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

Published on May 1, 2016in Cell Stem Cell 23.29
· 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
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)
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References48
Newest
Published on Sep 1, 2015in Scientific Reports 4.12
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
28 Citations Source Cite
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...
11 Citations Source Cite
Published on Aug 1, 2015in Nature 41.58
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...
80 Citations Source Cite
Published on Nov 1, 2014in Cell Stem Cell 23.29
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...
64 Citations Source Cite
Published on Oct 1, 2014in eLife 7.62
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...
155 Citations Source Cite
Published on Sep 18, 2014in PLOS Genetics 5.54
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...
49 Citations Source Cite
Published on Sep 1, 2014in Trends in Endocrinology and Metabolism 10.77
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...
38 Citations Source Cite
Published on Jul 1, 2014in Nature 41.58
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...
194 Citations Source Cite
Published on Jul 1, 2013in Stem Cells 5.59
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...
68 Citations Source Cite
Published on Jun 1, 2013in Cell 31.40
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...
458 Citations Source Cite
Cited By76
Newest
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...
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Published on Jun 1, 2019in Progress in Neurobiology 14.16
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...
6 Citations Source Cite
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...
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Published on May 9, 2019in Current Drug Targets 3.11
Xiaotong Wang1
Estimated H-index: 1
(HMU: Harbin Medical University),
Zhenbo Han5
Estimated H-index: 5
(HMU: Harbin Medical University)
+ 3 AuthorsYe Yuan4
Estimated H-index: 4
(HMU: Harbin Medical University)
1 Citations Source Cite
Published on May 5, 2019in Stem Cells International 3.99
James Spyrou1
Estimated H-index: 1
(University of Melbourne),
David K. Gardner76
Estimated H-index: 76
(University of Melbourne),
Alexandra J. Harvey14
Estimated H-index: 14
(University of Melbourne)
Reprogramming to pluripotency involves drastic restructuring of both metabolism and the epigenome. However, induced pluripotent stem cells (iPSC) retain transcriptional memory, epigenetic memory, and metabolic memory from their somatic cells of origin and acquire aberrant characteristics distinct from either other pluripotent cells or parental cells, reflecting incomplete reprogramming. As a critical link between the microenvironment and regulation of the epigenome, nutrient availability likely ...
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Published on May 1, 2019in Mitochondrion 3.23
Mauro Santibanez-Koref36
Estimated H-index: 36
(Centre for Life),
Helen Griffin22
Estimated H-index: 22
(Centre for Life)
+ 3 AuthorsGavin Hudson33
Estimated H-index: 33
(Newcastle University)
Abstract The mitochondrial genome has recently become the focus of several high-impact next-generation sequencing studies investigating the effect of mutations in disease and assessing the efficacy of mitochondrial replacement therapies. However, these studies have failed to take into consideration the capture of recurring translocations of mitochondrial DNA to the nuclear genome, known as nuclear mitochondrial sequences (NUMTs), continuing to align sequence data to the revised Cambridge referen...
1 Citations Source Cite
Published on Apr 1, 2019in Cancer Research 9.13
Petr Triska (SC: University of Southern California), Kristiyana Kaneva (Children's Hospital Los Angeles)+ 5 AuthorsXiaowu Gai25
Estimated H-index: 25
(SC: University of Southern California)
Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3 , MT-ND4 , and MT-ND5 , and at a mutation hotspot in MT-tRNA-M...
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