Department of Medicine, Tulane University, New Orleans, LA 70112, USA.
Department of Physiology, Tulane University, New Orleans, LA 70112, USA.
Cells. 2022 May 6;11(9):1572. doi: 10.3390/cells11091572.
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.
先前的研究表明 BNIP3 在心肌重构和向 HFrEF 的进展中起作用。我们利用多组学方法揭示了 BNIP3 在 HFrEF 发病机制中的相关分子机制。在 HFrEF 中敲低 BNIP3 可改善糖酵解、丙酮酸代谢、支链氨基酸分解代谢和氧化磷酸化，并恢复内质网（ER）-线粒体（mt）钙和离子稳态。BNIP3 对心脏代谢的这些影响与其对上述代谢途径中特定 mt 蛋白的相互作用和下调，和/或磷酸化有关，包括 MICOS 和 SLC25A 载体蛋白家族。BNIP3 通过其诱导的 VDAC1 二聚化及其对 VDAC1 丝氨酸 104 和丝氨酸 241 磷酸化的调节，以及 LETM1 的下调，影响 ER-mt-钙和离子稳态。在 ER 水平上，BNIP3 与酶 SERCA2a 和 PKA 信号复合物相互作用，导致 SERCA2a 和 PKA 介导的 Ser16 磷蛋白磷酸化下调。此外，BNIP3 通过调节 AMPK 丝氨酸 485/491 和丝氨酸 377 残基以及 PRKCE 苏氨酸 521 和苏氨酸 710 残基的磷酸化来减弱 AMPK 和 PRKCE 的活性。BNIP3 还与肌节、细胞骨架和细胞转录和翻译蛋白相互作用，并影响其表达和/或磷酸化。总之，BNIP3 调节多种病理生物学过程，是 HFrEF 的一个有吸引力的治疗靶点。
