
Aging Reduces an ERRalpha‐Directed Mitochondrial Glutaminase Expression Suppressing Glutamine Anaplerosis and Osteogenic Differentiation of Mesenchymal Stem Cells
Author(s) -
Huang Tongling,
Liu Renzhong,
Fu Xuekun,
Yao Dongsheng,
Yang Meng,
Liu Qingli,
Lu William W.,
Wu Chuanyue,
Guan Min
Publication year - 2017
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2470
Subject(s) - mesenchymal stem cell , biology , glutaminase , microbiology and biotechnology , stem cell , glutamine , cellular differentiation , downregulation and upregulation , cancer research , biochemistry , gene , amino acid
Aging deteriorates osteogenic capacity of mesenchymal stem/stromal cells (MSCs), contributing to imbalanced bone remodeling and osteoporosis. Glutaminase (Gls) catabolizes glutamine into glutamate at the first step of mitochondrial glutamine (Gln)‐dependent anaplerosis which is essential for MSCs upon osteogenic differentiation. Estrogen‐related receptor α (ERRα) regulates genes required for mitochondrial function. Here, we found that ERRα and Gls are upregulated by osteogenic induction in human MSCs (hMSCs). In contrast, osteogenic differentiation capacity and glutamine consumption of MSCs, as well as ERRα, Gls and osteogenic marker genes are significantly reduced with age. We demonstrated that ERRα binds to response elements on Gls promoter and affects glutamine anaplerosis through transcriptional induction of Gls. Conversely, mTOR inhibitor rapamycin, ERRα inverse agonist compound 29 or Gls inhibitor BPTES leads to reduced Gln anaplerosis and deteriorated osteogenic differentiation of hMSCs. Importantly, overexpression of ERRα or Gls restored impairment by these inhibitors. Finally, we proved that compensated ERRα or Gls expression indeed potentiated Gln anaplerosis and osteogenic capability of elderly mice MSCs in vitro . Together, we establish that Gls is a novel ERRα target gene and ERRα/Gls signaling pathway plays an important role in osteogenic differentiation of MSCs, providing new sights into novel regenerative therapeutics development. Our findings suggest that restoring age‐related mitochondrial Gln‐dependent anaplerosis may be beneficial for degenerative bone disorders such as osteoporosis. S tem C ells 2017;35:411–424