Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics

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 mitochon...

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Published inEMBO reports
Main Authors Molino, Diana, Pila‐castellanos, Irene, Marjault, Henri‐baptiste, Dias Amoedo, Nivea, Kopp, Katja, Rochin, Leila, Karmi, Ola, Sohn, Yang‐sung, Lines, Laetitia, Hamaï, Ahmed, Joly, Stéphane, Radreau, Pauline, Vonderscher, Jacky, Codogno, Patrice, Giordano, Francesca, Machin, Peter, Rossignol, Rodrigue, Meldrum, Eric, Arnoult, Damien, Ruggieri, Alessia, Nechushtai, Rachel, de Chassey, Benoit, Morel, Etienne
Format Journal Article
LanguageEnglish
Published EMBO Press 12.11.2020
Subjects
Cellular Biology
Life Sciences
Virology & Host Pathogen Interaction
NEET proteins
Microbiology
mitochondria
contact sites
morphodynamics
virus Subject Categories Membranes & Trafficking
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Summary: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 mito-chondrial 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.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201949019