title: Peroxisome proliferator-activated receptor-γ coactivator-1α mediates neuroprotection against excitotoxic brain injury in transgenic mice: role of mitochondria and X-linked inhibitor of apoptosis protein.
abstract: Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1α in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1α transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild-type mice but significantly less so in PGC-1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1α overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1α transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP.
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.|Minerva Medical Research Institute, Biomedicum-2 Helsinki, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäkelä
authors.affiliation: Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Mudò
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.|Minerva Medical Research Institute, Biomedicum-2 Helsinki, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Dan Duc
authors.initials: DD
authors.lastname: Pham
authors.affiliation: Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Liberto
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Ove
authors.initials: O
authors.lastname: Eriksson
authors.affiliation: Medicum, Department of Physiology, University of Helsinki, Helsinki, Finland.
authors.forename: Lauri
authors.identifier: http://orcid.org/0000-0001-8649-781X
authors.initials: L
authors.lastname: Louhivuori
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.|Minerva Medical Research Institute, Biomedicum-2 Helsinki, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Céline
authors.initials: C
authors.lastname: Bruelle
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Rabah
authors.initials: R
authors.lastname: Soliymani
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.|Clinicum, Division of Child Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Korhonen
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lalowski
authors.affiliation: Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
authors.forename: Natale
authors.initials: N
authors.lastname: Belluardo
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, 00014, Haartmaninkatu 8, FIN-00290, Helsinki, Finland.|Minerva Medical Research Institute, Biomedicum-2 Helsinki, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; C107521:Birc4 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D007608:Kainic Acid
keywords: PGC-1α; XIAP; kainic acid; mitochondria; neuron survival; proteomics