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Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+)
Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells throug...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999186/ https://www.ncbi.nlm.nih.gov/pubmed/33802063 http://dx.doi.org/10.3390/cells10030612 |
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author | Song, Seon Beom Park, Jin Sung Jang, So Young Hwang, Eun Seong |
author_facet | Song, Seon Beom Park, Jin Sung Jang, So Young Hwang, Eun Seong |
author_sort | Song, Seon Beom |
collection | PubMed |
description | Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells through SIRT1 activation upon treatment of nicotinamide (NAM). Further, mitochondria are maintained as short fragments in the treated cells. In the current study, molecular pathways for NAM-induced mitochondrial fragmentation were sought. NAM treatment induced mitochondrial fission, at least in part by activating dynamin-1-like protein (Drp1), and this was through attenuation of the inhibitory phosphorylation at serine 637 (S637) of Drp1. This Drp1 hypo-phosphorylation was attributed to SIRT1-mediated activation of AMP-activated protein kinase (AMPK), which in turn induced a decrease in cellular levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, a kinase targeting S637 of Drp1. Furthermore, in NAM-treated cells, cytosolic Ca(2+) was highly maintained; and, as a consequence, activity of calcineurin, a Drp1-dephosphorylating phosphatase, is expected to be elevated. These results suggest that NAD(+)-mediated SIRT1 activation facilitates mitochondrial fission through activation of Drp1 by suppressing its phosphorylation and accelerating its dephosphorylation. Additionally, it is suggested that there is a cycle of mitochondrial fragmentation and cytosolic Ca(2+)-mediated Drp1 dephosphorylation that may drive sustained mitochondrial fragmentation. |
format | Online Article Text |
id | pubmed-7999186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79991862021-03-28 Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) Song, Seon Beom Park, Jin Sung Jang, So Young Hwang, Eun Seong Cells Article Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells through SIRT1 activation upon treatment of nicotinamide (NAM). Further, mitochondria are maintained as short fragments in the treated cells. In the current study, molecular pathways for NAM-induced mitochondrial fragmentation were sought. NAM treatment induced mitochondrial fission, at least in part by activating dynamin-1-like protein (Drp1), and this was through attenuation of the inhibitory phosphorylation at serine 637 (S637) of Drp1. This Drp1 hypo-phosphorylation was attributed to SIRT1-mediated activation of AMP-activated protein kinase (AMPK), which in turn induced a decrease in cellular levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, a kinase targeting S637 of Drp1. Furthermore, in NAM-treated cells, cytosolic Ca(2+) was highly maintained; and, as a consequence, activity of calcineurin, a Drp1-dephosphorylating phosphatase, is expected to be elevated. These results suggest that NAD(+)-mediated SIRT1 activation facilitates mitochondrial fission through activation of Drp1 by suppressing its phosphorylation and accelerating its dephosphorylation. Additionally, it is suggested that there is a cycle of mitochondrial fragmentation and cytosolic Ca(2+)-mediated Drp1 dephosphorylation that may drive sustained mitochondrial fragmentation. MDPI 2021-03-10 /pmc/articles/PMC7999186/ /pubmed/33802063 http://dx.doi.org/10.3390/cells10030612 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Song, Seon Beom Park, Jin Sung Jang, So Young Hwang, Eun Seong Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title | Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title_full | Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title_fullStr | Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title_full_unstemmed | Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title_short | Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca(2+) |
title_sort | nicotinamide treatment facilitates mitochondrial fission through drp1 activation mediated by sirt1-induced changes in cellular levels of camp and ca(2+) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999186/ https://www.ncbi.nlm.nih.gov/pubmed/33802063 http://dx.doi.org/10.3390/cells10030612 |
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