Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes

Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with H...

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Autores principales:	Nils Bomer, Mario G. Pavez-Giani, Frederik E. Deiman, Annet N. Linders, Martijn F. Hoes, Christiane L.J. Baierl, Silke U. Oberdorf-Maass, Rudolf A. de Boer, Herman H.W. Silljé, Eugene Berezikov, Warner S. Simonides, B. Daan Westenbrink, Peter van der Meer
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	heart failure selenoproteins DIO2 human cardiomyocytes mtUPR mitochondrial function Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/379f9168c09b4bdca9868e63a97a417b
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spelling	oai:doaj.org-article:379f9168c09b4bdca9868e63a97a417b2021-11-11T17:19:12ZSelenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes10.3390/ijms2221119061422-00671661-6596https://doaj.org/article/379f9168c09b4bdca9868e63a97a417b2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11906https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.Nils BomerMario G. Pavez-GianiFrederik E. DeimanAnnet N. LindersMartijn F. HoesChristiane L.J. BaierlSilke U. Oberdorf-MaassRudolf A. de BoerHerman H.W. SilljéEugene BerezikovWarner S. SimonidesB. Daan WestenbrinkPeter van der MeerMDPI AGarticleheart failureselenoproteinsDIO2human cardiomyocytesmtUPRmitochondrial functionBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11906, p 11906 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	heart failure selenoproteins DIO2 human cardiomyocytes mtUPR mitochondrial function Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	heart failure selenoproteins DIO2 human cardiomyocytes mtUPR mitochondrial function Biology (General) QH301-705.5 Chemistry QD1-999 Nils Bomer Mario G. Pavez-Giani Frederik E. Deiman Annet N. Linders Martijn F. Hoes Christiane L.J. Baierl Silke U. Oberdorf-Maass Rudolf A. de Boer Herman H.W. Silljé Eugene Berezikov Warner S. Simonides B. Daan Westenbrink Peter van der Meer Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
description	Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.
format	article
author	Nils Bomer Mario G. Pavez-Giani Frederik E. Deiman Annet N. Linders Martijn F. Hoes Christiane L.J. Baierl Silke U. Oberdorf-Maass Rudolf A. de Boer Herman H.W. Silljé Eugene Berezikov Warner S. Simonides B. Daan Westenbrink Peter van der Meer
author_facet	Nils Bomer Mario G. Pavez-Giani Frederik E. Deiman Annet N. Linders Martijn F. Hoes Christiane L.J. Baierl Silke U. Oberdorf-Maass Rudolf A. de Boer Herman H.W. Silljé Eugene Berezikov Warner S. Simonides B. Daan Westenbrink Peter van der Meer
author_sort	Nils Bomer
title	Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
title_short	Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
title_full	Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
title_fullStr	Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
title_full_unstemmed	Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes
title_sort	selenoprotein dio2 is a regulator of mitochondrial function, morphology and uprmt in human cardiomyocytes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/379f9168c09b4bdca9868e63a97a417b
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Selenoprotein DIO2 Is a Regulator of Mitochondrial Function, Morphology and UPRmt in Human Cardiomyocytes

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