title: ATG3-dependent autophagy mediates mitochondrial homeostasis in pluripotency acquirement and maintenance.
abstract: Pluripotent stem cells, including induced pluripotent and embryonic stem cells (ESCs), have less developed mitochondria than somatic cells and, therefore, rely more heavily on glycolysis for energy production.1-3However, how mitochondrial homeostasis matches the demands of nuclear reprogramming and regulates pluripotency in ESCs is largely unknown. Here, we identified ATG3-dependent autophagy as an executor for both mitochondrial remodeling during somatic cell reprogramming and mitochondrial homeostasis regulation in ESCs. Dysfunctional autophagy by Atg3 deletion inhibited mitochondrial removal during pluripotency induction, resulting in decreased reprogramming efficiency and accumulation of abnormal mitochondria in established iPSCs. In Atg3 null mouse ESCs, accumulation of aberrant mitochondria was accompanied by enhanced ROS generation, defective ATP production and attenuated pluripotency gene expression, leading to abnormal self-renewal and differentiation. These defects were rescued by reacquisition of wild-type but not lipidation-deficient Atg3 expression. Taken together, our findings highlight a critical role of ATG3-dependent autophagy for mitochondrial homeostasis regulation in both pluripotency acquirement and maintenance.
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Kun
authors: K
authors: Liu
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Qian
authors: Q
authors: Zhao
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Pinglei
authors: P
authors: Liu
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Jiani
authors: J
authors: Cao
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Jiaqi
authors: J
authors: Gong
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|c School of Biological Sciences, Qufu Normal University , Qufu , China.
authors: Chaoqun
authors: C
authors: Wang
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Weixu
authors: W
authors: Wang
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Xiaoyan
authors: X
authors: Li
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Hongyan
authors: H
authors: Sun
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Chao
authors: C
authors: Zhang
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Yufei
authors: Y
authors: Li
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.
authors: Minggui
authors: M
authors: Jiang
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Graduate University of Chinese Academy of Sciences , Beijing , China.|d School of Biological Sciences, University of Science and Technology of China , Hefei , China.
authors: Shaohua
authors: S
authors: Zhu
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Qingyuan
authors: Q
authors: Sun
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Jianwei
authors: J
authors: Jiao
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Baoyang
authors: B
authors: Hu
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Xiaoyang
authors: X
authors: Zhao
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Wei
authors: W
authors: Li
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Quan
authors: Q
authors: Chen
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Qi
authors: Q
authors: Zhou
authors: a State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
authors: Tongbiao
authors: T
authors: Zhao
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D000066673:Cell Self Renewal; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; D044763:Ubiquitin-Conjugating Enzymes; C568853:Atg3 protein, mouse
keywords: ATG3; mitochondria; mitophagy; pluripotent stem cell; reprogramming