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Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia

Cardiomyopathy is a primary cause of death in Friedreich ataxia (FRDA) patients with defective iron-sulfur cluster (ISC) biogenesis due to loss of functional frataxin and in rare patients with functional loss of other ISC biogenesis factors. The mechanistic target of rapamycin (mTOR) and AKT signali...

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Autores principales: Tong, Wing-Hang, Ollivierre, Hayden, Noguchi, Audrey, Ghosh, Manik C., Springer, Danielle A., Rouault, Tracey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433723/
https://www.ncbi.nlm.nih.gov/pubmed/36061025
http://dx.doi.org/10.1016/j.heliyon.2022.e10371
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author Tong, Wing-Hang
Ollivierre, Hayden
Noguchi, Audrey
Ghosh, Manik C.
Springer, Danielle A.
Rouault, Tracey A.
author_facet Tong, Wing-Hang
Ollivierre, Hayden
Noguchi, Audrey
Ghosh, Manik C.
Springer, Danielle A.
Rouault, Tracey A.
author_sort Tong, Wing-Hang
collection PubMed
description Cardiomyopathy is a primary cause of death in Friedreich ataxia (FRDA) patients with defective iron-sulfur cluster (ISC) biogenesis due to loss of functional frataxin and in rare patients with functional loss of other ISC biogenesis factors. The mechanistic target of rapamycin (mTOR) and AKT signaling cascades that coordinate eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors, are crucial regulators of cardiovascular growth and homeostasis. We observed increased phosphorylation of AKT and dysregulation of multiple downstream effectors of mTORC1, including S6K1, S6, ULK1 and 4EBP1, in a cardiac/skeletal muscle specific FRDA conditional knockout (cKO) mouse model and in human cell lines depleted of ISC biogenesis factors. Knockdown of several mitochondrial metabolic proteins that are downstream targets of ISC biogenesis, including lipoyl synthase and subunit B of succinate dehydrogenase, also resulted in activation of mTOR and AKT signaling, suggesting that mTOR and AKT hyperactivations are part of the metabolic stress response to ISC deficiencies. Administration of rapamycin, a specific inhibitor of mTOR signaling, enhanced the survival of the Fxn cKO mice, providing proof of concept for the potential of mTOR inhibition to ameliorate cardiac disease in patients with defective ISC biogenesis. However, AKT phosphorylation remained high in rapamycin-treated Fxn cKO hearts, suggesting that parallel mTOR and AKT inhibition might be necessary to further improve the lifespan and healthspan of ISC deficient individuals.
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spelling pubmed-94337232022-09-02 Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia Tong, Wing-Hang Ollivierre, Hayden Noguchi, Audrey Ghosh, Manik C. Springer, Danielle A. Rouault, Tracey A. Heliyon Research Article Cardiomyopathy is a primary cause of death in Friedreich ataxia (FRDA) patients with defective iron-sulfur cluster (ISC) biogenesis due to loss of functional frataxin and in rare patients with functional loss of other ISC biogenesis factors. The mechanistic target of rapamycin (mTOR) and AKT signaling cascades that coordinate eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors, are crucial regulators of cardiovascular growth and homeostasis. We observed increased phosphorylation of AKT and dysregulation of multiple downstream effectors of mTORC1, including S6K1, S6, ULK1 and 4EBP1, in a cardiac/skeletal muscle specific FRDA conditional knockout (cKO) mouse model and in human cell lines depleted of ISC biogenesis factors. Knockdown of several mitochondrial metabolic proteins that are downstream targets of ISC biogenesis, including lipoyl synthase and subunit B of succinate dehydrogenase, also resulted in activation of mTOR and AKT signaling, suggesting that mTOR and AKT hyperactivations are part of the metabolic stress response to ISC deficiencies. Administration of rapamycin, a specific inhibitor of mTOR signaling, enhanced the survival of the Fxn cKO mice, providing proof of concept for the potential of mTOR inhibition to ameliorate cardiac disease in patients with defective ISC biogenesis. However, AKT phosphorylation remained high in rapamycin-treated Fxn cKO hearts, suggesting that parallel mTOR and AKT inhibition might be necessary to further improve the lifespan and healthspan of ISC deficient individuals. Elsevier 2022-08-23 /pmc/articles/PMC9433723/ /pubmed/36061025 http://dx.doi.org/10.1016/j.heliyon.2022.e10371 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Tong, Wing-Hang
Ollivierre, Hayden
Noguchi, Audrey
Ghosh, Manik C.
Springer, Danielle A.
Rouault, Tracey A.
Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title_full Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title_fullStr Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title_full_unstemmed Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title_short Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia
title_sort hyperactivation of mtor and akt in a cardiac hypertrophy animal model of friedreich ataxia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433723/
https://www.ncbi.nlm.nih.gov/pubmed/36061025
http://dx.doi.org/10.1016/j.heliyon.2022.e10371
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