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Abstract: FR-PO921

Mitochondrial Programming of Metabolic Signaling in Glomerular Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Oezel, Cem, University Hospital Cologne, Cologne, Germany
  • Schömig, Thomas, University Hospital Cologne, Cologne, Germany
  • Matin, Mahsa, University Hospital Cologne, Cologne, Germany
  • Odenthal, Johanna, University Hospital Cologne, Cologne, Germany
  • Schermer, Bernhard, University Hospital Cologne, Cologne, Germany
  • Coward, Richard, University of Bristol, Bristol, United Kingdom
  • Benzing, Thomas, University Hospital Cologne, Cologne, Germany
  • Brinkkoetter, Paul T., University Hospital Cologne, Cologne, Germany

Group or Team Name

  • Nephrolab Cologne

Metabolic signaling events are critical regulators of podocyte function. We have recently established a metabolic link between mitochondrial dysfunction and enhanced insulin signaling in podocytes. In this study, we interfered with OPA1 cleavage, a central regulatory hub that determines mitochondrial morphology under stress and in disease by conditional ablation of Oma1 gene expression.


Conventional Oma1 KO animals and conditional Phb2fl/fl;pod-cre mice were held in a pure C57/Bl6 background. Mice were characterized by observing survival and proteinuria while insulin-signaling activation was measured using histology and MS/MS. Oma 1 KO podocytes and Phb2 knockdown cells were utilized to further delineate the down-stream effects on MAPK, mTOR and GSK activation as well as MS/MS and seahorse measurements to assess glycolytic function and the metabolic status of the cells.


An impaired OPA1 degradation by depletion of either Oma1 or Phb2, both, led to an increased insulin sensitivity as evidenced by increased Akt and mTOR-activation in vitro and in vivo. However, only loss of Phb2 resulted in a disrupted slit-membrane, proteinuria and premature death as previously published while Oma1 KO animals presented with normal glomerular function. Oma1/Phb2 double KO podocytes presented with an improved mitochrondrial cristae formation and prolonged animal survival. On a functional level, aerobic glycolysis was disrupted in both cases. Proteome analysis of Oma1 knockout mice glomeruli revealed elevated translation of proteins associated with fatty-acid metabolism and Acetyl-CoA synthesis and an increase in ribosomal protein s6 phosphorylation.


Here, we identified OMA1 as a critical regulator of podocyte metabolism in vitro and in vivo and demonstrate that a stress-induced OPA1 processing by OMA1 promotes a metabolic switch in glomerular podocytes. However, this metabolic switch alone was not sufficient to cause podocyte injury. Using mice lacking prohibitin membrane scaffols as a model of mitochondrial dysfunction, we demonstrate that additional ablation of OMA1 protects mitochondrial cristae formation from degradation leading to a significantly prolonged survival as compared to prohibitin deficient mice.