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J. Biol. Chem. 287 (42): 35192-35200

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: The accumulation of calcium by mitochondria regulates cell survival.

Results: Purified mitochondria exhibit increased calcium uptake in the presence of NMDA receptor agonists.

Conclusion: Functional NMDA-like receptors may be present on mitochondria.

Significance: Learning how NMDA facilitates mitochondrial calcium uptake provides a new dimension to the understanding of cellular homeostasis and response to noxious stimuli.

Identification of an N-Methyl-D-aspartate Receptor in Isolated Nervous System Mitochondria*

Amit S. Korde{ddagger}, and William F. Maragos{ddagger}§1

From the {ddagger}Neurology Service, Hunter Holmes McGuire Veterans Hospital, Richmond, Virginia 23249 and
the §Department of Neurology, Virginia Commonwealth University, Richmond, Virginia 23298

ABSTRACT Back to Top

Abstract: NMDA ionotropic glutamate receptors gate the cytoplasmic influx of calcium, which may, depending on the intensity of the stimulus, subserve either normal synaptic communication or cell death. We demonstrate that when isolated mitochondria are exposed to calcium and NMDA agonists, there is a significant increase in mitochondrial calcium levels. The agonist/antagonist response studies on purified mitochondria suggest the presence of a receptor on mitochondria with features similar to plasma membrane NMDA receptors. Immunogold electron microscopy of hippocampal tissue sections revealed extensive localization of NR2a subunit immunoreactivity on mitochondria. Transient transfection of neuronal GT1-7 cells with an NR1-NR2a NMDA receptor subunit cassette specifically targeting mitochondria resulted in a significant increase in mitochondrial calcium and neuroprotection against glutamate-induced cell death. Mitochondria prepared from GT1-7 cells in which the NR1 subunit of NMDA receptors was silenced demonstrated a decrease in calcium uptake. Our findings are the first to demonstrate that mitochondria express a calcium transport protein that shares characteristics with the NMDA receptor and may play a neuroprotective role.

Key Words: Bioenergetics • Calcium • Glutamate Receptors • Mitochondria • Neuroprotection • GT1-7 • N-Methyl-D-aspartate Receptor

Received for publication November 8, 2011. Revision received August 22, 2012.

1 To whom correspondence should be addressed: Neurology Service, Hunter Holmes McGuire Veterans Hospital, Rm. 2B-175, 1201 Broad Rock Blvd., Richmond, Virginia 23294. Tel.: 804-675-5000 (ext. 3743); Fax: 804-675-5939; E-mail: william.maragos{at}va.gov.

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