Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart

JuFang Wang; Dhadendra Tomar; Thomas G Martin; Shubham Dubey; Praveen K Dubey; Jianliang Song; Gavin Landesberg; Michael G McCormick; Valerie D Myers; Salim Merali; Carmen Merali; Bonnie Lemster; Charles F McTiernan; Kamel Khalili; Muniswamy Madesh; Joseph Y Cheung; Jonathan A Kirk; Arthur M Feldman

doi:10.1016/j.jacbts.2022.12.013

Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart

JACC Basic Transl Sci. 2023 Apr 19;8(7):820-839. doi: 10.1016/j.jacbts.2022.12.013. eCollection 2023 Jul.

Authors

JuFang Wang^{1

2}, Dhadendra Tomar³, Thomas G Martin⁴, Shubham Dubey¹, Praveen K Dubey¹, Jianliang Song^{1

2}, Gavin Landesberg^{1

2}, Michael G McCormick¹, Valerie D Myers⁵, Salim Merali⁶, Carmen Merali⁶, Bonnie Lemster⁷, Charles F McTiernan⁷, Kamel Khalili², Muniswamy Madesh⁸, Joseph Y Cheung⁹, Jonathan A Kirk⁴, Arthur M Feldman^{1

2}

Affiliations

¹ Department of Medicine, Division of Cardiology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
² Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
³ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
⁴ Department of Cell and Molecular Physiology, Loyola University Strich School of Medicine, Maywood, Illinois, USA.
⁵ Renovacor, Inc, Greenwich, Connecticut, USA.
⁶ Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA.
⁷ Department of Medicine, Division of Cardiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁸ Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
⁹ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

B-cell lymphoma 2-associated athanogene-3 (Bag3) is expressed in all animal species, with Bag3 levels being most prominent in the heart, the skeletal muscle, the central nervous system, and in many cancers. Preclinical studies of Bag3 biology have focused on animals that have developed compromised cardiac function; however, the present studies were performed to identify the pathways perturbed in the heart even before the occurrence of clinical signs of dilatation and failure of the heart. These studies show that hearts carrying variants that knockout one allele of BAG3 have significant alterations in multiple cellular pathways including apoptosis, autophagy, mitochondrial homeostasis, and the inflammasome.

Keywords: Bcl2-associated athanogene-3; apoptosis; caspase; metabolism; tumor necrosis factor.

Abstract

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