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J. Biol. Chem., Vol. 280, Issue 32, 28894-28902, August 12, 2005

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Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons^*

Yulia E. Kushnareva, Sandra E. Wiley, Manus W. Ward¶, Alexander Y. Andreyev||, and Anne N. Murphy**

From the MitoKor, San Diego, California 92121

Neuronal death in response to excitotoxic levels of glutamate is dependent upon mitochondrial Ca²⁺ accumulation and is associated with a drop in ATP levels and a loss in ionic homeostasis. Yet the mapping of temporal events in mitochondria subsequent to Ca²⁺ sequestration is incomplete. By isolating mitochondria from primary cultures, we discovered that glutamate treatment of cortical neurons for 10 min caused 44% inhibition of ADP-stimulated respiration, whereas the maximal rate of electron transport (uncoupler-stimulated respiration) was inhibited by 10%. The Ca²⁺ load in mitochondria from glutamate-treated neurons was estimated to be 167 ± 19 nmol/mg protein. The glutamate-induced Ca²⁺ load was less than the maximal Ca²⁺ uptake capacity of the mitochondria determined in vitro (363 ± 35 nmol/mg protein). Comparatively, mitochondria isolated from cerebellar granule cells demonstrated a higher Ca²⁺ uptake capacity (686 ± 71 nmol/mg protein) than the cortical mitochondria, and the glutamate-induced load of Ca²⁺ was a smaller percentage of the maximal Ca²⁺ uptake capacity. Thus, this study indicated that Ca²⁺-induced impairment of mitochondrial ATP production is an early event in the excitotoxic cascade that may contribute to decreased cellular ATP and loss of ionic homeostasis that precede commitment to neuronal death.

Received for publication, March 21, 2005 , and in revised form, June 2, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Del E. Webb Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037.

Present address: Walther Cancer Institute, University of California San Diego, La Jolla, CA 92093.

^¶ Present address: Royal College of Surgeons in Ireland, Dept of Physiology, 123 St Stephen's Green, Dublin 2, Ireland.

^|| Present address: Dept. of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093.

^** To whom correspondence should be addressed: BioEnergetix, LLC, 310 Cole Ranch Rd., Encinitas, CA 92024. Fax: 760-635-0033; E-mail: anmurphy{at}cox.net.

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