Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism

Autor: Antonio C. Bianco, Balázs Gereben, Imre Kalló, Sungro Jo, Anikó Zeöld, Zsuzsanna Bardóczi, Anthony Oliva, Rafael Arrojo e Drigo, John L. Bixby, Vance Lemmon, Zsolt Liposits
Rok vydání: 2012
Předmět:
Male
medicine.medical_specialty
Middle Cerebral Artery
Thyroid Hormones
Glycosylation
endocrine system diseases
Deiodinase
Endoplasmic Reticulum
Hippocampus
Iodide Peroxidase
Polymerase Chain Reaction
Brain Ischemia
Brain ischemia
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Oxygen Consumption
Internal medicine
medicine
Animals
Immunoprecipitation
Cells
Cultured
030304 developmental biology
Cell Nucleus
Neurons
0303 health sciences
Thyroid hormone receptor
Receptors
Thyroid Hormone
biology
General Neuroscience
Dentate gyrus
Thyroid
DNA
Articles
HSP40 Heat-Shock Proteins
medicine.disease
Immunohistochemistry
Cell Hypoxia
Rats
Microscopy
Electron
Endocrinology
medicine.anatomical_structure
biology.protein
Signal transduction
Nucleus
030217 neurology & neurosurgery
Hormone
Signal Transduction
Zdroj: Journal of Neuroscience; Vol 32
ISSN: 1529-2401
Popis: 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.
Databáze: OpenAIRE
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