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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
Author(s) -
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
Publication year - 2016
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13157
Subject(s) - biology , neuroprotection , mitochondrion , coactivator , microbiology and biotechnology , mitochondrial biogenesis , kainic acid , xiap , programmed cell death , peroxisome proliferator activated receptor , genetically modified mouse , transgene , receptor , apoptosis , glutamate receptor , biochemistry , caspase , pharmacology , transcription factor , gene
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 .