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J. Biol. Chem., Vol. 281, Issue 17, 11658-11668, April 28, 2006

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Synaptic Mitochondria Are More Susceptible to Ca²⁺Overload than Nonsynaptic Mitochondria^*

Maile R. Brown^¶1, Patrick G. Sullivan^¶||, and James W. Geddes^¶||2

From the Graduate Center for Gerontology, Sanders-Brown Center on Aging, ^¶Spinal Cord and Brain Injury Research Center, and the ^||Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536

Mitochondria in nerve terminals are subjected to extensive Ca²⁺fluxes and high energy demands, but the extent to which the synaptic mitochondria buffer Ca²⁺ is unclear. In this study, we identified a difference in the Ca²⁺ clearance ability of nonsynaptic versus synaptic mitochondrial populations enriched from rat cerebral cortex. Mitochondria were isolated using Percoll discontinuous gradients in combination with high pressure nitrogen cell disruption. Mitochondria in the nonsynaptic fraction originate from neurons and other cell types including glia, whereas mitochondria enriched from a synaptosomal fraction are predominantly neuronal and presynaptic in origin. There were no differences in respiration or initial Ca²⁺ loads between nonsynaptic and synaptic mitochondrial populations. Following both bolus and infusion Ca²⁺ addition, nonsynaptic mitochondria were able to accumulate significantly more exogenously added Ca ²⁺ than the synaptic mitochondria before undergoing mitochondrial permeability transition, observed as a loss in mitochondrial membrane potential and decreased Ca²⁺ uptake. The limited ability of synaptic mitochondria to accumulate Ca²⁺ could result from several factors including a primary function of ATP production to support the high energy demand of presynaptic terminals, their relative isolation in comparison with the threads or clusters of mitochondria found in the soma of neurons and glia, or the older age and increased exposure to oxidative damage of synaptic versus nonsynaptic mitochondria. By more readily undergoing permeability transition, synaptic mitochondria may initiate neuron death in response to insults that elevate synaptic levels of intracellular Ca²⁺, consistent with the early degeneration of distal axon segments in neurodegenerative disorders.

Received for publication, September 20, 2005 , and in revised form, January 25, 2006.

^* This work was supported by National Institutes of Health, United States Public Health Service Grants AG10836 and NS045726 (to J. W. G.) and NS048191 and NS046426 (to P. G. S.). 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.

¹ Predoctoral trainee under National Institutes of Health Training Grant AG00264. Present address: Dept. of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.

² To whom correspondence should be addressed: B379 BBSRB, University of Kentucky, Lexington, KY 40536-0509. Tel.: 859-323-5135; Fax: 859-257-5737; E-mail: jgeddes{at}uky.edu.

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