Polycystin-2-dependent control of cardiomyocyte autophagy. (May 2018)

• Record Type: Journal Article
• Authors: Criollo, Alfredo; Altamirano, Francisco; Pedrozo, Zully; Schiattarella, Gabriele G.; Li, Dan L.; Rivera-Mejías, Pablo; Sotomayor-Flores, Cristian; Parra, Valentina; Villalobos, Elisa; Battiprolu, Pavan K.; Jiang, Nan; May, Herman I.; Morselli, Eugenia; Somlo, Stefan; de Smedt, Humbert; Gillette, Thomas G.; Lavandero, Sergio; Hill, Joseph A.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 118(2018)
• Page Start: 110
• Page End: 121
• Publication Date: 2018-05
• Subjects: Polycystin-2 -- Autophagy -- Stress -- Heart -- Calcium; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.03.002
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: Polycystin-2 (PC2) ablation suppress autophagic flux in cardiomyocytes. PC2 modulates autophagic flux in multiple cell types in a Ca 2+ -dependent manner. Overexpression of PC2 increases autophagy and requires PC2 Ca 2+ channel activity. PC2 ablation governs Ca 2+ cycling via sarcoplasmic reticulum Ca 2+ stores. Cardiomyocyte-specific PC2 KO mice exhibit normal basal cardiac function.