Cyclophilin A participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia.
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.
Zhu
Changlian
C
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, 405 30 Göteborg, Sweden. changlian.zhu@neuro.gu.se
Wang
Xiaoyang
X
Deinum
Johanna
J
Huang
Zhiheng
Z
Gao
Jianfeng
J
Modjtahedi
Nazanine
N
Neagu
Martha R
MR
Nilsson
Michael
M
Eriksson
Peter S
PS
Hagberg
Henrik
H
Luban
Jeremy
J
Kroemer
Guido
G
Blomgren
Klas
K
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D021984:Cyclophilin A / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding
D051033:Apoptosis Inducing Factor; D021984:Cyclophilin A