TMEM135 maintains the equilibrium of osteogenesis and adipogenesis by regulating mitochondrial dynamics

Disturbance in the differentiation process of bone marrow mesenchymal stem cells (BMSCs) leads to osteoporosis. Mitochondrial dynamics plays a pivotal role in the metabolism and differentiation of BMSCs. However, the mechanisms underlying mitochondrial dynamics and their impact on the differentiation equilibrium of BMSCs remain unclear. We investigated the mitochondrial morphology and markers related to mitochondrial dynamics during BMSCs osteogenic and adipogenic differentiation. Bioinformatics was used to screen potential genes regulating BMSCs differentiation through mitochondrial dynamics. Subsequently, we evaluated the impact of Transmembrane protein 135 (TMEM135) deficiency on bone homeostasis by comparing Tmem135 knockout mice with their littermates. The mechanism of TMEM135 in mitochondrial dynamics and BMSCs differentiation was also investigated in vivo and in vitro. Distinct changes in mitochondrial morphology were observed between osteogenic and adipogenic differentiation of BMSCs, manifesting as fission in the late stage of osteogenesis and fusion in adipogenesis. Additionally, we revealed that TMEM135, a modulator of mitochondrial dynamics, played a functional role in regulating the equilibrium between adipogenesis and osteogenesis. The TMEM135 deficiency impaired mitochondrial fission and disrupted crucial mitochondrial energy metabolism during osteogenesis. Tmem135 knockout mice showed osteoporotic phenotype, characterized by reduced osteogenesis and increased adipogenesis. Mechanistically, TMEM135 maintained intracellular calcium ion homeostasis and facilitated the dephosphorylation of dynamic-related protein 1 at Serine 637 in BMSCs. Our findings underscore the significant role of TMEM135 as a modulator in orchestrating the differentiation trajectory of BMSCs and promoting a shift in mitochondrial dynamics toward fission. This ultimately contributes to the osteogenesis process. This work has provided promising biological targets for the treatment of osteoporosis. Mitochondria undergo fusion during the early stages of osteogenic differentiation, transitioning to fission at the later stages. In contrast, adipogenesis follows an inverse pattern, wherein mitochondria display fusion at later stages. Transmembrane protein 135 (TMEM135), a modulator of mitochondrial dynamics, plays a functional role in regulating the equilibrium between adipogenesis and osteogenesis by regulating the calcium/calmodulin-dependent phosphatase calcineurin signaling