Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics

Diana Molino, Irene Pila-Castellanos, Henri Baptiste Marjault, Nivea Dias Amoedo, Katja Kopp, Leila Rochin, Ola Karmi, Yang Sung Sohn, Laetitia Lines, Ahmed Hamaï, Stéphane Joly, Pauline Radreau, Jacky Vonderscher, Patrice Codogno, Francesca Giordano, Peter Machin, Rodrigue Rossignol, Eric Meldrum, Damien Arnoult, Alessia RuggieriRachel Nechushtai, Benoit de Chassey*, Etienne Morel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER–mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research.

Original languageAmerican English
Article numbere49019
JournalEMBO Reports
Volume21
Issue number12
DOIs
StatePublished - 3 Dec 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors

Keywords

  • NEET proteins
  • contact sites
  • mitochondria
  • morphodynamics
  • virus

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