Disease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations

@article{Liang2020DiseasespecificPI,
  title={Disease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations},
  author={Kristina Xiao Liang and Cecilie Katrin Kristiansen and Sepideh Mostafavi and Guro Hel{\'e}n Vatne and Gina Alien Zantingh and Atefeh Kianian and Charalampos Tzoulis and Lena Elise H{\o}yland and Mathias Ziegler and Roberto Megias Perez and Jessica Furriol and Zhuoyuan Zhang and Novin Balafkan and Yu Hong and Richard Siller and Gareth John Sullivan and Laurence A. Bindoff},
  journal={EMBO Molecular Medicine},
  year={2020},
  volume={12}
}
Mutations in POLG disrupt mtDNA replication and cause devastating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post‐mortem brain tissue. We confirmed the same loss of mtDNA… 
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POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
ABSTRACT 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…
Stem cell derived astrocytes with POLG mutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons
TLDR
These studies provide a robust astroglia-neuronal interaction model for future investigation of mitochondrial involvement in neurogenesis and neurodegenerative diseases and demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astroCytes.
Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?
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…
Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells
TLDR
Recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies are summarized and patho-mechanistic insights as well as new therapeutic approaches that were uncovered are explored with this experimental platform.
N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation
Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations
TLDR
It is found that double treatment with nicotinamide riboside and metformin rescued mitophagy defects and mitochondrial dysfunction in POLG-mutant astrocytes and this study demonstrates the therapeutic potential of NR and meetformin in these incurable mitochondrial diseases.
A perspective on human cell models for POLG-spectrum disorders: advantages and disadvantages of CRISPR-Cas-based vs. patient-derived iPSC models
TLDR
This review provides an overview of the current approaches to model neurogenetic disorders in a human cellular and neuronal environment with a focus on POLG-spectrum disorders and the necessity of using neuronal cells and the advantages and pitfalls of currently available cell model approaches.
Distinct Mitochondrial Remodeling During Mesoderm Differentiation in a Human-Based Stem Cell Model
TLDR
It is found that mitochondrial content decreases continuously during mesoderm differentiation, despite increased mitochondrial activity and higher levels of ATP-linked respiration, and it is erroneous to assume that increased OXPHOS activity during differentiation requires a simultaneous expansion of mitochondrial content.
Distinct mitochondrial remodeling during early cardiomyocyte development in a human-based stem cell model
TLDR
It is found that differentiated cardiomyocytes have significantly lower level of mitochondria content compared to their original source, pluripotent stem cells, although the efficiency of ATP generation via mitochondria respiration increases.
Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration
TLDR
The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain.
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