期刊
NATURE CELL BIOLOGY
卷 19, 期 4, 页码 341-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3491
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资金
- National Institutes of Health [R37-CA076584, R01-GM057587, R21-CA161108, 5T32CA009161-40]
- New York State Health Department [NYSTEM-N11G-255]
- American-Italian Cancer Foundation
- Italian Ministry of Health
- Italian Ministry of Education, University and Research [20129JLHSY_002, RBAP11FXBC_002, RBFR10EGVP_001]
- Telethon [GGP15219/B]
- Italian Cystic Fibrosis Research Foundation [19/2014]
- Italian Association for Cancer Research [IG-18624]
- University of Ferrara
- Perlmutter Cancer Center Support Grant [P30CA016087]
- Stowers Institute for Medical Research
Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded by Kif1bp) is an interactor of the mitochondrial-associated kinesin Kif1B alpha. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation. Defects in KBP degradation in mESCs result in an unscheduled increase in mitochondrial biogenesis, enhanced respiration and ROS production, and inhibition of cell proliferation. Silencing of Kif1B alpha reverts the aberrant increase in mitochondria induced by KBP stabilization. Notably, following differentiation, Kif1bp(-/-) mESCs display impaired expansion of the mitochondrial mass and form smaller embryoid bodies. Thus, KBP proteolysis limits the accumulation of mitochondria in mESCs to preserve their optimal fitness, whereas KBP accumulation promotes mitochondrial biogenesis in differentiating cells.
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