SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression

Abstract

Sterol regulatory element binding protein 1 (SREBP1) has emerged as a central regulator of lipid metabolism, playing a pivotal role in cancer progression. However, the oncogenic potential of SREBP1a is still underexplored. This study investigates the multifaceted contributions of SREBP1a on tumorigenesis, with a particular focus on ovarian cancer. Elevated expression of the SREBP1a isoform was found to enhance proliferation, migration, and invasion of ovarian cancer cells. Mechanistically, SREBP1a induces mitochondrial fission by upregulating DRP1 expression and promoting its activation through ser616 phosphorylation, resulting in a fragmented mitochondrial network that supports enhanced bioenergetic flexibility. In parallel, SREBP1a drives PINK1-Parkin-mediated mitophagy. This coupling of mitochondrial fission and mitophagy possibly ensures mitochondrial quality control, enhances cellular bioenergetics, and increases ATP production, supporting rapid cell proliferation and migration. Experimental evidences reveal that SREBP1 directly regulates DRP1 and PINK1 transcription, reinforcing its role in regulating mitochondrial dynamics. Furthermore, targeting SREBP1 using Fatostatin, a small-molecule inhibitor, effectively disrupts mitochondrial fission, impairs mitophagy, and attenuates tumor progression. These findings highlight the novel role of SREBP1a as a key regulator of mitochondrial dynamics, establishing it as a promising therapeutic target in ovarian cancer. Future studies should explore combinatorial strategies integrating SREBP1a inhibition with existing therapies to improve treatment outcomes.

Keywords: DRP1; Fatostatin; Ovarian cancer; PINK1-Parkin mitophagy; SREBP1a.