Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics.
Forkhead box g1 (Foxg1) is a nuclear-cytosolic transcription factor essential for the forebrain development and involved in neurodevelopmental and cancer pathologies. Despite the importance of this protein, little is known about the modalities by which it exerts such a large number of cellular functions. Here we show that a fraction of Foxg1 is localized within the mitochondria in cell lines, primary neuronal or glial cell cultures, and in the mouse cortex. Import of Foxg1 in isolated mitochondria appears to be membrane potential-dependent. Amino acids (aa) 277-302 were identified as critical for mitochondrial localization. Overexpression of full-length Foxg1 enhanced mitochondrial membrane potential (ΔΨm) and promoted mitochondrial fission and mitosis. Conversely, overexpression of the C-term Foxg1 (aa 272-481), which is selectively localized in the mitochondrial matrix, enhanced organelle fusion and promoted the early phase of neuronal differentiation. These findings suggest that the different subcellular localizations of Foxg1 control the machinery that brings about cell differentiation, replication, and bioenergetics, possibly linking mitochondrial functions to embryonic development and pathological conditions.
Scuola Normale Superiore, 56126 Pisa, Italy;
Laura
L
Pancrazi
Institute of Neuroscience, Italian National Research Council, 35121 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy;
Giulietta
G
Di Benedetto
Institute of Neuroscience, Italian National Research Council, 56124 Pisa, Italy;
Laura
L
Colombaioni
Institute of Neuroscience, Italian National Research Council, 56124 Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy;
Grazia
G
Della Sala
Scuola Normale Superiore, 56126 Pisa, Italy;
Giovanna
G
Testa
Institute of Neuroscience, Italian National Research Council, 56124 Pisa, Italy;
Francesco
F
Olimpico
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB20XY, United Kingdom;
Aurelio
A
Reyes
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB20XY, United Kingdom;
Massimo
M
Zeviani
Institute of Neuroscience, Italian National Research Council, 35121 Padova, Italy; Venetian Institute of Molecular Medicine, 35129 Padova, Italy; Department Biomedical Sciences, University of Padova, 35121 Padova, Italy tullio.pozzan@unipd.it costa@in.cnr.it.
Tullio
T
Pozzan
Scuola Normale Superiore, 56126 Pisa, Italy; Institute of Neuroscience, Italian National Research Council, 56124 Pisa, Italy; tullio.pozzan@unipd.it costa@in.cnr.it.
Mario
M
Costa
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004734:Energy Metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins
Rett syndrome; autism; brain cortex; cancer; development