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Cited by 33Thyroid Disorders and TreatmentsCellular transport and secretionChemical Analysis and Environmental Impact

Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain

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Salas-Lucia, Federico, Fekete, Csaba, Sinkó, Richárd, Egri, Péter, Rada, Kristóf, Ruska, Yvette, Gereben, Balázs, Bianco, Antonio C·2023·eLife
DOI 10.7554/elife.82683PMC PMC10241515

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Abstract

The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3’s active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.

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  • Neurons take up and package T3 into endosomes, which are subsequently retrogradely transported to the cell nucleus, where it regulates gene transcription.

    “Neurons take up and package T3 into endosomes, which are subsequently retrogradely transported to the cell nucleus, where it regulates gene transcription (43).”

    From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [43]

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Authors
Salas-Lucia, F., Fekete, C., Sinkó, R., Egri, P., Rada, K., Ruska, Y., Gereben, B., & Bianco, A. C.
Affiliations
  • University of Chicago (US)
  • HUN-REN Institute of Experimental Medicine (HU)
  • Semmelweis University (HU)
Corresponding author
  • Gereben, Balázs
  • Bianco, Antonio C
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-05-19
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.82683
PMC
PMC10241515
OpenAlex
W4377091463
Cited by
33
References
12
Citations by year
2026: 7 · 2025: 12 · 2024: 8 · 2023: 5 · 2022: 1
FWCI
6.56
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Chicago (cc-by)
Funders
  • National Research, Development and Innovation Office (The Hungarian National Brain Research Program 2)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK58538, DK65055, DK15070)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
Keywords
thyroid hormone signaling, type 3 deiodinase, retrograde transport, microtubules, MCT8, clathrin-mediated endocytosis
MeSH terms
Animals, Axons, Brain, Neurons, Thyroid Hormones, Symporters, Mice

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