Complement protein C1q induces endothelial apoptosis through C1qBP regulation of mitochondrial function in lung endothelial cells in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis, with pulmonary complications as the leading cause of mortality. Although abnormal activation of the complement system is implicated in SSc pathogenesis, the role of complement protein C1q in pulmonary endothelial injury remains unclear. In this study, we employed a bleomycin (BLM)-induced SSc mouse model and cultured lung microvascular endothelial cells to investigate the effect of C1q on mitochondrial function and endothelial apoptosis. We further investigated the involvement of complement component 1q subcomponent-binding protein (C1qBP) in this process. We performed immunohistochemistry, Western blotting, immunoprecipitation, mitochondrial function assays, and flow cytometry to assess protein expression, mitochondrial integrity, and apoptotic responses. Expression of C1q and C1qBP was significantly elevated in the SSc model group, accompanied by translocation of prohibitin 2 (PHB2) from the mitochondria to the cytoplasm, loss of mitochondrial membrane potential, reduced ATP synthesis, and increased apoptosis. Knockdown of C1qBP inhibited PHB2 translocation, improved mitochondrial function, reduced endothelial apoptosis, and attenuated lung fibrosis. C1q regulates the mitochondrial localization of PHB2 via C1qBP, inducing mitochondrial dysfunction and endothelial apoptosis, thereby contributing to SSc-associated lung injury. Targeting the C1q-C1qBP-PHB2 axis may provide a new therapeutic strategy for SSc.