SFXN1 promotes bladder cancer metastasis by restraining PINK1-dependent mitophagy.

Abstract

Sideroflexin 1 (SFXN1), a newly identified mitochondrial serine transporter, exhibits great potential to modulate mitochondrial function and promote tumor development. However, its role in bladder cancer (BLCA) remains unclear. Our study revealed that SFXN1 was enriched in clinical BLCA tissues, and high SFXN1 expression in BLCA was positively associated with the progression and poor prognosis. Further, SFXN1 deficiency remarkably suppressed the proliferation and metastasis of BLCA cells in vitro and in vivo, indicating an oncogenic role of SFXN1 in BLCA. Additionally, our results demonstrated that SFXN1 promotes metastasis through its unknown function of restraining PINK1 (PTEN-induced kinase 1)-dependent mitophagy rather than its classical role as a mitochondrial serine transporter to mediate one-carbon metabolism. Mechanistically, SFXN1 acted as a bridge to promote PINK1 degradation by interacting with PARL (presenilin-associated rhomboid-like protein) and MPP-β (mitochondrial processing peptidase-β), leading to mitophagy arrest. Notably, when mitophagy was restrained by highly-expressed SFXN1, mitochondrial reactive oxygen species were considerably enriched, thus activating TGF-β (transforming growth factor-β)-mediated epithelial-mesenchymal transition and promoting metastasis of BLCA cells. This study highlights SFXN1 as a novel promising therapeutic target for BLCA and identifies a new mitophagic modulator to improve our understanding of an association between mitophagy and BLCA progression. Schematic diagram of the proposed mechanism by which SFXN1 promotes bladder cancer metastasis by restraining PINK1-dependent mitophagy. SFXN1 is upregulated in BLCA tissues, and promotes BLCA metastasis through its unrevealed function of restraining PINK1-dependent mitophagy rather than its classical role as a mitochondrial serine transporter to promote cell proliferation. Specifically, SFXN1 acted as an essential bridging factor to promote PINK1 degradation by interacting with PARL and MPP-β on the IMM, leading to mitophagy arrest and mtROS accumulation, thus activated TGF-β-mediated EMT and promoted BLCA metastasis (This figure was created by Figdraw).