The Journal of Experimental Medicine
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Published online July 16, 2007
doi:10.1084/jem.20070193
The Journal of Experimental Medicine, Vol. 204, No. 8, 1741-1748
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Zhu et al.
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BRIEF DEFINITIVE REPORT

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

Changlian Zhu1,3, Xiaoyang Wang2,3, Johanna Deinum4, Zhiheng Huang1,3, Jianfeng Gao1,3, Nazanine Modjtahedi5, Martha R. Neagu6,7, Michael Nilsson1, Peter S. Eriksson1, Henrik Hagberg2, Jeremy Luban6,7, Guido Kroemer5, and Klas Blomgren1,8

1 Center for Brain Repair and Rehabilitation and 2 Perinatal Center, Institute of Neuroscience and Physiology, Göteborg University, 405 30 Göteborg, Sweden
3 Department of Pediatrics, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
4 AstraZeneca R&D, 431 83 Mölndal, Sweden
5 Institut National de la Santé et de la Recherche Médicale, U848, Institute Gustave Roussy, 94805 Villejuif, France
6 Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
7 Department of Microbiology, Columbia University, New York, NY 10032
8 Department of Pediatric Oncology, Queen Silvia Children's Hospital, 416 85 Göteborg, Sweden

CORRESPONDENCE Changlian Zhu: changlian.zhu{at}neuro.gu.se

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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