title: Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects.
abstract: Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. Here, we show that reprogramming of elderly fibroblasts restores age-associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes.
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashizume
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Ohnishi
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mito
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Kaori
authors.initials: K
authors.lastname: Iashikawa
authors.affiliation: 1] Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Soda
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.affiliation: Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Togayachi
authors.affiliation: 1] Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan [2] Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kawahara-cho 53, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.affiliation: 1] Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan [2] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan [3] TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hayashi
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000369:Aged, 80 and over; D000375:Aging; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D002648:Child; D004272:DNA, Mitochondrial / Q000032:analysis; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D005998:Glycine / Q000096:biosynthesis; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007223:Infant; D008049:Lipase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D000217:Acyltransferases; C085461:Aeromonas hydrophilia lipase-acyltransferase; D008049:Lipase; D005998:Glycine