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The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

ABSTRACT: 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?. 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? 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.

SUBMITTER: Donato V

PROVIDER: S-EPMC5376241 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

Donato Valerio V Bonora Massimo M Simoneschi Daniele D Sartini Davide D Kudo Yasusei Y Saraf Anita A Florens Laurence L Washburn Michael P MP Stadtfeld Matthias M Pinton Paolo P Pagano Michele M

Nature cell biology 20170320 4

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 Kif1Bα. 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 t ...[more]

PMID: 28319092

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The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

Publications

The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

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