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Cited by 24Mitochondrial Function and PathologyThyroid Disorders and TreatmentsAdipose Tissue and Metabolism

Differential effects of 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine on mitochondrial respiratory pathways in liver from hypothyroid rats

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Silvestri, Elena, Lombardi, Assunta, Coppola, Maria, Gentile, Alessandra, Cioffi, Federica, Senese, Rosalba, Goglia, Fernando, Lanni, Antonia +2 more·2018·Cellular Physiology and Biochemistry
DOI 10.1159/000491620
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Abstract

Background/Aims: Both 3,5-diiodo-L-thyronine (3,5-T2) and 3,5,3’-triiodo-L-tyronine (T3) affect energy metabolism having mitochondria as a major target. However, the underlying mechanisms are poorly understood. Here, using a model of chemically induced hypothyroidism in male Wistar rats, we investigated the effect of administration of either 3,5-T2 or T3 on liver oxidative capacity through their influence on mitochondrial processes including: proton-leak across the mitochondrial inner membrane; complex I-, complex II- and glycerol-3-phosphate-linked respiratory pathways; respiratory complex abundance and activities as well as individual complex aggregation into supercomplexes. Methods: Hypothyroidism was induced by propylthiouracil and iopanoic acid; 3,5-T2 and T3 were intraperitoneally administered at 25 and 15 µg/100 g BW for 1 week, respectively. Resulting alterations in mitochondrial function were studied by combining respirometry, Blue Native-PAGE followed by in-gel activity, and Western blot analyses. Results: Administration of 3,5-T2 and T3 to hypothyroid (hypo) rats enhanced mitochondrial respiration rate with only T3 effectively stimulating proton-leak (450% vs. Hypo). T3 significantly enhanced complex I (+145% vs. Hypo), complex II (+66% vs. Hypo), and glycerol-3 phosphate dehydrogenase (G3PDH)-linked oxygen consumptions (about 6- fold those obtained in Hypo), while 3,5-T2 administration selectively restored Euthyroid values of complex II- and increased G3PDH- linked respiratory pathways (+165% vs. Hypo). The mitochondrial abundance of all respiratory complexes and of G3PDH was increased by T3 administration whereas 3,5-T2 only increased complex V and G3PDH abundance. 3,5-T2 enhanced complex I and complex II in gel activities with less intensity than did T3, and T3 also enhanced the activity of all other respiratory complexes tested. In addition, only T3 enhanced individual respiratory component complex assembly into supercomplexes. Conclusions: The reported data highlight novel molecular mechanisms underlying the effect elicited by iodothyronine administration to hypothyroid rats on mitochondrial processes related to alteration in oxidative capacity in the liver. The differential effects elicited by the two iodothyronines indicate that 3,5-T2, by influencing the kinetic properties of specific mitochondrial respiratory pathways, would promote a rapid response of the organelle, while T3, by enhancing the abundance of respiratory chain component and favoring the organization of respiratory chain complex in supercomplexes, would induce a slower and prolonged response of the organelle.

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  • No information had been published on 3,5-T2 concentrations reached in the circulation or in target tissues like liver in those studies.

    “Unfortunately, no information had been published on 3,5-T2 concentrations reached in the circulation or in those target tissues like liver, where beneficial effects such as antisteatotic activity and increased lipid metabolism were reported (15, 17, 28, 89, 90).”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [89]

    The Animal treatment section reports serum T3 and T4 levels and the administered 3,5-T2 dose, but not circulating or liver 3,5-T2 concentrations. The Introduction discusses prior metabolic and antisteatotic findings without saying whether those studies published such concentrations. Our copy therefore does not establish the claim about what had been published across those studies. (LLM, conf=0.72)

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Authors
Silvestri, E., Lombardi, A., Coppola, M., Gentile, A., Cioffi, F., Senese, R., Goglia, F., Lanni, A., Moreno, M., & de Lange, P.
Affiliations
  • University of Sannio (IT)
  • University of Naples Federico II (IT)
  • University of Campania "Luigi Vanvitelli" (IT)
ORCID
Venue
Cellular Physiology and Biochemistry
Publisher
S. Karger AG
Published
2018
Volume
47
Issue
6
Pages
2471-2483
ISSN
  • 1015-8987 (ISSN-L)
  • 1421-9778
DOI
10.1159/000491620
OpenAlex
W2830975420
Cited by
24
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 5
FWCI
0.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by-nc-nd)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
3,5-diiodo-L-thyronine, triiodothyronine, hypothyroidism, liver mitochondria, mitochondrial respiration, proton leak, respiratory chain complexes, supercomplexes, glycerol-3-phosphate dehydrogenase, propylthiouracil, iopanoic acid, thyroid hormone replacement, oxidative capacity, energy metabolism
MeSH terms
Animals, Diiodothyronines, Electron Transport, Hypothyroidism, Male, Mitochondria, Liver, Triiodothyronine, Rats, Wistar, Rats

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