BACKGROUND To study the effect of estrogen-related receptor α (ERRα) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) on mesenchymal stem cells (MSCs) apoptosis, and further investigated its detailed molecular mechanisms in the absence of serum, hypoxia, and high glucose conditions. MATERIAL AND METHODS In our study, we first evaluated the expression rates of CD14, CD34, CD45, CD44, CD29, and Sca-1 surface markers on MSCs by flow cytometry. Then, the ability of osteogenic and fatty differentiation of MSCs was determined by osteogenic differentiation and adipogenesis reagent kit. Next, Annexin V-APC/7-AAD apoptosis kit was used for detecting the apoptosis rate of MSCs. RT-PCR and Western blotting were used for detection of mRNA expression and proteins expression, respectively. RESULTS Our data showed that the MSCs used in our study were capable of self-renewal and differentiating into many cell lineages, such as osteogenic differentiation and adipogenesis. Our results further showed that over-expression of PGC-1α could protect MSCs from apoptosis induced by rotenone. We also found that PGC-1α over-expression could enhance the expression of anti-apoptotic gene Bcl-2, and inhibit the expression of pro-apoptotic gene Bax in MSCs. In addition, our data demonstrated that PGC-1α could induce upregulation of Bcl-2 and further promote the survival of MSCs by interacting with ERRα. CONCLUSIONS In the absence of serum, hypoxia and high glucose conditions, PGC-1α can regulate the expression of Bcl-2 and promote the survival of MSCs via PGC-1α/ERRα interaction.