RRC ID 33706
Author Hashizume O, Ohnishi S, Mito T, Shimizu A, Ishikawa K, Nakada K, Soda M, Mano H, Togayachi S, Miyoshi H, Okita K, Hayashi J.
Title Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects.
Journal Sci Rep
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.
Volume 5
Pages 10434
Published 2015-5-22
DOI 10.1038/srep10434
PII srep10434
PMID 26000717
PMC PMC5377050
MeSH Acyltransferases / antagonists & inhibitors Acyltransferases / genetics* Acyltransferases / metabolism Aged, 80 and over Aging* Cell Differentiation Cell Line Cellular Reprogramming Child DNA, Mitochondrial / analysis Epigenesis, Genetic* Fibroblasts / cytology Fibroblasts / metabolism Gene Dosage Glycine / biosynthesis Glycine Hydroxymethyltransferase / genetics* Glycine Hydroxymethyltransferase / metabolism Humans Induced Pluripotent Stem Cells / cytology Induced Pluripotent Stem Cells / metabolism Infant Lipase / antagonists & inhibitors Lipase / genetics* Lipase / metabolism Mitochondria / metabolism* Oligonucleotide Array Sequence Analysis Oxygen Consumption Phenotype RNA Interference RNA, Small Interfering / metabolism Reactive Oxygen Species / metabolism Real-Time Polymerase Chain Reaction Sequence Analysis, DNA
IF 3.998
Times Cited 37
DNA material GNP Clone IRAL034F16 (HGY093736) CSII-EF-RfA-IRES-Puro (RDB12869) CS-RfA-CG (RDB04390) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)