation of aconitase, accompanying induction of the apoptosis of CGCs. Suppression of the apoptosis of CGCs mediated by the Ca2+ influx or neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and adenylate cyclase activating polypeptide-38 (PACAP-38) attenuated the aconitase inactivation as well as the lactate dehydrogenase (LDH)-release and the decrease in MTT reduction. On the other hand, the levels of intracellular glutathione and manganese superoxide dismutase-2 mRNA decreased under the low K+ condition, supporting a cause for oxidative stress at low K+ due to a loss of anti-oxidant activity. Thus, the inactivation of aconitase is also caused by a deprivation of Ca2+ influx into neurons, suggesting that aconitase is a key mitochondrial enzyme influencing the viability of neurons in response to oxidative stress.

Original languageEnglish
Pages (from-to)504-515
Number of pages12
JournalJournal of Neuroscience Research
Volume71
Issue number4
DOIs
StatePublished - 2003/02/15

Keywords

  • Apoptosis
  • BDNF
  • Calcium
  • Cerebellar granule cells
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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