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Tahrir, Farzaneh G.; Knezevic, Tijana; Gupta, Manish K.; Gordon, Jennifer; Cheung, Joseph Y.; Feldman, Arthur M.; Khalili, Kamel
Journal of cellular physiology, April 2017, Letnik: 232, Številka: 4Journal Article
Mitochondrial abnormalities impact the development of myofibrillar myopathies. Therefore, understanding the mechanisms underlying the removal of dysfunctional mitochondria from cells is of great importance toward understanding the molecular events involved in the genesis of cardiomyopathy. Earlier studies have ascribed a role for BAG3 in the development of cardiomyopathy in experimental animals leading to the identification of BAG3 mutations in patients with heart failure which may play a part in the onset of disease development and progression. BAG3 is co‐chaperone of heat shock protein 70 (HSP70), which has been shown to modulate apoptosis and autophagy, in several cell models. In this study, we explore the potential role of BAG3 in mitochondrial quality control. We demonstrate that siRNA mediated suppression of BAG3 production in neonatal rat ventricular cardiomyocytes (NRVCs) significantly elevates the level of Parkin, a key component of mitophagy. We found that both BAG3 and Parkin are recruited to depolarized mitochondria and promote mitophagy. Suppression of BAG3 in NRVCs significantly reduces autophagy flux and eliminates clearance of Tom20, an essential import receptor for mitochondria proteins, after induction of mitophagy. These observations suggest that BAG3 is critical for the maintenance of mitochondrial homeostasis under stress conditions, and disruptions in BAG3 expression impact cardiomyocyte function. J. Cell. Physiol. 232: 797–805, 2017. © 2016 Wiley Periodicals, Inc. BAG3 is critical for homeostasis of skeletal and cardiac tissues. Here we demonstrate that knockdown of BAG3 expression increased the level of Parkin, a key regulator of autophagy in neonatal rat ventricular cardiomyocytes. Furthermore, a decrease in the level of BAG3 promotes translocation of Parkin to the depolarized mitochondria and its degradation. BAG3 suppression significantly decreased the clearance of Tom20, an essential import receptor for mitochondria protein, after treatment with electron uncoupler, suggesting that mitophagy is impaired in the absence of BAG3. These observations ascribe a critical role for BAG3 in the maintenance of mitochondrial function under stress conditions.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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