Mitochondrial localization of the Forkhead box class O transcription factor FOXO3a in brain

FOXO3a is member of the Forkhead box class O transcription factors, which functions in diverse pathways to regulate cellular metabolism, differentiation, and apoptosis. FOXO3a shuttles between the cytoplasm and nucleus and may be activated in neurons by stressors, including seizures. A subset of nuc...

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Bibliographic Details
Published in:Journal of neurochemistry 2013-03, Vol.124 (6), p.749-756
Main Authors: Caballero‐Caballero, Aurelien, Engel, Tobias, Martinez‐Villarreal, Jaime, Sanz‐Rodriguez, Amaya, Chang, Patrick, Dunleavy, Mark, Mooney, Claire M., Jimenez‐Mateos, Eva M., Schindler, Clara K., Henshall, David C.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Brain - metabolism
Cell Line
Cell Survival - physiology
CREB
Cytoplasm
Forkhead Box Protein O3
Forkhead in rhabdomyosarcoma
Forkhead Transcription Factors - metabolism
hippocampus
Hippocampus - chemistry
Hippocampus - metabolism
HT22
Humans
Male
Mice
Mice, Inbred C57BL
mitochondria
Mitochondria - chemistry
Mitochondria - metabolism
Mitochondrial DNA
Neurochemistry
Neurons
Proteins
Rats
Rats, Sprague-Dawley
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Summary:FOXO3a is member of the Forkhead box class O transcription factors, which functions in diverse pathways to regulate cellular metabolism, differentiation, and apoptosis. FOXO3a shuttles between the cytoplasm and nucleus and may be activated in neurons by stressors, including seizures. A subset of nuclear transcription factors may localize to mitochondria, but whether FOXO3a is present within brain mitochondria is unknown. Here, we report that purified mitochondrial fractions from rat, mouse, and human hippocampus, as well as HT22 hippocampal cells, contain FOXO3a protein. Immunogold electron microscopy supported the presence of FOXO3a within brain mitochondria, and chromatin immunoprecipitation analysis suggested FOXO3a was associated with mitochondrial DNA. Over‐expression of a mitochondrially targeted FOXO3a fusion protein in HT22 cells, but not primary hippocampal neurons, conferred superior protection against glutamate toxicity than FOXO3a alone. Mitochondrial FOXO3a levels were reduced in the damaged region of the mouse hippocampus after status epilepticus, while mitochondrial fractions from the hippocampus of patients with temporal lobe epilepsy displayed higher levels of FOXO3a than controls. These results support mitochondria as a site of FOXO3a localization, which may contribute to the overall physiological and pathophysiological functions of this transcription factor. ‘Mitochondrial localization of the Forkhead box class O transcription factor FOXO3a in brain’ We identify a novel subcellular localization for FOXO3a, a transcription factor involved in development, life‐span, and apoptosis control. We show that FOXO3a resides in mitochondria in the mouse, rat, and human hippocampus, where it may target mitochondrial DNA. We also found changes to levels of mitochondrial FOXO3a in experimental seizure models and human epilepsy. These findings open a new area of research on FOXO3a.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.12133