The trophoblast is a critical cell for placental development and embryo implantation in the placenta. We previously reported that placenta-derived mesenchymal stem cells (PD-MSCs) increase trophoblast invasion through several signaling pathways. However, the paracrine effects of PD-MSCs on mitochondrial function in trophoblasts are still unclear.Therefore, the objective of the study was to analyze the mitochondrial function of trophoblasts in response to cocultivation with PD-MSCs. The results showed that PD-MSCs regulate the balance between cell survival and death and protect damaged mitochondria in trophoblasts from oxidative stress. Moreover, PD-MSCs upregulate factors involved in mitochondrial autophagy in trophoblast cells. Finally, PD-MSCs improve trophoblast invasion. Taken together, the data indicate that PD-MSCs can regulate trophoblast invasion through dynamic effects on mitochondrial energy metabolism. These results support the fundamental role of mitochondrial energy mechanism in trophoblast invasion and suggest a new therapeutic strategy for infertility. K E Y W O R D S invasion, mitochondria, mitochondrial autophagy, placenta-derived mesenchymal stem cells, trophoblast 1 | INTRODUCTION Normal placentation requires adequate invasion of trophoblast cells into the maternal endometrium of the uterus. During pregnancy, trophoblasts play a role in embryonic and placental development through effects on mononuclear cytotrophoblast cell fusion and differentiation into syncytiotrophoblasts, which form the maternalfetal interface. Several studies have reported that numerous microenvironmental and cellular factors, including hypoxia inducible factor 1-alpha (HIF1-α), matrix metalloproteinase (MMP), and Rho family members, are involved in trophoblast invasion (Carter et al., 2015; Soares et al., 2017). First, transcription factors such as HIF1-α, which responds to hypoxia, are involved to placental development by stimulating trophoblast invasion. The overexpression of HIF1-α enhances trophoblast invasion via the autophagy pathway (Choi et al., 2012;Highet et al., 2015;Ietta et al., 2006). Second, MMPs are enzymes essential for invasion with the primary role of digesting the extracellular matrix. MMP-2 and MMP-9 are widely known as gelatinases that digest type IV collagen, the major collagen constituent of the basement membrane. MMP-2/9 deficiency leads to poorThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.