HSPA1A transcriptionally activated by HSF1 facilitates mitophagy via inducing PINK1 phosphorylation to suppress mitochondrial apoptosis in hyperplastic prostate

Abstract Benign prostatic hyperplasia (BPH) is a highly prevalent, age-related disorder in men, defined by nonmalignant enlargement of the prostate, which results in bothersome lower urinary tract symptoms and impaired quality of life. Heat shock protein family A member 1 A (HSPA1A)/HSP70, as a molecular chaperone, plays a critical role in cellular stress protection, attenuating apoptosis and oxidative stress across various diseases. This study delineates the mechanistic framework by which HSP70 modulates mitochondrial quality control in BPH. In vitro and in vivo models reveal that lack of HSP70 triggers pronounced mitochondrial fragmentation, boosts reactive oxygen species accumulation, and disrupts mitochondrial membrane potential, resulting in enhanced apoptosis and alleviated BPH progression. Mechanistically, HSP70 facilitates PINK1/Parkin mediated mitophagy by promoting PINK1 autophosphorylation at Ser228, thereby enhancing the elimination of damaged mitochondria and suppressing mitochondrial apoptosis, while also orchestrating mitochondrial fission via regulation of DRP1 and MFF phosphorylation. HSPA1A is transcriptionally upregulated by HSF1, establishing an axis essential for mitophagy and apoptosis resistance in prostatic hyperplasia. Collectively, these findings position HSP70 as a central regulator of mitochondrial integrity and cell survival in BPH, and its manipulation holds translational promise for ameliorating prostatic hyperplasia.