Polycystin-2-dependent control of cardiomyocyte autophagy

Alfredo Criollo, Francisco Altamirano, Zully Pedrozo, Gabriele G. Schiattarella, Dan L. Li, Pablo Rivera-Mejías, Cristian Sotomayor-Flores, Valentina Parra, Elisa Villalobos, Pavan K. Battiprolu, Nan Jiang, Herman I. May, Eugenia Morselli, Stefan Somlo, Humbert de Smedt, Thomas G. Gillette, Sergio Lavandero, Joseph A Hill

Research output: Contribution to journalArticle

6 Scopus citations


Aims: Considerable evidence points to critical roles of intracellular Ca2+ homeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Ca2+ handling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Ca2+ homeostasis and autophagy. Methods and results: Activation of autophagic flux triggered by mTOR inhibition either pharmacologically (rapamycin) or by means of nutrient depletion was suppressed in cells depleted of PC2. Moreover, cardiomyocyte-specific PC2 knockout mice (αMhc-cre;Pkd2F/F mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca2+ chelation using BAPTA-AM, whereas removal of extracellular Ca2+ had no effect, pointing to a role of intracellular Ca2+ homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca2+ mobilization, we over-expressed either wild-type PC2 (WT) or a Ca2+-channel deficient PC2 mutant (PC2-D509V). PC2 over-expression increased autophagic flux, whereas PC2-D509V expression did not. Importantly, autophagy induction triggered by PC2 over-expression was attenuated by BAPTA-AM, supporting a model of PC2-dependent control of autophagy through intracellular Ca2+. Furthermore, PC2 ablation was associated with impaired Ca2+ handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca2+ stores. Finally, we provide evidence that Ca2+-mediated autophagy elicited by PC2 is a mechanism conserved across multiple cell types. Conclusion: Together, this study unveils PC2 as a novel regulator of autophagy acting through control of intracellular Ca2+ homeostasis.

Original languageEnglish (US)
Pages (from-to)110-121
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
StatePublished - May 1 2018


  • Autophagy
  • Calcium
  • Heart
  • Polycystin-2
  • Stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Criollo, A., Altamirano, F., Pedrozo, Z., Schiattarella, G. G., Li, D. L., Rivera-Mejías, P., Sotomayor-Flores, C., Parra, V., Villalobos, E., Battiprolu, P. K., Jiang, N., May, H. I., Morselli, E., Somlo, S., de Smedt, H., Gillette, T. G., Lavandero, S., & Hill, J. A. (2018). Polycystin-2-dependent control of cardiomyocyte autophagy. Journal of Molecular and Cellular Cardiology, 118, 110-121. https://doi.org/10.1016/j.yjmcc.2018.03.002