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Cell Death Dis. 2020 Jan 30;11(1):77. doi: 10.1038/s41419-020-2280-z.

Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice.

Li T1,2,3, Li K1,2, Zhang S1,2, Wang Y1,2,3, Xu Y1,2, Cronin SJF4, Sun Y1,2, Zhang Y2,3, Xie C2,5, Rodriguez J2, Zhou K2,5, Hagberg H6, Mallard C6,7, Wang X1,6,7, Penninger JM4,8, Kroemer G9,10,11,12,13, Blomgren K5,14, Zhu C15,16,17,18.

Author information

1
Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
2
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
3
Department of Pediatrics, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, 450018, China.
4
Institute of Molecular Biotechnology, Austrian Academy of Sciences, 1030, Vienna, Austria.
5
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
6
Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
7
Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
8
Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
9
Equipe labellisée par la Ligue contre le cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
10
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
11
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
12
Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China.
13
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
14
Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden.
15
Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. changlian.zhu@neuro.gu.se.
16
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden. changlian.zhu@neuro.gu.se.
17
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. changlian.zhu@neuro.gu.se.
18
Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden. changlian.zhu@neuro.gu.se.

Abstract

Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.

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