Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism.
In neurons, the type 3 deiodinase (D3) inactivates thyroid hormone and reduces oxygen consumption, thus creating a state of cell-specific hypothyroidism. Here we show that hypoxia leads to nuclear import of D3 in neurons, without which thyroid hormone signaling and metabolism cannot be reduced. After unilateral hypoxia in the rat brain, D3 protein level is increased predominantly in the nucleus of the neurons in the pyramidal and granular ipsilateral layers, as well as in the hilus of the dentate gyrus of the hippocampal formation. In hippocampal neurons in culture as well as in a human neuroblastoma cell line (SK-N-AS), a 24 h hypoxia period redirects active D3 from the endoplasmic reticulum to the nucleus via the cochaperone Hsp40 pathway. Preventing nuclear D3 import by Hsp40 knockdown resulted an almost doubling in the thyroid hormone-dependent glycolytic rate and quadrupling the transcription of thyroid hormone target gene ENPP2. In contrast, Hsp40 overexpression increased nuclear import of D3 and minimized thyroid hormone effects in cell metabolism. In conclusion, ischemia/hypoxia induces an Hsp40-mediated translocation of D3 to the nucleus, facilitating thyroid hormone inactivation proximal to the thyroid hormone receptors. This adaptation decreases thyroid hormone signaling and may function to reduce ischemia-induced hypoxic brain damage.
Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sungro
S
Jo
Imre
I
Kalló
Zsuzsanna
Z
Bardóczi
Rafael
R
Arrojo e Drigo
Anikó
A
Zeöld
Zsolt
Z
Liposits
Anthony
A
Oliva
Vance P
VP
Lemmon
John L
JL
Bixby
Balázs
B
Gereben
Antonio C
AC
Bianco
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D050956:HSP40 Heat-Shock Proteins / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007453:Iodide Peroxidase / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D020768:Middle Cerebral Artery / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013963:Thyroid Hormones / Q000502:physiology
D050956:HSP40 Heat-Shock Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D004247:DNA; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase