DRP1 bridges complement component C5a and podocyte injury in lupus nephritis

Lupus nephritis (LN) is a frequent and serious manifestation of systemic lupus erythematosus (SLE), affecting over 50% of clinical patients. Occurrence and progression of LN is the end result of complex interactions between regulation of immune responses and pathological processes involving renal resident cells. Podocytes, which comprise the glomerular filtration barrier (GFB), anchor to the basement membrane through foot process extensions and interact with adjacent podocytes to form the slit diaphragm. In this issue of Molecular Therapy, Ye et al. provide compelling evidence that enhanced mitochondrial fission is responsible for podocyte damage in LN, 1 Ye B. Chen B. Guo C. Xiong N. Huang Y. Li M. Lai Y. Li J. Zhou M. Wang S. et al. C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis. Mol. Ther. 2024; https://doi.org/10.1016/j.ymthe.2024.03.003 Google Scholar which leads to the disruption of the GFB, thus causing the development of proteinuria. 2 Anders H.J. Saxena R. Zhao M.H. Parodis I. Salmon J.E. Mohan C. Lupus nephritis. Nat. Rev. Dis. Primers. 2020; 6: 7 Google Scholar ,3 Grahammer F. Schell C. Huber T.B. The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nat. Rev. Nephrol. 2013; 9: 587-598 Google Scholar The authors show that C5a receptor 1 (C5aR1) expressed on the surface of podocytes recognizes complement component C5a, leading to the mobilization and influx of calcium, which upregulates the phosphorylation of dynamin-related protein 1 (DRP1) Ser-616 and results in increased mitochondrial fission and podocyte injury. This work unveils a pivotal role of the complement C5a-C5aR1 axis in mitochondrial fission and podocyte damage in LN, providing novel molecular targets for promising clinical interventions.