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Abstract: PO1714

UCP2 Regulates Mitochondrial Dynamics and Podocyte Injury by OMA1-Dependent Proteolytic Processing of OPA1

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Yang, Qianqian, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • Xu, Lingling, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • Zhou, Yang, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • Jiang, Lei, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • Yang, Junwei, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
Background

Podocyte injury and loss are pivotal events in the progression of glomerular diseases, such as diabetic kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS). Disordered mitochondrial dynamics leads to mitochondrial dysfunction, which is extensively involved in podocyte injury. The mitochondrial inner membrane uncoupling protein, UCP2, is involved in the regulation of mitochondrial dynamics, but the specific mechanism is unknown.

Methods

The function and structure of podocyte were detected by electron microscopy, immunofluorescent staining, PAS staining, and urinary albumin. A Seahorse Bioscience XF24 Extracellular Flux Analyzer was used to measure dissolved oxygen in culture medium around adherent cells. Mitochondrial membrane potential was detected using TMRM dye. The content of ATP in cells of each well was determined with an ATP Assay Kit.

Results

We reported that the mitochondrial inner membrane UCP2 expression in podocyte was corelated with proteinuria level in patients. Mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by diabetes or adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2 deleted podocyte exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocyte and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

Conclusion

Our findings suggest that UCP2 protects mitochondrial dynamics balance by OMA1-dependent proteolytic processing of OPA1.

Funding

  • Government Support – Non-U.S.