High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition

Kranthi Kumari Naga, Patrick G. Sullivan, James W. Geddes

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Mitochondria isolated from synaptosomes are more sensitive to Ca 2+ 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 Ca 2+ 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.

Original languageEnglish
Pages (from-to)7469-7475
Number of pages7
JournalJournal of Neuroscience
Volume27
Issue number28
DOIs
StatePublished - Jul 11 2007

Keywords

  • Astrocytes
  • Calcium
  • Caspase-independent
  • Cyclosporine A
  • Necrosis
  • Ppif

ASJC Scopus subject areas

  • General Neuroscience

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