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.