Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria

Mitochondria are highly dynamic organelles constantly undergoing fusion and fission. Ca(2+) regulates many aspects of mitochondrial physiology by modulating the activity of several mitochondrial proteins. We previously showed that inhibition of constitutive IP3R-mediated Ca(2+) transfer to the mitoc...

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Autores principales: Lovy, Alenka, Ahumada-Castro, Ulises, Bustos, Galdo, Farias, Paula, Gonzalez-Billault, Christian, Molgó, Jordi, Cardenas, Cesar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261923/
https://www.ncbi.nlm.nih.gov/pubmed/32523953
http://dx.doi.org/10.3389/fcell.2020.00378
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author Lovy, Alenka
Ahumada-Castro, Ulises
Bustos, Galdo
Farias, Paula
Gonzalez-Billault, Christian
Molgó, Jordi
Cardenas, Cesar
author_facet Lovy, Alenka
Ahumada-Castro, Ulises
Bustos, Galdo
Farias, Paula
Gonzalez-Billault, Christian
Molgó, Jordi
Cardenas, Cesar
author_sort Lovy, Alenka
collection PubMed
description Mitochondria are highly dynamic organelles constantly undergoing fusion and fission. Ca(2+) regulates many aspects of mitochondrial physiology by modulating the activity of several mitochondrial proteins. We previously showed that inhibition of constitutive IP3R-mediated Ca(2+) transfer to the mitochondria leads to a metabolic cellular stress and eventually cell death. Here, we show that the decline of mitochondrial function generated by a lack of Ca(2+) transfer induces a DRP-1 independent mitochondrial fragmentation that at an early time is mediated by an increase in the NAD+/NADH ratio and activation of SIRT1. Subsequently, AMPK predominates and drives the fragmentation. SIRT1 activation leads to the deacetylation of cortactin, favoring actin polymerization, and mitochondrial fragmentation. Knockdown of cortactin or inhibition of actin polymerization prevents fragmentation. These data reveal SIRT1 as a new player in the regulation of mitochondrial fragmentation induced by metabolic/bioenergetic stress through regulating the actin cytoskeleton.
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spelling pubmed-72619232020-06-09 Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria Lovy, Alenka Ahumada-Castro, Ulises Bustos, Galdo Farias, Paula Gonzalez-Billault, Christian Molgó, Jordi Cardenas, Cesar Front Cell Dev Biol Cell and Developmental Biology Mitochondria are highly dynamic organelles constantly undergoing fusion and fission. Ca(2+) regulates many aspects of mitochondrial physiology by modulating the activity of several mitochondrial proteins. We previously showed that inhibition of constitutive IP3R-mediated Ca(2+) transfer to the mitochondria leads to a metabolic cellular stress and eventually cell death. Here, we show that the decline of mitochondrial function generated by a lack of Ca(2+) transfer induces a DRP-1 independent mitochondrial fragmentation that at an early time is mediated by an increase in the NAD+/NADH ratio and activation of SIRT1. Subsequently, AMPK predominates and drives the fragmentation. SIRT1 activation leads to the deacetylation of cortactin, favoring actin polymerization, and mitochondrial fragmentation. Knockdown of cortactin or inhibition of actin polymerization prevents fragmentation. These data reveal SIRT1 as a new player in the regulation of mitochondrial fragmentation induced by metabolic/bioenergetic stress through regulating the actin cytoskeleton. Frontiers Media S.A. 2020-05-25 /pmc/articles/PMC7261923/ /pubmed/32523953 http://dx.doi.org/10.3389/fcell.2020.00378 Text en Copyright © 2020 Lovy, Ahumada-Castro, Bustos, Farias, Gonzalez-Billault, Molgó and Cardenas. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Lovy, Alenka
Ahumada-Castro, Ulises
Bustos, Galdo
Farias, Paula
Gonzalez-Billault, Christian
Molgó, Jordi
Cardenas, Cesar
Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title_full Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title_fullStr Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title_full_unstemmed Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title_short Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca(2+) Transfer to Mitochondria
title_sort concerted action of ampk and sirtuin-1 induces mitochondrial fragmentation upon inhibition of ca(2+) transfer to mitochondria
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261923/
https://www.ncbi.nlm.nih.gov/pubmed/32523953
http://dx.doi.org/10.3389/fcell.2020.00378
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