DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth
Jonathan Barra, Isaiah Crosbourne, Cassandra L. Roberge, Ramon Bossardi Ramos, Janine S. A. Warren, Kailie Matteson, Ling Wang, Frances Jourd’heuil, Sergey M. Borisov, Erin Bresnahan, Jose Javier Bravo‐Cordero, Ruslan I. Dmitriev, David Jourd’heuil, Alejandro P. Adam, John M. Lamar, David T. Corr, Margarida Barroso
Abstract
Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1-dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells.