POU2F1 promotes hypertensive cardiac fibrosis by regulating mitochondrial homeostasis through PINK1/Parkin-dependent mitophagy
TL;DR
A novel role is identified for POU2F1 in hypertensive cardiac fibrosis, demonstrating that it exacerbates disease progression by disrupting mitochondrial homeostasis through transcriptional activation of PINK1, accompanied by alterations consistent with enhanced PINK1/Parkin-mediated mitophagy signaling.
Abstract
Hypertension-induced cardiac fibrosis is a major risk factor for heart failure; although disrupted mitochondrial homeostasis has been confirmed to serve a critical role in the pathological process, its upstream regulatory factors remain incompletely understood. In the current study, RNA sequencing and bioinformatics analyses identified POU domain class 2 transcription factor 1 (POU2F1) as a hub transcriptional regulator in the fibrotic cardiac tissues of spontaneously hypertensive rats (SHRs). The expression levels of POU2F1 were associated with the severity of myocardial fibrosis, and cardiac expression of PTEN-induced kinase 1 (PINK1) and Parkin in SHRs. Complementing these in vivo observations, angiotensin II stimulation significantly upregulated POU2F1 expression in cardiac fibroblasts (CFs) in vitro. Furthermore, POU2F1 expression exhibited a positive correlation with fibroblast activation, as indicated by α-smooth muscle actin fluorescence intensity. Mechanistically, POU2F1 knockdown attenuated CF activation, improved mitochondrial structure and energy metabolism, and restored PINK1/Parkin-mediated mitophagy balance in vivo and in vitro. Conversely, POU2F1 overexpression was associated with enhanced PINK1/Parkin-mediated mitophagy signaling. Crucially, through chromatin immunoprecipitation-quantitative PCR, electrophoretic mobility shift assay and dual-luciferase reporter assay, it was demonstrated that POU2F1 can directly bind to the PINK1 promoter to activate its transcription. In conclusion, the present study identified a novel role for POU2F1 in hypertensive cardiac fibrosis, demonstrating that it exacerbates disease progression by disrupting mitochondrial homeostasis through transcriptional activation of PINK1, accompanied by alterations consistent with enhanced PINK1/Parkin-mediated mitophagy.