Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons

被引:72
作者
Barsukova, Anna [1 ,2 ]
Komarov, Alexander [1 ,2 ]
Hajnoczky, Gyoergy [3 ]
Bernardi, Paolo [4 ,5 ]
Bourdette, Dennis [6 ]
Forte, Michael [1 ,2 ]
机构
[1] Vollum Inst, Portland, OR 97239 USA
[2] Oregon Hlth & Sci Univ, Portland, OR 97239 USA
[3] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
[4] Univ Padua, Dept Biomed Sci, Padua, Italy
[5] Univ Padua, CNR Inst Neurosci, Padua, Italy
[6] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA
基金
美国国家卫生研究院;
关键词
calcium homeostasis; cortical neurons; mitochondria; mutant mice; neurodegeneration neuroprotection; CYCLOPHILIN-D; CELL-DEATH; BENZODIAZEPINE-RECEPTOR; SYNAPTIC MITOCHONDRIA; ENDOPLASMIC-RETICULUM; CALCIUM; TRANSPORT; DISEASE; SIGNALS; LOCALIZATION;
D O I
10.1111/j.1460-9568.2010.07576.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The participation of mitochondria in cellular and neuronal Ca2+ homeostatic networks is now well accepted. Yet, critical tests of specific mitochondrial pathways in neuronal Ca2+ responses have been hampered because the identity of mitochondrial proteins that must be integrated within this dynamic system remain uncertain. One putative pathway for Ca2+ efflux from mitochondria exists through the formation of the permeability transition pore (PTP) that is often associated with cellular and neuronal death. Here, we have evaluated neuronal Ca2+ dynamics and the PTP in single adult neurons in wild-type mice and those missing cyclophilin D (CyPD), a key regulator of the PTP. Using high-resolution time-lapse imaging, we demonstrate that PTP opening only follows simultaneous activation with two physiological stimuli that generate critical threshold levels of cytosolic and mitochondrial Ca2+. Our results are the first to demonstrate CyPD-dependent PTP opening in normal neuronal Ca2+ homeostatic mechanisms not leading to activation of cell death pathways. As neurons in mice lacking CyPD are protected in a number of neurodegenerative disease models, the results suggest that improved viability of CyPD-knockout animals in these pathological states may be due to the transient, rather than persistent, activation of the PTP in mutant mitochondria, thereby shielding neurons from cytoplasmic Ca2+ overload.
引用
收藏
页码:831 / 842
页数:12
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