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The Journal of Neuroscience, July 11, 2007, 27(28):7469-7475; doi:10.1523/JNEUROSCI.0646-07.2007

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Cellular/Molecular
High Cyclophilin D Content of Synaptic Mitochondria Results in Increased Vulnerability to Permeability Transition

Kranthi Kumari Naga,¹ Patrick G. Sullivan,^1,2 and James W. Geddes^1,2

¹Spinal Cord and Brain Injury Research Center and ²Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536

Correspondence should be addressed to Dr. James W. Geddes, B379 Biomedical & Biological Sciences Research Building, Spinal Cord and Brain Injury Research Center, 741 South Limestone Street, University of Kentucky, Lexington, KY 40536-0509. Email: jgeddes{at}uky.edu

Mitochondria isolated from synaptosomes are more sensitive to Ca²⁺ overload and the resultant opening of the mitochondrial permeability transition pore (mPTP) than nonsynaptic mitochondria. To identify the mechanisms underlying these differences in Ca²⁺ dynamics, we examined relative levels of mPTP components in synaptic versus nonsynaptic mitochondria. Synaptic mitochondria had higher levels of cyclophilin D when compared with nonsynaptic mitochondria, whereas levels of the voltage-dependent anion channel and the adenine nucleotide translocase were similar in the two mitochondrial fractions. These differences in Ca²⁺ handling between synaptic and nonsynaptic mitochondria were greatly reduced in cyclophilin D null [Ppif^–/– (peptidylprolyl isomerase F)] mice. Higher concentrations of cyclosporine A, which interacts with cyclophilin D to delay mPTP opening, were necessary to increase the Ca²⁺ uptake capacity of synaptic versus nonsynaptic mitochondria. To determine whether the differences in Ca²⁺ handling might reflect the relative abundance of neuronal and glial mitochondria in the two mitochondrial fractions, we compared cyclophilin D levels in primary cortical neurons and astrocytes. Primary rat cortical neurons possess higher cyclophilin D levels than do primary astrocytes. In the adult rat brain, cyclophilin D immunoreactivity was abundant in neurons but sparse in astrocytes. Together, these results demonstrate that the Ca²⁺ handling differences observed in synaptic versus nonsynaptic mitochondria are primarily the result of the high levels of cyclophilin D in synaptic mitochondria, reflecting the greater proportion of neuronal mitochondria in this fraction. The high levels of cyclophilin D in neuronal mitochondria result in their greater vulnerability to mPT and in higher levels of cyclosporine A being required to inhibit mPTP opening.

Key words: calcium; necrosis; cyclosporine A; Ppif; caspase-independent; astrocytes

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Received Feb. 13, 2007; revised May 1, 2007; accepted May 29, 2007.

Correspondence should be addressed to Dr. James W. Geddes, B379 Biomedical & Biological Sciences Research Building, Spinal Cord and Brain Injury Research Center, 741 South Limestone Street, University of Kentucky, Lexington, KY 40536-0509. Email: jgeddes{at}uky.edu

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