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 M. Barroso

Research output: Contribution to journalArticlepeer-review

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. (Figure presented.)

Original languageEnglish
Pages (from-to)650-667
Number of pages18
JournalOncogene
Volume43
Issue number9
DOIs
StatePublished - 23 Feb 2024

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