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Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

Type 2 diabetic cardiomyopathy features Ca(2+) signaling abnormalities, notably an altered mitochondrial Ca(2+) handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca(2+) homeostasis, the reticulum–mitochondrial Ca(2+) coupling, and/or the mitochondrial Ca(2+)...

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Autores principales: Dia, Maya, Gomez, Ludovic, Thibault, Helene, Tessier, Nolwenn, Leon, Christelle, Chouabe, Christophe, Ducreux, Sylvie, Gallo-Bona, Noelle, Tubbs, Emily, Bendridi, Nadia, Chanon, Stephanie, Leray, Aymeric, Belmudes, Lucid, Couté, Yohann, Kurdi, Mazen, Ovize, Michel, Rieusset, Jennifer, Paillard, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704523/
https://www.ncbi.nlm.nih.gov/pubmed/33258101
http://dx.doi.org/10.1007/s00395-020-00835-7
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author Dia, Maya
Gomez, Ludovic
Thibault, Helene
Tessier, Nolwenn
Leon, Christelle
Chouabe, Christophe
Ducreux, Sylvie
Gallo-Bona, Noelle
Tubbs, Emily
Bendridi, Nadia
Chanon, Stephanie
Leray, Aymeric
Belmudes, Lucid
Couté, Yohann
Kurdi, Mazen
Ovize, Michel
Rieusset, Jennifer
Paillard, Melanie
author_facet Dia, Maya
Gomez, Ludovic
Thibault, Helene
Tessier, Nolwenn
Leon, Christelle
Chouabe, Christophe
Ducreux, Sylvie
Gallo-Bona, Noelle
Tubbs, Emily
Bendridi, Nadia
Chanon, Stephanie
Leray, Aymeric
Belmudes, Lucid
Couté, Yohann
Kurdi, Mazen
Ovize, Michel
Rieusset, Jennifer
Paillard, Melanie
author_sort Dia, Maya
collection PubMed
description Type 2 diabetic cardiomyopathy features Ca(2+) signaling abnormalities, notably an altered mitochondrial Ca(2+) handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca(2+) homeostasis, the reticulum–mitochondrial Ca(2+) coupling, and/or the mitochondrial Ca(2+) entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum–mitochondria interface revealed tighter interactions not compatible with Ca(2+) transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca(2+) sensors were performed to measure Ca(2+) fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R–VDAC interaction and a reduced IP3-stimulated Ca(2+) transfer to mitochondria, with no changes in reticular Ca(2+) level, cytosolic Ca(2+) transients, and mitochondrial Ca(2+) uniporter function. Disruption of organelle Ca(2+) exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca(2+) transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum–mitochondria Ca(2+) miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca(2+) dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00395-020-00835-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-77045232020-12-03 Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy Dia, Maya Gomez, Ludovic Thibault, Helene Tessier, Nolwenn Leon, Christelle Chouabe, Christophe Ducreux, Sylvie Gallo-Bona, Noelle Tubbs, Emily Bendridi, Nadia Chanon, Stephanie Leray, Aymeric Belmudes, Lucid Couté, Yohann Kurdi, Mazen Ovize, Michel Rieusset, Jennifer Paillard, Melanie Basic Res Cardiol Original Contribution Type 2 diabetic cardiomyopathy features Ca(2+) signaling abnormalities, notably an altered mitochondrial Ca(2+) handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca(2+) homeostasis, the reticulum–mitochondrial Ca(2+) coupling, and/or the mitochondrial Ca(2+) entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum–mitochondria interface revealed tighter interactions not compatible with Ca(2+) transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca(2+) sensors were performed to measure Ca(2+) fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R–VDAC interaction and a reduced IP3-stimulated Ca(2+) transfer to mitochondria, with no changes in reticular Ca(2+) level, cytosolic Ca(2+) transients, and mitochondrial Ca(2+) uniporter function. Disruption of organelle Ca(2+) exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca(2+) transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum–mitochondria Ca(2+) miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca(2+) dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00395-020-00835-7) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-11-30 2020 /pmc/articles/PMC7704523/ /pubmed/33258101 http://dx.doi.org/10.1007/s00395-020-00835-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Contribution
Dia, Maya
Gomez, Ludovic
Thibault, Helene
Tessier, Nolwenn
Leon, Christelle
Chouabe, Christophe
Ducreux, Sylvie
Gallo-Bona, Noelle
Tubbs, Emily
Bendridi, Nadia
Chanon, Stephanie
Leray, Aymeric
Belmudes, Lucid
Couté, Yohann
Kurdi, Mazen
Ovize, Michel
Rieusset, Jennifer
Paillard, Melanie
Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title_full Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title_fullStr Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title_full_unstemmed Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title_short Reduced reticulum–mitochondria Ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
title_sort reduced reticulum–mitochondria ca(2+) transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy
topic Original Contribution
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704523/
https://www.ncbi.nlm.nih.gov/pubmed/33258101
http://dx.doi.org/10.1007/s00395-020-00835-7
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