POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia

Yang, Hong; Kristiansen, Cecilie Katrin; Chen, Anbin; Nido, Gonzalo S.; Høyland, Lena Elise; Ziegler, Mathias; Sullivan, Gareth J.; Bindoff, Laurence A.; Liang, Kristina Xiao

doi:10.1016/j.expneurol.2023.114429

Cited by 3 publications

(6 citation statements)

References 36 publications

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“…The current research identified a notable difference in the ability to restore mtDNA levels in iPSC-derived NSCs carrying compound heterozygous POLG mutations, in comparison to both controls and homozygous mutation carriers. This discovery aligns well with the previous study, 38 which also highlighted a greater mitochondrial functional impairment in compound heterozygous NSCs compared to their homozygous counterparts. While both studies agree on the more severe impact of compound heterozygous POLG mutations in NSCs, it's intriguing to note the differences in manifestations across different cell types.…”

Section: Of 15supporting

confidence: 92%

“…This therapeutic strategy might have broad implications, given the pervasive role of POLG in mitochondrial diseases. In conclusion, the observations from the present study and our previous paper 38 underline the complexity of the cellular response to POLG mutations, dependent not only on the type of mutation (homozygous or compound heterozygous) but also the specific cell lineage. These discoveries pave the way for more targeted therapeutic strategies.…”

Section: Of 15supporting

confidence: 76%

“…This study, in combination with the previously published findings, 38 has significantly advanced our understanding of the pathological mechanisms behind POLG mutations and the effect they have on mtDNA maintenance, particularly in NSCs. The current research identified a notable difference in the ability to restore mtDNA levels in iPSC-derived NSCs carrying compound heterozygous POLG mutations, in comparison to both controls and homozygous mutation carriers.…”

Section: Of 15supporting

confidence: 65%

“…While both studies agree on the more severe impact of compound heterozygous POLG mutations in NSCs, it's intriguing to note the differences in manifestations across different cell types. The previously published findings, 38 reported no observed functional differences between compound heterozygous and homozygous mutations in fibroblasts, iPSCs, or astrocytes, emphasizing the vulnerability of NSCs in the context of POLG mutations. In this study, the use of EtBr to induce mtDNA depletion, followed by studying repopulation rates in the current study, offers a functional perspective to support the earlier observations 38 regarding the disturbance of mtDNA copy number.…”

Section: Of 15mentioning

confidence: 51%

“…The previously published findings, 38 reported no observed functional differences between compound heterozygous and homozygous mutations in fibroblasts, iPSCs, or astrocytes, emphasizing the vulnerability of NSCs in the context of POLG mutations. In this study, the use of EtBr to induce mtDNA depletion, followed by studying repopulation rates in the current study, offers a functional perspective to support the earlier observations 38 regarding the disturbance of mtDNA copy number. Moreover, the current findings suggest a potential therapeutic approach, as dNs supplementation was found to mitigate the effects of EtBr-induced mtDNA depletion and improve repopulation rates in both patient-derived NSCs.…”

Section: Of 15mentioning

confidence: 51%

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Deoxyribonucleoside treatment rescues EtBr‐induced mtDNA depletion in iPSC‐derived neural stem cells with POLG mutations

et al. 2023

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Mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (Pol‐γ), lead to diseases driven by defective mtDNA maintenance. Despite being the most prevalent cause of mitochondrial disease, treatments for POLG‐related disorders remain elusive. In this study, we used POLG patient‐induced pluripotent stem cell (iPSC)‐derived neural stem cells (iNSCs), one homozygous for the POLG mutation c.2243G>C and one compound heterozygous with c.2243G>C and c.1399G>A, and treated these iNSCs with ethidium bromide (EtBr) to study the rate of depletion and repopulation of mtDNA. In addition, we investigated the effect of deoxyribonucleoside (dNs) supplementation on mtDNA maintenance during EtBr treatment and post‐treatment repopulation in the same cells. EtBr‐induced mtDNA depletion occurred at a similar rate in both patient and control iNSCs, however, restoration of mtDNA levels was significantly delayed in iNSCs carrying the compound heterozygous POLG mutations. In contrast, iNSC with the homozygous POLG mutation recovered their mtDNA at a rate similar to controls. When we treated cells with dNs, we found that this reduced EtBr‐induced mtDNA depletion and significantly increased repopulation rates in both patient iNSCs. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation also within intact neural lineage cells and suggest that those with compound heterozygous mutation have a more severe defect of mtDNA synthesis. Our findings further highlight the potential for dNs to improve mtDNA replication in the presence of POLG mutations, suggesting that this may offer a new therapeutic modality for mitochondrial diseases caused by disturbed mtDNA homeostasis.

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Section: Of 15supporting

confidence: 92%

Section: Of 15supporting

confidence: 76%

Section: Of 15supporting

confidence: 65%

Section: Of 15mentioning

confidence: 51%

Section: Of 15mentioning

confidence: 51%

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Deoxyribonucleoside treatment rescues EtBr‐induced mtDNA depletion in iPSC‐derived neural stem cells with POLG mutations

et al. 2023

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Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells

Walter‐Manucharyan,

Martin,

Pfützner

et al. 2024

Dev Growth Differ

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Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8‐NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase‐γ by 2′‐3′‐dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.

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Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation

Aguilar,

Jakubek,

Zorzano

et al. 2024

Eur J Clin Investigation

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Objectives and scopePrimary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient‐derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.InsightsThe central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.SummaryIn summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.

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POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia

Cited by 3 publications

References 36 publications

Deoxyribonucleoside treatment rescues EtBr‐induced mtDNA depletion in iPSC‐derived neural stem cells with POLG mutations

Deoxyribonucleoside treatment rescues EtBr‐induced mtDNA depletion in iPSC‐derived neural stem cells with POLG mutations

Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells

Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation

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