title: Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs.
abstract: 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.
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Eunju
authors.initials: E
authors.lastname: Kang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tippner-Hedges
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Clifford D L
authors.initials: CD
authors.lastname: Folmes
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Nuria Marti
authors.initials: NM
authors.lastname: Gutierrez
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Yeonmi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Van Dyken
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Riffat
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Koski
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Hayama
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Amato
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jensen
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: David
authors.initials: D
authors.lastname: Battaglia
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lee
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Don P
authors.initials: DP
authors.lastname: Wolf
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic address: taosheng.huang@cchmc.org.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA. Electronic address: mitalipo@ohsu.edu.
authors.forename: Shoukhrat
authors.initials: S
authors.lastname: Mitalipov
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D001773:Blood Cells / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D012867:Skin / Q000166:cytology
chemical_list: D004272:DNA, Mitochondrial