Multiomics Approach Reveals an Important Role of BNIP3 in Myocardial Remodeling and the Pathogenesis of Heart Failure with Reduced Ejection Fraction

Antoine H. Chaanine, Leeann Higgins, Lothar Lauterboeck, Todd Markowski, Qinglin Yang, Patrice Delafontaine

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Previous work showed a role of BNIP3 in myocardial remodeling and progression to HFrEF. We utilized a multiomics approach to unravel BNIP3-related molecular mechanisms in the pathogenesis of HFrEF. BNIP3 knockdown in HFrEF improved glycolysis, pyruvate metabolism, branched-chain amino acid catabolism, and oxidative phosphorylation, and restored endoplasmic reticulum (ER)–mitochondrial (mt) calcium and ion homeostasis. These effects of BNIP3 on cardiac metabolism were related to its interaction and downregulation, and/or phosphorylation, of specific mt-proteins involved in the aforementioned metabolic pathways, including the MICOS and SLC25A families of carrier proteins. BNIP3 affected ER–mt-calcium and ion homeostasis via its interaction-induced VDAC1 dimerization and modulation of VDAC1 phosphorylation at Ser104 and Ser241, and the downregulation of LETM1. At the ER level, BNIP3 interacted with the enzyme SERCA2a and the PKA signaling complex, leading to the downregulation of SERCA2a and PKA-mediated Ser16 phospholamban phosphorylation. Additionally, BNIP3 attenuated AMPK and PRKCE activity by modulating AMPK phosphorylation at Ser485/491 and Ser377 residues, and PRKCE phosphorylation at Thr521 and Thr710 residues. BNIP3 also interacted with sarcomeric, cytoskeletal, and cellular transcription and translation proteins, and affected their expression and/or phosphorylation. In conclusion, BNIP3 modulates multiple pathobiological processes and constitutes an attractive therapeutic target in HFrEF.

Original languageEnglish (US)
Article number1572
JournalCells
Volume11
Issue number9
DOIs
StatePublished - May 1 2022

Bibliographical note

Funding Information:
This work has been supported by internal grant award to A.H.C., and the Carol Lavin Bernick Faculty Grant award to A.H.C.; and the NIH/ NHLBI R01-HL070241 grant award to P.D.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • BNIP3
  • PKA signaling
  • apoptosis
  • calcium cycling
  • heart failure
  • metabolic remodeling
  • myocardial remodeling

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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