title: Mitochondrial localization of the forkhead box class O transcription factor FOXO3a in brain.
abstract: 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.
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Caballero-Caballero
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Jaime
authors.initials: J
authors.lastname: Martinez-Villarreal
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.forename: Patrick
authors.initials: P
authors.lastname: Chang
authors.forename: Mark
authors.initials: M
authors.lastname: Dunleavy
authors.forename: Claire M
authors.initials: CM
authors.lastname: Mooney
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: Clara K
authors.initials: CK
authors.lastname: Schindler
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors