RRC ID 47774
Author Donato V, Bonora M, Simoneschi D, Sartini D, Kudo Y, Saraf A, Florens L, Washburn MP, Stadtfeld M, Pinton P, Pagano M.
Title The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.
Journal Nat Cell Biol
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 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 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 Kif1Bα 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.
Volume 19(4)
Pages 341-351
Published 2017-4-1
DOI 10.1038/ncb3491
PII ncb3491
PMID 28319092
PMC PMC5376241
MeSH Acetylation Alcohol Oxidoreductases / metabolism* Animals Carrier Proteins / metabolism* Cell Differentiation Cell Proliferation Cell Respiration Cell Self Renewal F-Box Proteins / metabolism* HEK293 Cells Humans Kinesins / metabolism Lentivirus / metabolism Mice Mitochondria / metabolism* Mitochondrial Proteins Mouse Embryonic Stem Cells / metabolism* Mutant Proteins / metabolism Nerve Tissue Proteins / metabolism* Organelle Biogenesis* Protein Binding Protein Stability Proteolysis RNA, Small Interfering / metabolism Substrate Specificity
IF 20.042
Times Cited 20
Mice RBRC01965