N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation

Liang, Kristina Xiao; Vatne, Guro Helén; Kristiansen, Cecilie Katrin; Ievglevskyi, Oleksandr; Kondratskaya, Elena; Glover, Joel C.; Chen, Anbin; Sullivan, Gareth J.; Bindoff, Laurence A.

doi:10.1016/j.expneurol.2020.113536

Cited by 22 publications

(42 citation statements)

References 54 publications

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“…Mutations in POLG (OMIM# 174763) are responsible for an array of mitochondrial disorders with neurological manifestations, including progressive external ophthalmoplegia (PEO) [ 124 ]. The effects of compound heterozygous POLG mutations resulting in autosomal recessive PEO were analysed using patient derived iPSC-NSCs [ 125 ] and iPSC-DANs [ 126 ]. Consistent with the prominent role played by POLG in mtDNA replication, mutant iPSC-NSCs and iPSC-DANs displayed reduced mtDNA copy number and CI subunit expression, features of which were seen in neurons isolated from the patient brain tissues, but not iPSCs or fibroblasts [ 125 , 126 ].…”

Section: Functional Studiesmentioning

confidence: 99%

“…The effects of compound heterozygous POLG mutations resulting in autosomal recessive PEO were analysed using patient derived iPSC-NSCs [ 125 ] and iPSC-DANs [ 126 ]. Consistent with the prominent role played by POLG in mtDNA replication, mutant iPSC-NSCs and iPSC-DANs displayed reduced mtDNA copy number and CI subunit expression, features of which were seen in neurons isolated from the patient brain tissues, but not iPSCs or fibroblasts [ 125 , 126 ]. Consequently, a reduction in the NAD + :NADH ratio was identified in POLG patient iPSC-NSCs compared to controls, while the undifferentiated patient iPSCs trended towards an increased NAD + :NADH ratio [ 125 ].…”

Section: Functional Studiesmentioning

confidence: 99%

“…With disruptions in OXPHOS being touted as a major contributor to ROS production [ 127 ], POLG patient-derived iPSC-NSCs and iPSC-DANs showed increased ROS levels that could be improved following N-acetylcysteine amide supplementation [ 125 , 126 ]. An increase in ROS was otherwise not detected in the patient iPSCs, while patient fibroblasts showed reduced ROS levels instead when compared to controls [ 125 ].…”

Section: Functional Studiesmentioning

confidence: 99%

“…An increase in ROS was otherwise not detected in the patient iPSCs, while patient fibroblasts showed reduced ROS levels instead when compared to controls [ 125 ]. Reduced ATP levels were also seen in patient iPSCs, iPSC-NSCs, and fibroblasts, but not iPSC-DANs [ 125 , 126 ]. Such differences between cell types highlight the importance of utilising iPSC-derived clinically relevant cell types to replicate tissue specific defects for the purposes of therapeutic investigations.…”

Section: Functional Studiesmentioning

confidence: 99%

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Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

McKnight

Low

Elliott

et al. 2021

IJMS

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Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modelling these disorders is challenging as many non-human models of mitochondrial disease do not completely recapitulate human phenotypes for known disease genes. Additionally, access to disease-relevant cell or tissue types from patients is often limited. To overcome these difficulties, many groups have turned to human pluripotent stem cells (hPSCs) to model mitochondrial disease for both nuclear-DNA (nDNA) and mitochondrial-DNA (mtDNA) contexts. Leveraging the capacity of hPSCs to differentiate into clinically relevant cell types, these models permit both detailed investigation of cellular pathomechanisms and validation of promising treatment options. Here we catalogue hPSC models of mitochondrial disease that have been generated to date, summarise approaches and key outcomes of phenotypic profiling using these models, and discuss key criteria to guide future investigations using hPSC models of mitochondrial disease.

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Section: Functional Studiesmentioning

confidence: 99%

Section: Functional Studiesmentioning

confidence: 99%

Section: Functional Studiesmentioning

confidence: 99%

Section: Functional Studiesmentioning

confidence: 99%

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Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

McKnight

Low

Elliott

et al. 2021

IJMS

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“…[36] On the vascular side we applied N-acetylcysteine amide (NACA), [37] a more lipophilic (and thus more bioavailable and BBB-permeable) -albeit much less widely used -version of the parent molecule NAC, both proven to reduce neurotoxicity. [38][39][40] 2. Results & Discussion…”

Section: Introductionmentioning

confidence: 99%

Continuous monitoring reveals protective effects ofN-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

Matthiesen

Voulgaris

Nikolakopoulou

et al. 2021

Preprint

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Microphysiological systems mimic the in vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. We report the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2-minute temporal resolution. We showcase its capabilities in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol-ene epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell-substrate endothelial resistance monitoring allows us to capture formation and breakdown of our blood-brain barrier model, consisting of co-cultured hiPSC-derived endothelial-like and astrocyte-like cells. We observe clear cellular disruption when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and report on the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide. Using metabolomic network analysis, we further find drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like ours opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.

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Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids

Chen,

Yangzom,

Hong

et al. 2024

Advanced Science

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In this research, a 3D brain organoid model is developed to study POLG‐related encephalopathy, a mitochondrial disease stemming from POLG mutations. Induced pluripotent stem cells (iPSCs) derived from patients with these mutations is utilized to generate cortical organoids, which exhibited typical features of the diseases with POLG mutations, such as altered morphology, neuronal loss, and mitochondiral DNA (mtDNA) depletion. Significant dysregulation is also identified in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK‐STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory dopamine‐glutamate (DA GLU) neurons. This novel model effectively mirrors both the molecular and pathological attributes of diseases with POLG mutations, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG‐related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.

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N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation

Cited by 22 publications

References 54 publications

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

Continuous monitoring reveals protective effects ofN-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids

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