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Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia

Journal article
Authors Changlian Zhu
Xiaoyang Wang
J. Deinum
Z. Huang
J. Gao
N. Modjtahedi
M. R. Neagu
Michael Nilsson
Peter S Eriksson
Henrik Hagberg
J. Luban
G. Kroemer
Klas Blomgren
Published in J Exp Med
Volume 204
Issue 8
Pages 1741-8
ISSN 0022-1007 (Print)
Publication year 2007
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences
Pages 1741-8
Language en
Keywords apoptosis-inducing factor, cyclophilin A, hypoxia-ischemia, brain
Subject categories Neurobiology, Neuroscience, Experimental brain research


Upon cerebral hypoxia-ischemia (HI), apoptosis-inducing factor (AIF) can move from mitochondria to nuclei, participate in chromatinolysis, and contribute to the execution of cell death. Previous work (Cande, C., N. Vahsen, I. Kouranti, E. Schmitt, E. Daugas, C. Spahr, J. Luban, R.T. Kroemer, F. Giordanetto, C. Garrido, et al. 2004. Oncogene. 23:1514-1521) performed in vitro suggests that AIF must interact with cyclophilin A (CypA) to form a proapoptotic DNA degradation complex. We addressed the question as to whether elimination of CypA may afford neuroprotection in vivo. 9-d-old wild-type (WT), CypA(+/-), or CypA(-/-) mice were subjected to unilateral cerebral HI. The infarct volume after HI was reduced by 47% (P = 0.0089) in CypA(-/-) mice compared with their WT littermates. Importantly, CypA(-/-) neurons failed to manifest the HI-induced nuclear translocation of AIF that was observed in WT neurons. Conversely, CypA accumulated within the nuclei of damaged neurons after HI, and this nuclear translocation of CypA was suppressed in AIF-deficient harlequin mice. Immunoprecipitation of AIF revealed coprecipitation of CypA, but only in injured, ischemic tissue. Surface plasmon resonance revealed direct molecular interactions between recombinant AIF and CypA. These data indicate that the lethal translocation of AIF to the nucleus requires interaction with CypA, suggesting a model in which two proteins that normally reside in separate cytoplasmic compartments acquire novel properties when moving together to the nucleus.

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