期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 28, 页码 7469-7475出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0646-07.2007
关键词
calcium; necrosis; cyclosporine A; Ppif; caspase-independent; astrocytes
资金
- NIA NIH HHS [AG10836, P01 AG010836] Funding Source: Medline
- NINDS NIH HHS [P01 NS058484, R01 NS045726, NS045726, NS058484] Funding Source: Medline
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 Ca(2+) dynamics, we examined relative levels of mPTP components in synaptic versus nonsynaptic mitochondria. Synaptic mitochondria had higher levels of cyclophilinDwhencompared 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 Ca(2+) 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 Dto delay m PTP opening, were necessary to increase the Ca(2+) 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 Ca(2+) 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.
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