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Abstract: TH-PO673

Loss of the Master Regulator of Mitochondrial Fusion Opa1 in Renal Tubules Is Not Sufficient to Drive Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Cassina, Laura, San Raffaele Scientific Institute, Milan, Italy
  • Chiaravalli, Marco, San Raffaele Scientific Istitute, Milano, Italy
  • Maserati, Martina, San Raffaele Scientific Institute, Milan, Italy
  • Boletta, Alessandra, San Raffaele Scientific Institute, Milan, Italy

Group or Team Name

  • Molecular basis of Polycystic Kidney Disease Unit

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder. The most commonly mutated gene, PKD1, encodes for polycystin-1 (PC1). We showed enhanced glycolysis and reduced mitochondrial-derived ATP in Pkd1 mutant cells and kidneys (Rowe et al. 2013). A direct role of PC1 on mitochondrial regulation has been recently shown, either at the mitochondria-associated membranes, MAMs (Padovano et al. 2017), or by direct translocation of the PC1 C-terminal tail (CTT) in the mitochondrial matrix (Lin et al. 2018). We wondered whether mitochondrial dysfunction is a driver, or else a modifier, in PKD.


Transmission electron microscopy (TEM) on kidney sections, Seahorse XFe96 Analyzer for mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), mitochondrial network morphology by mt-DsRFP live imaging, genetic ablation of Opa1 using Ksp-Cre line.


We detected alterations in mitochondrial network morphology, in OCR, and in ECAR in Pkd1-/- cells. We found decreased number of mitochondria, many with aberrant cristae, mitochondrial fragmentation, and decreased mitochondrial respiration in the cystic epithelia of Pkd1fl/−:Ksp-Cre kidneys at P4. At the molecular level we identified decreased mitochondrial pro-fusion protein Opa1, and increased fission regulator Drp1 in the cystic kidneys. To determine the contribution of reduced Opa1 and the consequent mitochondrial alterations in renal epithelia, we generated Opa1fl/fl:Ksp-Cre mice. Animals are born at the expected mendelian ratio and die within the first three months of life. At sacrifice gross kidney enlargement was observed, and this is mostly due to expansion of DBA positive tubules. Decreased mitochondrial respiration was observed, but cells maintained a cuboidal shape. Despite the increase in the kidney volume over time, we detected only mild tubule dilation at P60, and no overt cyst formation.


Our data indicate that deletion of PC1 in the kidney epithelium results in alteration in mitochondrial structure and fitness. Surprisingly, decreasing mitochondrial proficiency by means of Opa1 ablation is not sufficient per se to drive cystogenesis. We are currently verifying if crossing Opa1fl/+ with Pkd1fl/−:Ksp-Cre accelerates disease progression and/or other molecular players are involved in PKD.


  • Private Foundation Support