Cargando…

POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition

We showed previously that POLG mutations cause major changes in mitochondrial function, including loss of mitochondrial respiratory chain (MRC) complex I, mitochondrial DNA (mtDNA) depletion and an abnormal NAD(+)/NADH ratio in both neural stem cells (NSCs) and astrocytes differentiated from induced...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Anbin, Kristiansen, Cecilie Katrin, Høyland, Lena Elise, Ziegler, Mathias, Wang, Jian, Sullivan, Gareth John, Li, Xingang, Bindoff, Laurence A., Liang, Kristina Xiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103491/
https://www.ncbi.nlm.nih.gov/pubmed/35298342
http://dx.doi.org/10.1080/15384101.2022.2044136
_version_ 1784707569204330496
author Chen, Anbin
Kristiansen, Cecilie Katrin
Høyland, Lena Elise
Ziegler, Mathias
Wang, Jian
Sullivan, Gareth John
Li, Xingang
Bindoff, Laurence A.
Liang, Kristina Xiao
author_facet Chen, Anbin
Kristiansen, Cecilie Katrin
Høyland, Lena Elise
Ziegler, Mathias
Wang, Jian
Sullivan, Gareth John
Li, Xingang
Bindoff, Laurence A.
Liang, Kristina Xiao
author_sort Chen, Anbin
collection PubMed
description We showed previously that POLG mutations cause major changes in mitochondrial function, including loss of mitochondrial respiratory chain (MRC) complex I, mitochondrial DNA (mtDNA) depletion and an abnormal NAD(+)/NADH ratio in both neural stem cells (NSCs) and astrocytes differentiated from induced pluripotent stem cells (iPSCs). In the current study, we looked at mitochondrial remodeling as stem cells transit pluripotency and during differentiation from NSCs to both dopaminergic (DA) neurons and astrocytes comparing the process in POLG-mutated and control stem cells. We saw that mitochondrial membrane potential (MMP), mitochondrial volume, ATP production and reactive oxygen species (ROS) changed in similar ways in POLG and control NSCs, but mtDNA replication, MRC complex I and NAD(+) metabolism failed to remodel normally. In DA neurons differentiated from NSCs, we saw that POLG mutations caused failure to increase MMP and ATP production and blunted the increase in mtDNA and complex I. Interestingly, mitochondrial remodeling during astrocyte differentiation from NSCs was similar in both POLG-mutated and control NSCs. Further, we showed downregulation of the SIRT3/AMPK pathways in POLG-mutated cells, suggesting that POLG mutations lead to abnormal mitochondrial remodeling in early neural development due to the downregulation of these pathways. [Figure: see text]
format Online
Article
Text
id pubmed-9103491
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-91034912022-05-14 POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition Chen, Anbin Kristiansen, Cecilie Katrin Høyland, Lena Elise Ziegler, Mathias Wang, Jian Sullivan, Gareth John Li, Xingang Bindoff, Laurence A. Liang, Kristina Xiao Cell Cycle Research Paper We showed previously that POLG mutations cause major changes in mitochondrial function, including loss of mitochondrial respiratory chain (MRC) complex I, mitochondrial DNA (mtDNA) depletion and an abnormal NAD(+)/NADH ratio in both neural stem cells (NSCs) and astrocytes differentiated from induced pluripotent stem cells (iPSCs). In the current study, we looked at mitochondrial remodeling as stem cells transit pluripotency and during differentiation from NSCs to both dopaminergic (DA) neurons and astrocytes comparing the process in POLG-mutated and control stem cells. We saw that mitochondrial membrane potential (MMP), mitochondrial volume, ATP production and reactive oxygen species (ROS) changed in similar ways in POLG and control NSCs, but mtDNA replication, MRC complex I and NAD(+) metabolism failed to remodel normally. In DA neurons differentiated from NSCs, we saw that POLG mutations caused failure to increase MMP and ATP production and blunted the increase in mtDNA and complex I. Interestingly, mitochondrial remodeling during astrocyte differentiation from NSCs was similar in both POLG-mutated and control NSCs. Further, we showed downregulation of the SIRT3/AMPK pathways in POLG-mutated cells, suggesting that POLG mutations lead to abnormal mitochondrial remodeling in early neural development due to the downregulation of these pathways. [Figure: see text] Taylor & Francis 2022-03-17 /pmc/articles/PMC9103491/ /pubmed/35298342 http://dx.doi.org/10.1080/15384101.2022.2044136 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper
Chen, Anbin
Kristiansen, Cecilie Katrin
Høyland, Lena Elise
Ziegler, Mathias
Wang, Jian
Sullivan, Gareth John
Li, Xingang
Bindoff, Laurence A.
Liang, Kristina Xiao
POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title_full POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title_fullStr POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title_full_unstemmed POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title_short POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
title_sort polg mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via sirt3/ampk pathway inhibition
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103491/
https://www.ncbi.nlm.nih.gov/pubmed/35298342
http://dx.doi.org/10.1080/15384101.2022.2044136
work_keys_str_mv AT chenanbin polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT kristiansenceciliekatrin polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT høylandlenaelise polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT zieglermathias polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT wangjian polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT sullivangarethjohn polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT lixingang polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT bindofflaurencea polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition
AT liangkristinaxiao polgmutationsleadtoabnormalmitochondrialremodelingduringneuraldifferentiationofhumanpluripotentstemcellsviasirt3ampkpathwayinhibition