PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure

Heart failure (HF) is associated with mitochondrial quality control, a key process in quality control. Peroxisome Proliferator-activated Receptor γ coactivator 1 α (PGC-1α) regulates Mitophagy, but its role in HF remains unclear. This study investigates the role of PGC-1α in HF and its mechanism in Mitophagy. Myocardial injury was induced in AC16 cells using pentobarbital, followed by PGC-1α overexpression and treatment with Apoptosis inhibitor HY-19696 and Mitophagy inhibitor Mdivi-1. A rat HF model was established via aortic constriction, with PGC-1α overexpressed through lentiviral injection. In the cell model, PGC-1α overexpression increased Creatine Kinase isoenzyme MB (CK-MB), cardiac troponin T (cTnT), Lactate Dehydrogenase (LDH) levels, reduced cell viability and mitochondrial membrane potential, enhanced Apoptosis and ROS production. These effects were attenuated by Apoptosis inhibitor HY-19696. PGC 1α also promoted Mitophagy related changes, including an increased LC3 II to LC3 I ratio, and this response was suppressed by Mdivi 1. In the rat model, PGC-1α overexpression aggravated myocardial injury, Apoptosis, and damage markers, whereas pharmacological inhibition of Apoptosis or Mitophagy alleviated these effects. PGC-1α exacerbates HF by promoting Apoptosis and enhancing Mitophagy through the Hypoxia-inducible factor-1 (HIF-1)/BCL2 interacting protein 3 (BNIP3) pathway. Therefore, PGC-1α changed mitochondrial dynamic homeostasis and promoted HIF-1α/BNIP3-dependent Mitophagy in HF.

Apoptosis; BNIP3; HIF-1α; Heart failure; Mitophagy; PGC-1α.