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

Polycystin-2-dependent control of cardiomyocyte autophagy.

Author information

1
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Chile.
2
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
3
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile; Instituto de Ciencias Biomédicas, Facultad Medicina, Universidad de Chile, Chile.
4
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Department of Advanced Biomedical Sciences, Federico II University, Via Pansini 5, 80131 Naples, Italy.
5
Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
6
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
7
Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
8
Department of Internal Medicine, Yale University, New Haven, CT, USA.
9
Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven 3000, Belgium.
10
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Advanced Center for Chronic Diseases (ACCDiS), Center for Exercise, Metabolism and Cancer Studies (CEMC), Universidad de Chile, Chile; Instituto de Ciencias Biomédicas, Facultad Medicina, Universidad de Chile, Chile; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile. Electronic address: slavander@uchile.cl.
11
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. Electronic address: joseph.hill@utsouthwestern.edu.

Abstract

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

PMID:
29518398
DOI:
10.1016/j.yjmcc.2018.03.002
[Indexed for MEDLINE]

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