Mäkelä, Johanna;
Mudò, Giuseppa;
Pham, Dan Duc;
Di Liberto, Valentina;
Eriksson, Ove;
Louhivuori, Lauri;
Bruelle, Céline;
Soliymani, Rabah;
Baumann, Marc;
Korhonen, Laura;
Lalowski, Maciej;
Belluardo, Natale;
Lindholm, Dan
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
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Media type:
E-Article
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
Contributor:
Mäkelä, Johanna;
Mudò, Giuseppa;
Pham, Dan Duc;
Di Liberto, Valentina;
Eriksson, Ove;
Louhivuori, Lauri;
Bruelle, Céline;
Soliymani, Rabah;
Baumann, Marc;
Korhonen, Laura;
Lalowski, Maciej;
Belluardo, Natale;
Lindholm, Dan
Description:
<jats:title>Abstract</jats:title><jats:p>Peroxisome proliferator‐activated receptor gamma coactivator‐1α (<jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐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 <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α transgenic mice compared with wild‐type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (<jats:styled-content style="fixed-case">OXPHOS</jats:styled-content>) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. <jats:italic>In vivo</jats:italic> kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild‐type mice but significantly less so in <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α overexpression can induce a delay in cell death. Immunoblotting showed that X‐linked inhibitor of apoptosis protein (<jats:styled-content style="fixed-case">XIAP</jats:styled-content>) was increased in <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α transgenic hippocampus with no significant changes in Bcl‐2 or Bcl‐X. Collectively, these results show that <jats:styled-content style="fixed-case">PGC</jats:styled-content>‐1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of <jats:styled-content style="fixed-case">OXPHOS</jats:styled-content> proteins and the anti‐apoptotic protein <jats:styled-content style="fixed-case">XIAP</jats:styled-content>.</jats:p>