title: Evidence for the Role of BAG3 in Mitochondrial Quality Control in Cardiomyocytes.
abstract: 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.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Farzaneh G
authors.initials: FG
authors.lastname: Tahrir
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Tijana
authors.initials: T
authors.lastname: Knezevic
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.|Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.|Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D004734:Energy Metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498807:BAG3 protein, rat; D061988:Proteasome Inhibitors; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein