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Abstract
Apoptosis-inducing factor (AIF) may contribute to neuronal cell death, and its influence is particularly prominent in the immature brain after hypoxia–ischemia (HI). A brain-specific AIF splice-isoform (AIF2) has recently been discovered, but has not yet been characterized at the genetic level. The aim of this study was to determine the functional and regulatory profile of AIF2 under physiological conditions and after HI in mice. We generated AIF2 knockout (KO) mice by removing the AIF2-specific exon and found that the relative expression of Aif1 mRNA increased in Aif2 KO mice and that this increase became even more pronounced as Aif2 KO mice aged compared to their wild-type (WT) littermates. Mitochondrial morphology and function, reproductive function, and behavior showed no differences between WT and Aif2 KO mice. However, lack of AIF2 enhanced brain injury in neonatal mice after HI compared to WT controls, and this effect was linked to increased oxidative stress but not to caspase-dependent or -independent apoptosis pathways. These results indicate that AIF2 deficiency exacerbates free radical production and HI-induced neonatal brain injury.
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1 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, Children’s Hospital of Zhengzhou University, Zhengzhou, China
3 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, Children’s Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
4 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
5 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
6 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Pediatrics, Second Affiliated Hospital of Hainan Medical University, Haikou, China
7 Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
8 Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
9 Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
10 Institute of Biomedical Science of Fudan University, Shanghai, China
11 Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
12 Center for Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
13 INSERM unit U1030, Gustave Roussy Cancer Campus, Villejuif, France
14 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Metabolomics and Cell Biology Platforms, GRCC, Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Labex Immuno-Oncology, Paris, France
15 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden