Polycystin-2-dependent control of cardiomyocyte autophagy

J Mol Cell Cardiol. 2018 May:118:110-121. doi: 10.1016/j.yjmcc.2018.03.002. Epub 2018 Mar 6.


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.

Keywords: Autophagy; Calcium; Heart; Polycystin-2; Stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Calcium / metabolism
  • HeLa Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Knockout
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Stress, Mechanical
  • TRPP Cation Channels / metabolism*


  • Autophagy-Related Proteins
  • RNA, Messenger
  • TRPP Cation Channels
  • polycystic kidney disease 2 protein
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Calcium
  • Sirolimus