Polycystin-2-dependent control of cardiomyocyte autophagy

Item Type:	Article
Title:	Polycystin-2-dependent control of cardiomyocyte autophagy
Creators Name:	Criollo, A. and Altamirano, F. and Pedrozo, Z. and Schiattarella, G.G. and Li, D.L. and Rivera-Mejías, P. and Sotomayor-Flores, C. and Parra, V. and Villalobos, E. and Battiprolu, P.K. and Jiang, N. and May, H.I. and Morselli, E. and Somlo, S. and de Smedt, H. and Gillette, T.G. and Lavandero, S. and Hill, J.A.
Abstract:	AIMS: Considerable evidence points to critical roles of intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) 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;Pkd2(F/F) mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca(2+) chelation using BAPTA-AM, whereas removal of extracellular Ca(2+) had no effect, pointing to a role of intracellular Ca(2+) homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca(2+) mobilization, we over-expressed either wild-type PC2 (WT) or a Ca(2+)-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 Ca(2+). Furthermore, PC2 ablation was associated with impaired Ca(2+) handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca(2+) stores. Finally, we provide evidence that Ca(2+)-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 Ca(2+) homeostasis.
Keywords:	Polycystin-2, Autophagy, Stress, Heart, Calcium, Animals, Mice
Source:	Journal of Molecular and Cellular Cardiology
ISSN:	0022-2828
Publisher:	Elsevier
Volume:	118
Page Range:	110-121
Date:	May 2018
Official Publication:	https://doi.org/10.1016/j.yjmcc.2018.03.002
PubMed:	View item in PubMed

Repository Staff Only: item control page