Reactive oxygen species stimulate mitochondrial allele segregation toward homoplasmy in human cells |
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| Authors: | Feng Ling Rong Niu Hideyuki Hatakeyama Yu-ichi Goto Takehiko Shibata Minoru Yoshida |
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| Affiliation: | La Jolla Institute for Allergy and Immunology;aChemical Genetics Laboratory, RIKEN, Saitama 351-0198, Japan;dCellular and Molecular Biology Laboratory, RIKEN, Saitama 351-0198, Japan;bJapan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan;cDepartment of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan |
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| Abstract: | Mitochondria that contain a mixture of mutant and wild-type mitochondrial (mt) DNA copies are heteroplasmic. In humans, homoplasmy is restored during early oogenesis and reprogramming of somatic cells, but the mechanism of mt-allele segregation remains unknown. In budding yeast, homoplasmy is restored by head-to-tail concatemer formation in mother cells by reactive oxygen species (ROS)–induced rolling-circle replication and selective transmission of concatemers to daughter cells, but this mechanism is not obvious in higher eukaryotes. Here, using heteroplasmic m.3243A > G primary fibroblast cells derived from MELAS patients treated with hydrogen peroxide (H2O2), we show that an optimal ROS level promotes mt-allele segregation toward wild-type and mutant mtDNA homoplasmy. Enhanced ROS level reduced the amount of intact mtDNA replication templates but increased linear tandem multimers linked by head-to-tail unit-sized mtDNA (mtDNA concatemers). ROS-triggered mt-allele segregation correlated with mtDNA-concatemer production and enabled transmission of multiple identical mt-genome copies as a single unit. Our results support a mechanism by which mt-allele segregation toward mt-homoplasmy is mediated by concatemers. |
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