RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer

Human RIPK4 mutation leads to Bartsocas-Papas syndrome (BPS), characterized by severe skin, craniofacial and limb abnormalities. Currently, our understanding of RIPK4's function has focused on epidermal differentiation and development, whether RIPK4 regulates skeletal homeostasis remains largely elusive. Herein, through global RIPK4 ablation in adult mice, we demonstrate that RIPK4 deficiency leads to osteoporosis, promotes myeloid-biased hematopoiesis and osteolineage RIPK4 plays a crucial role in bone formation and myeloid hematopoiesis. Further detailed investigation pinpoints that RIPK4 interacts with mitochondrial fusion protein MFN2 in a kinase-dependent manner. RIPK4 facilitates the phosphorylation of MFN2, which subsequently undergoes degradation through the proteasome pathway and disrupts the dynamic equilibrium of mitochondrial fission and fusion. Additionally, we also show that osteolineage RIPK4 maintains bone marrow myelopoiesis by MFN2-mediated mitochondrial transfer. More interestingly, while osteocytic RIPK4 could modestly influence the osteogenesis, it is insufficient to sustain bone marrow myelopoiesis owing to the limited amount of mitochondria transfer. These findings decipher the essential role of RIPK4 in maintaining skeletal homeostasis and unveil an unappreciated mechanism of RIPK4-MFN2 axis in regulating osteogenesis and bone marrow myelopoiesis.