Abstract: SA-PO221

Loss of OMA1 Activates the mTOR Pathway but Fails to Rescue PHB2 Deficient Podocytes Independent of Stress-Induced OPA1 Processing

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Brinkkoetter, Paul T., University Hospital Cologne, Cologne, Germany
  • Kuczkowski, Alexander, University Hospital Cologne, Cologne, Germany
  • Schoenfelder, Kristina, University Hospital of Cologne, Cologne, Germany
  • Schermer, Bernhard, University Hospital Cologne, Cologne, Germany
  • Benzing, Thomas, University of Cologne, Köln, Germany
Background

The dynamin-like GTPase OPA1 is conceived as a central regulatory hub that controls mitochondrial dynamics, fusion and fission respectively, under stress and in states of disease. Stress-induced OPA1 processing by the metalloendopeptidase OMA1 triggers mitochondrial fission as seen in podocyte-specific knock-out mice lacking prohibitin membrane scaffolds as a model of impaired mitochondrial function.

Results

As reported previously, loss of prohibitins resulted in increased insulin and mTOR signaling and, subsequently, renal failure and premature death after 4-5 weeks after birth. Here, we studied the interplay between the peptidase OMA1 and prohibitins and their effect on mitochondrial function and the activation of the mTOR signaling cascade in glomerular podocytes. In contrast to neurons, genetic depletion of OMA1 failed to rescue renal function in PHB2 deficient podocytes and did not prolong animal survival despite stabilizing mitochondrial morphology. OMA1 single knock-out animals showed increased mTOR signaling activity at baseline without compromising renal function or animal survival. This activating effect on mTOR was additive to the PHB2 effect as OMA1/PHB2 double knock-out animals showed even stronger levels of mTOR activation.

Conclusion

Taken together, impairment of mitochondrial dynamics results in activation of mTOR, which is not sufficient to cause podocyte disease at baseline. Additional insults, such as increased cellular stress or a destabilized slit-diaphragm as shown for PHB2 are required to induce podocyte disease. These findings not only emphasize the central role of mitochondria to control insulin and mTOR signaling in podocytes but also provide additional evidence for an additional function of prohibitins in podocytes beyond their established role as protein scaffolds at the inner mitochondrial membrane to control mitochondrial fusion and fission.

Funding

  • Government Support - Non-U.S.