PMID- 30150300
OWN - NLM
STAT- MEDLINE
DCOM- 20190304
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 41
DP  - 2018 Oct 12
TI  - Active mitochondria support osteogenic differentiation by stimulating beta-catenin 
      acetylation.
PG  - 16019-16027
LID - 10.1074/jbc.RA118.004102 [doi]
AB  - Bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) can differentiate 
      into osteoblasts (OBs), adipocytes, or chondrocytes. As BMSCs undergo OB 
      differentiation, they up-regulate mitochondrial oxidative phosphorylation 
      (OxPhos). Here, we investigated the mechanism(s) connecting mitochondrial OxPhos 
      to OB differentiation. First, we found that treating BMSC-like C3H10T1/2 cells 
      with an OxPhos inhibitor reduces their osteogenic potential. Interestingly, ATP 
      levels were not reduced, as glycolysis compensated for the decreased OxPhos. 
      Thus, mitochondria support OB differentiation not only by supplying ATP, but also 
      by other mechanisms. To uncover these mechanisms, we stimulated OxPhos in 
      C3H10T1/2 cells by replacing media glucose with galactose and observed that this 
      substitution increases both OxPhos and osteogenesis even in the absence of 
      osteoinducers. beta-Catenin, an important signaling pathway in osteogenesis, was 
      found to be responsive to OxPhos stimulation. beta-Catenin activity is maintained by 
      acetylation, and mitochondria generate the acetyl donor acetyl-CoA, which upon 
      entering the Krebs cycle is converted to citrate capable of exiting mitochondria. 
      Cytosolic citrate is converted back to acetyl-CoA by ATP citrate lyase (ACLY). We 
      found that inhibiting ACLY with SB204990 (SB) reverses the galactose-induced 
      beta-catenin activity and OB differentiation. This suggested that acetylation is 
      involved in beta-catenin activation after forced OxPhos stimulation, and using 
      immunoprecipitation, we indeed detected SB-sensitive beta-catenin acetylation. Both 
      beta-catenin acetylation and activity increased during osteoinduction coincident 
      with OxPhos activation. These findings suggest that active mitochondria support 
      OB differentiation by promoting beta-catenin acetylation and thus activity.
CI  - (c) 2018 Shares et al.
FAU - Shares, Brianna H
AU  - Shares BH
AD  - From the Center for Musculoskeletal Research, University of Rochester, Rochester, 
      New York 14624.
FAU - Busch, Melanie
AU  - Busch M
AD  - From the Center for Musculoskeletal Research, University of Rochester, Rochester, 
      New York 14624.
FAU - White, Noelle
AU  - White N
AD  - From the Center for Musculoskeletal Research, University of Rochester, Rochester, 
      New York 14624.
FAU - Shum, Laura
AU  - Shum L
AUID- ORCID: 0000-0002-0167-4133
AD  - From the Center for Musculoskeletal Research, University of Rochester, Rochester, 
      New York 14624.
FAU - Eliseev, Roman A
AU  - Eliseev RA
AUID- ORCID: 0000-0002-6783-7388
AD  - From the Center for Musculoskeletal Research, University of Rochester, Rochester, 
      New York 14624 roman_eliseev@urmc.rochester.edu.
LA  - eng
GR  - K01 AR064610/AR/NIAMS NIH HHS/United States
GR  - R01 AR072601/AR/NIAMS NIH HHS/United States
GR  - TL1 TR000096/TR/NCATS NIH HHS/United States
GR  - UL1 TR000042/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180827
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CTNNB1 protein, mouse)
RN  - 0 (beta Catenin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - 3T3 Cells
MH  - Acetylation
MH  - Adenosine Triphosphate/metabolism
MH  - Adipocytes/metabolism
MH  - Animals
MH  - Bone Marrow Cells/cytology
MH  - *Cell Differentiation
MH  - Cell Proliferation
MH  - Glucose/metabolism
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mitochondria/*metabolism
MH  - Osteoblasts/metabolism
MH  - Osteogenesis/*physiology
MH  - Oxidative Phosphorylation
MH  - Signal Transduction
MH  - Wnt Signaling Pathway
MH  - beta Catenin/*metabolism
PMC - PMC6187642
OTO - NOTNLM
OT  - acetylation
OT  - bone marrow mesenchymal stem cells
OT  - mesenchymal stem cells (MSCs)
OT  - mitochondria
OT  - osteoblast
OT  - osteogenesis
OT  - beta-catenin
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/08/29 06:00
MHDA- 2019/03/05 06:00
PMCR- 2019/10/12
CRDT- 2018/08/29 06:00
PHST- 2018/05/22 00:00 [received]
PHST- 2018/08/21 00:00 [revised]
PHST- 2018/08/29 06:00 [pubmed]
PHST- 2019/03/05 06:00 [medline]
PHST- 2018/08/29 06:00 [entrez]
PHST- 2019/10/12 00:00 [pmc-release]
AID - S0021-9258(20)35140-1 [pii]
AID - RA118.004102 [pii]
AID - 10.1074/jbc.RA118.004102 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Oct 12;293(41):16019-16027. doi: 10.1074/jbc.RA118.004102. Epub 
      2018 Aug 27.