Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming.
Successful generation of induced pluripotent stem cells entails a major metabolic switch from mitochondrial oxidative phosphorylation to glycolysis during the reprogramming process. The mechanism of this metabolic reprogramming, however, remains elusive. Here, our results suggest that an Atg5-independent autophagic process mediates mitochondrial clearance, a characteristic event involved in the metabolic switch. We found that blocking such autophagy, but not canonical autophagy, inhibits mitochondrial clearance, in turn, preventing iPSC induction. Furthermore, AMPK seems to be upstream of this autophagic pathway and can be targeted by small molecules to modulate mitochondrial clearance during metabolic reprogramming. Our work not only reveals that the Atg5-independent autophagy is crucial for establishing pluripotency, but it also suggests that iPSC generation and tumorigenesis share a similar metabolic switch.
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Tianhua
T
Ma
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.|Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China.
Jun
J
Li
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Yue
Y
Xu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Chen
C
Yu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Tao
T
Xu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Haixia
H
Wang
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Kai
K
Liu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Nan
N
Cao
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Bao-ming
BM
Nie
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Sai-yong
SY
Zhu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Shaohua
S
Xu
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Ke
K
Li
Center for Stem Cell and Regenerative Medicine, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 99, Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.
Wan-guo
WG
Wei
Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China.
Yuzhang
Y
Wu
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
Kun-liang
KL
Guan
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
Sheng
S
Ding
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D015153:Blotting, Western; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012265:Ribonucleotides; D049452:Green Fluorescent Proteins; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus