title: Impaired ROS Scavenging System in Human Induced Pluripotent Stem Cells Generated from Patients with MERRF Syndrome.
abstract: Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial disorder characterized by myoclonus epilepsy, generalized seizures, ataxia and myopathy. MERRF syndrome is primarily due to an A to G mutation at mtDNA 8344 that disrupts the mitochondrial gene for tRNA(Lys). However, the detailed mechanism by which this tRNA(Lys) mutation causes mitochondrial dysfunction in cardiomyocytes or neurons remains unclear. In this study, we generated human induced pluripotent stem cells (hiPSCs) that carry the A8344G genetic mutation from patients with MERRF syndrome. Compared with mutation-free isogenic hiPSCs, MERRF-specific hiPSCs (MERRF-hiPSCs) exhibited reduced oxygen consumption, elevated reactive oxygen species (ROS) production, reduced growth, and fragmented mitochondrial morphology. We sought to investigate the induction ability and mitochondrial function of cardiomyocyte-like cells differentiated from MERRF-hiPSCs. Our data demonstrate that that cardiomyocyte-like cells (MERRF-CMs) or neural progenitor cells (MERRF-NPCs) differentiated from MERRF-iPSCs also exhibited increased ROS levels and altered antioxidant gene expression. Furthermore, MERRF-CMs or -NPCs contained fragmented mitochondria, as evidenced by MitoTracker Red staining and transmission electron microscopy. Taken together, these findings showed that MERRF-hiPSCs and MERRF-CM or -NPC harboring the A8344G genetic mutation displayed contained mitochondria with an abnormal ultrastructure, produced increased ROS levels, and expressed upregulated antioxidant genes.
authors.affiliation: Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Shih-Jie
authors.initials: SJ
authors.lastname: Chou
authors.affiliation: Institute of Pharmacology, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Tseng
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Chien-Tsun
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Lai
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chian-Shiu
authors.initials: CS
authors.lastname: Chien
authors.affiliation: Institute of Pharmacology, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Institute of Pharmacology, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.affiliation: Institute of Pharmacology, Taipei, Taiwan.|Institute of Clinical Medicine, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000293:Adolescent; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D017243:MERRF Syndrome / Q000378:metabolism* / Q000473:pathology; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D053140:Organelle Shape; D010101:Oxygen Consumption; D017354:Point Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species