BNIP3 promotes HIF-1α-driven melanoma growth by curbing intracellular iron homeostasis

BNIP3 is a mitophagy receptor with context-dependent roles in cancer, but whether and how it modulates melanoma growth in vivo remains unknown. Here, we found that elevated BNIP3 levels correlated with poorer melanoma patient's survival and depletion of BNIP3 in B16-F10 melanoma cells compromised tumor growth in vivo. BNIP3 depletion halted mitophagy and enforced a PHD2-mediated downregulation of HIF-1 alpha and its glycolytic program both in vitro and in vivo. Mechanistically, we found that BNIP3-deprived melanoma cells displayed increased intracellular iron levels caused by heightened NCOA4-mediated ferritinophagy, which fostered PHD2-mediated HIF-1 alpha destabilization. These effects were not phenocopied by ATG5 or NIX silencing. Restoring HIF-1 alpha levels in BNIP3-depleted melanoma cells rescued their metabolic phenotype and tumor growth in vivo, but did not affect NCOA4 turnover, underscoring that these BNIP3 effects are not secondary to HIF-1 alpha. These results unravel an unexpected role of BNIP3 as upstream regulator of the pro-tumorigenic HIF-1 alpha glycolytic program in melanoma cells.