The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.
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.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
Valerio
V
Donato
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121, Italy.
Massimo
M
Bonora
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
Daniele
D
Simoneschi
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
Davide
D
Sartini
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|Department of Oral Molecular Pathology, Tokushima University Graduate School 3-18-15 Kuramoto, Tokushima 770-8504, Japan.
Yasusei
0000-0002-0392-7720
Y
Kudo
The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
Anita
A
Saraf
The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
Laurence
L
Florens
The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.|Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.
Michael P
0000-0001-7568-2585
MP
Washburn
Skirball Institute of Biomolecular Medicine and Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University School of Medicine, 522 First Avenue, New York, New York 10016, USA.
Matthias
M
Stadtfeld
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121, Italy.
Paolo
P
Pinton
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.|Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
Michele
M
Pagano
D000107:Acetylation; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019069:Cell Respiration; D000066673:Cell Self Renewal; D044783:F-Box Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D001678:Organelle Biogenesis; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000378:metabolism; D013379:Substrate Specificity
C000619640:BLOC1S1 protein, mouse; D002352:Carrier Proteins; D044783:F-Box Proteins; C518314:Fbx15 protein, mouse; C554342:KBP protein, mouse; C490398:Kif1b protein, mouse; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D000429:Alcohol Oxidoreductases; C023159:L-threonine 3-dehydrogenase; D016547:Kinesins