Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming

Tianhua Ma; Jun Li; Yue Xu; Chen Yu; Tao Xu; Haixia Wang; Kai Liu; Nan Cao; Bao-ming Nie; Sai-yong Zhu; Shaohua Xu; Ke Li; Wan-guo Wei; Yuzhang Wu; Kun-liang Guan; Sheng Ding

doi:10.1038/ncb3256

Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming

Nat Cell Biol. 2015 Nov;17(11):1379-87. doi: 10.1038/ncb3256. Epub 2015 Oct 26.

Authors

Tianhua Ma^{1

2}, Jun Li^{1

2

3}, Yue Xu^{1

2}, Chen Yu^{1

2}, Tao Xu^{1

2}, Haixia Wang^{1

2}, Kai Liu^{1

2}, Nan Cao^{1

2}, Bao-ming Nie^{1

2}, Sai-yong Zhu^{1

2}, Shaohua Xu^{1

2}, Ke Li^{1

2}, Wan-guo Wei⁴, Yuzhang Wu³, Kun-liang Guan⁵, Sheng Ding^{1

2}

Affiliations

¹ Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
² Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, USA.
³ Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China.
⁴ 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.
⁵ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.

PMID: 26502054
DOI: 10.1038/ncb3256

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Aminoimidazole Carboxamide / analogs & derivatives
Aminoimidazole Carboxamide / pharmacology
Animals
Autophagy*
Autophagy-Related Protein 5
Blotting, Western
Cells, Cultured
Cellular Reprogramming*
Embryo, Mammalian / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
Fibroblasts / ultrastructure
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron
Microscopy, Fluorescence
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism*
Mitochondria / metabolism*
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleotides / pharmacology
Sirolimus / pharmacology

Substances

Atg5 protein, mouse
Autophagy-Related Protein 5
Microtubule-Associated Proteins
Octamer Transcription Factor-3
Pou5f1 protein, mouse
Ribonucleotides
Green Fluorescent Proteins
Aminoimidazole Carboxamide
AMP-Activated Protein Kinases
AICA ribonucleotide
Sirolimus