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

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.
Competing Interests: This work has been supported by a grant from Renovacor, Inc, Greenwich, Connecticut, USA. The work described in this paper was funded in part by a structured research agreement between Renovacor, Inc, and Temple University Office of Technology Transfer. Dr Tomar has received NIH grant K99DK120876. Drs Myers, Cheung, and Feldman have equity in Renovacor, Inc, a public biotechnology company of which Dr Feldman is the Founder and Chief Scientific Advisor. Drs Cheung and Feldman and hold equity in Renovacor. Dr Khalili is the Co-Founder and Chief Scientific Advisor of Excision Bio Therapeutics, Inc, a company that is developing CRISPR-Cas-9–based therapeutics. Drs Cheung, Kirk, and Feldman have submitted a provisional patent to the Temple Office of Technology Transfer and to the Loyola University-Chicago Tech Transfer Office regarding discoveries associated with the present work. Drs Khalili, Cheung, and Feldman held previous U.S. patent #11236389 that was licensed through Temple University to Renovacor, Inc, including U.S. patents #61/934,483 (BAG3 as a target for therapy of heart failure) and #62/205,990 (BAG3 composition and methods), the approval of which is pending. Dr Khalili has licensed technology to Excision. Drs Khalili and Feldman’s laboratory work is monitored by a specific member of the Committee on Conflicts of Interest, and each have individual oversight guidelines that govern their relationships with their companies as well as with other investigators in the University. Yearly reports are submitted to the Committee, and the individual member of the committee assigned to their programs meets with Dr Feldman or Dr Khalili annually. For its part, Temple University has significant financial interests in the technology licensed to Renovacor, Inc. The financial interests are being managed in accordance with Temple University’s Institutional policy.
(© 2023 The Authors.)