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Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs.

Published on May 1, 2016in Cell Stem Cell21.46
· DOI :10.1016/j.stem.2016.02.005
Eunju Kang13
Estimated H-index: 13
(Oregon National Primate Research Center),
Xinjian Wang20
Estimated H-index: 20
(Cincinnati Children's Hospital Medical Center)
+ 20 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
Cite
Abstract
Summary The genetic integrity of iPSCs is an important consideration for therapeutic application. In this study, we examine the accumulation of somatic mitochondrial genome (mtDNA) mutations in skin fibroblasts, blood, and iPSCs derived from young and elderly subjects (24–72 years). We found that pooled skin and blood mtDNA contained low heteroplasmic point mutations, but a panel of ten individual iPSC lines from each tissue or clonally expanded fibroblasts carried an elevated load of heteroplasmic or homoplasmic mutations, suggesting that somatic mutations randomly arise within individual cells but are not detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, and many mutations were non-synonymous or resided in RNA coding genes and thus can lead to respiratory defects. Our results highlight a need to monitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine the metabolic status of iPSCs destined for clinical applications.
  • References (48)
  • Citations (76)
Cite
References48
Newest
Published on Sep 1, 2015in Scientific Reports4.01
Osamu Hashizume7
Estimated H-index: 7
,
Sakiko Ohnishi2
Estimated H-index: 2
+ 9 AuthorsHiroyuki Miyoshi47
Estimated H-index: 47
Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects
Published on Sep 1, 2015in Mutation Research
Yong-Gang Yao41
Estimated H-index: 41
(KIZ: Kunming Institute of Zoology),
Sachiko Kajigaya40
Estimated H-index: 40
,
Neal S. Young102
Estimated H-index: 102
Abstract Determination mitochondrial DNA (mtDNA) sequences from extremely small amounts of DNA extracted from tissue of limited amounts and/or degraded samples is frequently employed in medical, forensic, and anthropologic studies. Polymerase chain reaction (PCR) amplification followed by DNA cloning is a routine method, especially to examine heteroplasmy of mtDNA mutations. In this review, we compare the mtDNA mutation patterns detected by three different sequencing strategies. Cloning and sequ...
Published on Aug 1, 2015in Nature43.07
Hong Ma27
Estimated H-index: 27
(Oregon National Primate Research Center),
Clifford D.L. Folmes17
Estimated H-index: 17
(Mayo Clinic)
+ 23 AuthorsRiffat Ahmed10
Estimated H-index: 10
(OHSU: Oregon Health & Science University)
Mitochondria have a major role in energy production via oxidative phosphorylation, which is dependent on the expression of critical genes encoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorders with limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy (that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generated genetically corrected pluripotent stem cells (PSCs) from pat...
Published on Nov 1, 2014in Cell Stem Cell21.46
Bjarki Johannesson10
Estimated H-index: 10
(New York Stem Cell Foundation),
Ido Sagi7
Estimated H-index: 7
(HUJI: Hebrew University of Jerusalem)
+ 15 AuthorsSamantha Stern1
Estimated H-index: 1
(New York Stem Cell Foundation)
Summary The recent finding that reprogrammed human pluripotent stem cells can be derived by nuclear transfer into human oocytes as well as by induced expression of defined factors has revitalized the debate on whether one approach might be advantageous over the other. Here we compare the genetic and epigenetic integrity of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonat...
Published on Oct 1, 2014in eLife7.55
Young Seok Ju18
Estimated H-index: 18
(Wellcome Trust Sanger Institute),
Ludmil B. Alexandrov42
Estimated H-index: 42
(Wellcome Trust Sanger Institute)
+ 47 AuthorsAdam Shlien31
Estimated H-index: 31
(Wellcome Trust Sanger Institute)
The DNA in a cell's nucleus must be copied faithfully, and divided equally, when a cell divides to produce two new cells. Mistakes—or mutations—are sometimes made during the copying process, and mutations can also be introduced by exposing DNA to damaging agents known as mutagens, such as UV light or cigarette smoke. These mutations are then maintained in all of the descendants of the cell. Most of these mutations have no impact on the cell's characteristics (‘passenger mutations’). However, ‘dr...
Published on Sep 18, 2014in PLOS Genetics5.22
Laura C. Greaves23
Estimated H-index: 23
(Newcastle University),
Marco Nooteboom4
Estimated H-index: 4
(Newcastle University)
+ 9 AuthorsThomas B. L. Kirkwood67
Estimated H-index: 67
(Newcastle University)
Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell populatio...
Published on Sep 1, 2014in Trends in Endocrinology and Metabolism9.78
Emma Yu7
Estimated H-index: 7
(University of Cambridge),
Martin R. Bennett61
Estimated H-index: 61
(University of Cambridge)
Mitochondria are often regarded as the cellular powerhouses through their ability to generate ATP, the universal fuel for metabolic processes. However, in recent years mitochondria have been recognised as critical regulators of cell death, inflammation, metabolism, and the generation of reactive oxygen species (ROS). Thus, mitochondrial dysfunction directly promotes cell death, inflammation, and oxidative stress and alters metabolism. These are key processes in atherosclerosis and there is now e...
Published on Jul 1, 2014in Nature43.07
Hong Ma27
Estimated H-index: 27
(Oregon National Primate Research Center),
Robert Morey9
Estimated H-index: 9
(UCSD: University of California, San Diego)
+ 23 AuthorsKaren Sabatini6
Estimated H-index: 6
(UCSD: University of California, San Diego)
Genome-wide analysis of matched human IVF embryonic stem cells (IVF ES cells), induced pluripotent stem cells (iPS cells) and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) reveals that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT; NT ES cells and iPS cells derived from the same somatic cells contain comparable numbers of de novo copy number variations, but whereas DNA methylation and transcriptome profiles of NT ES cells and...
Published on Jul 1, 2013in Stem Cells5.61
Clifford D.L. Folmes17
Estimated H-index: 17
(Mayo Clinic),
Almudena Martinez-Fernandez16
Estimated H-index: 16
(Mayo Clinic)
+ 7 AuthorsTimothy J. Nelson27
Estimated H-index: 27
Mitochondrial diseases display pathological phenotypes according to the mixture of mutant versus wild-type mitochondrial DNA (mtDNA), known as heteroplasmy. We herein examined the impact of nuclear reprogramming and clonal isolation of induced pluripotent stem cells (iPSC) on mitochondrial heteroplasmy. Patient-derived dermal fibroblasts with a prototypical mitochondrial deficiency diagnosed as MELAS demonstrated mitochondrial dysfunction with reduced oxidative reserve due to heteroplasmy at pos...
Published on Jun 1, 2013in Cell36.22
Masahito Tachibana14
Estimated H-index: 14
(Oregon National Primate Research Center),
Paula Amato21
Estimated H-index: 21
(OHSU: Oregon Health & Science University)
+ 20 AuthorsHathaitip Sritanaudomchai9
Estimated H-index: 9
(MU: Mahidol University)
Summary Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer (NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors tha...
Cited By76
Newest
Published on Aug 26, 2019in Journal of Human Genetics3.54
Go Hun Seo2
Estimated H-index: 2
(UOU: University of Ulsan),
Arum Oh1
Estimated H-index: 1
(UOU: University of Ulsan)
+ 9 AuthorsHan-Wook Yoo23
Estimated H-index: 23
(UOU: University of Ulsan)
Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient....
Published on 2019in Journal of Biological Chemistry
Amir Bahat1
Estimated H-index: 1
,
Atan Gross25
Estimated H-index: 25
Published on Apr 24, 2019in bioRxiv
Rui Ye1
Estimated H-index: 1
(HKU: University of Hong Kong),
Jie Ruan + 10 AuthorsXun Xu57
Estimated H-index: 57
As next generation sequencing (NGS) and liquid biopsy become more prevalent in clinical and research area, especially cancer diagnosis, targeted therapy guidance and disease surveillance, there is an increasing need for better methods to reduce cost and to improve sensitivity and specificity. Since the error rate of NGS is around 1%, it is difficult to identify mutations with frequency lower than 1% accurately and efficiently because of low Signal-to- Noise Ratio (SNR). Here we propose a likelih...
Published on Aug 19, 2019in Nature Biotechnology31.86
T. Deuse23
Estimated H-index: 23
(UCSF: University of California, San Francisco),
X. Hu2
Estimated H-index: 2
(UCSF: University of California, San Francisco)
+ 16 AuthorsZeynep Koşaloğlu-Yalçın (La Jolla Institute for Allergy and Immunology)
The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of elicitin...
Published on Jun 19, 2019in Human and Ecological Risk Assessment2.01
Daniel A. Axelrad17
Estimated H-index: 17
(EPA: United States Environmental Protection Agency),
R. Woodrow Setzer32
Estimated H-index: 32
(EPA: United States Environmental Protection Agency)
+ 7 AuthorsMichael J. Stewart1
Estimated H-index: 1
(EPA: United States Environmental Protection Agency)
Published on Jun 18, 2019in Cells
Huanzheng Li , Jesse Slone + 1 AuthorsTaosheng Huang13
Estimated H-index: 13
The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging and related diseases is mtDNA instability over the life of an individual. The mutation rate of mammalian mtDNA is significantly higher than the mutation rate observed for nuclear DNA, due to the poor fidelity of DNA polymerase and the R...
Published on Jun 1, 2019in Progress in Neurobiology10.66
Anne Grünewald22
Estimated H-index: 22
(University of Lübeck),
Kishore R. Kumar13
Estimated H-index: 13
(Kolling Institute of Medical Research),
Carolyn M. Sue43
Estimated H-index: 43
(Kolling Institute of Medical Research)
Abstract New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson’s disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the d...
Published on Jun 1, 2019in Neurology Genetics
Christopher Newell4
Estimated H-index: 4
,
Aneal Khan13
Estimated H-index: 13
+ 6 AuthorsIveta Sosova
Objective We developed a novel, hybrid method combining both blue-native (BN-PAGE) and clear-native (CN-PAGE) polyacrylamide gel electrophoresis, termed BCN-PAGE, to perform in-gel activity stains on the mitochondrial electron transport chain (ETC) complexes in skin fibroblasts. Methods Four patients aged 46–65 years were seen in the Metabolic Clinic at Alberta Children9s Hospital and investigated for mitochondrial disease and had BN-PAGE or CN-PAGE on skeletal muscle that showed incomplete asse...
Published on May 27, 2019in Protein & Cell7.58
Meiyan Wang (UCSD: University of California, San Diego), Lei Zhang5
Estimated H-index: 5
(Salk Institute for Biological Studies),
Fred H. Gage189
Estimated H-index: 189
(Salk Institute for Biological Studies)
Neuropsychiatric disorders are complex disorders characterized by heterogeneous genetic variations, variable symptoms, and widespread changes in anatomical pathology. In the context of neuropsychiatric disorders, limited access to relevant tissue types presents challenges for understanding disease etiology and developing effective treatments. Induced pluripotent stem cells (iPSCs) reprogrammed from patient somatic cells offer an opportunity to recapitulate disease development in relevant cell ty...