Mitochondrial <scp>DNA</scp> mutations in <scp>iPS</scp> cells: mt<scp>DNA</scp> integrity as standard <scp>iPSC</scp> selection criteria?

Hämäläinen, Riikka H.

doi:10.15252/embj.201695185

Cited by 13 publications

(4 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mtDNA encodes required subunits of the electron transport and oxidative phosphorylation complexes as well as the ribosomal and transfer RNAs required for their translation 18 . As a result, it is critical to evaluate whether mtDNA integrity is preserved throughout the process of generating COs 19 . The integrity of mtDNA can be evaluated by identifying the: (1) haplogroup, which is defined by a set of genetic variants associated with maternal ancestry; (2) percentage of heteroplasmy (mix of normal and mutated mtDNA) or homoplasmy (uniform collection of mtDNA, either mutated or normal) and; (3) copy number.…”

Section: Resultsmentioning

confidence: 99%

Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells

Duong

Evstratova

Sivitilli

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Mitochondrial health plays a crucial role in human brain development and diseases. However, the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ethical and logistical concerns. As a result, the development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues. To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples.

show abstract

Section: Resultsmentioning

confidence: 99%

Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells

Duong

Evstratova

Sivitilli

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Hence, differences in mtDNA profiles might contribute to behavioral heterogeneity among iPSC clones (Kelly et al , 2013 ; Carelli et al , 2022 ). Several groups have, therefore, argued that screening for mtDNA modifications should become part of the routine quality control of all newly generated iPSC lines, in a similar manner as nuclear chromosomal rearrangements are currently monitored (Hämäläinen, 2016 ; Lorenz & Prigione, 2016 ; Carelli et al , 2022 ; Rossi et al , 2022 ).…”

Section: Induced Pluripotent Stem Cells ( Ipscs ) ...mentioning

confidence: 99%

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids

2023

View full text Add to dashboard Cite

Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

show abstract

“…However, a factor limiting the use of organoids is the gap in our knowledge about mechanisms of organoid development from iPSCs. Particularly, we do not know the details on a contribution of mitochondrial dysfunction to the disruption of developmental program in cells obtained from iPSCs, i.e., mutations of mitochondrial DNA abundantly present in iPSCs lead to significant functional defects in cells derived from iPSCs [ 157 ]. The same phenomenon was demonstrated in neurons derived from iPSCs obtained from persons with schizophrenia [ 158 ], but it remains unclear whether the presence of such defects is a direct consequence of mutations in the cell genome in a specific pathology, or whether they arise as a result of reprogramming and subsequent differentiation.…”

Section: Application Of In Vitro Nvu/bbb Models For Studying Mitochondria-related Changes In Cell Metabolism: Current Trends and Challengmentioning

confidence: 99%

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

Салмина

Kharitonova

Gorina

et al. 2021

IJMS

View full text Add to dashboard Cite

Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease.

show abstract

Mitochondrial DNA mutations in iPS cells: mtDNA integrity as standard iPSC selection criteria?

Cited by 13 publications

References 11 publications

Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells

Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

Contact Info

Product

Resources

About