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 language | American English |
|---|---|
| Article number | e49019 |
| Journal | EMBO Reports |
| Volume | 21 |
| Issue number | 12 |
| DOIs | |
| State | Published - 3 Dec 2020 |
Bibliographical note
Funding Information:We thank Dr. Rappaport, Dr. Schmidt‐Chanasit and Dr. Mikaelian for kindly sharing reagents and advices with us. We thank our team of colleagues as well at ENYO Pharma and at INEM for fruitful discussions and constant support. We also acknowledge the INEM‐associated imaging, metabolic platform, and FACS facilities (SFR Necker INSERM US24, CNRS UMS 3633). We thank Ivan Nemazanyy at INEM for its help with designing and performing the Seahorse© essays. The present work has benefited from Imagerie‐Gif core facility supported by I’Agence Nationale de la Recherche (ANR‐11‐EQPX‐0029, ANR‐10‐INBS‐04, ANR‐11‐IDEX‐0003‐02). F.G and L.R. were supported by ANR Jeune Chercheur (ANR0015TD), ATIP‐Avenir Program. Work in A.R.’s laboratory was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 240245660—SFB 1129 TP13. RN acknowledges BSF (Binational Science Foundation (BSF) Grant No. 2015831). This work was supported by institutional funding from INSERM (U1151SE19KA and U115120K), University de Paris (16CONV30UPDE and L17V22CONV02) and grants from ANR (ANR‐17‐CE14‐0030‐02 and ANR‐17‐CE13‐0015‐003), to P.C. and E.Mo.
Funding Information:
We thank Dr. Rappaport, Dr. Schmidt-Chanasit and Dr. Mikaelian for kindly sharing reagents and advices with us. We thank our team of colleagues as well at ENYO Pharma and at INEM for fruitful discussions and constant support. We also acknowledge the INEM-associated imaging, metabolic platform, and FACS facilities (SFR Necker INSERM US24, CNRS UMS 3633). We thank Ivan Nemazanyy at INEM for its help with designing and performing the Seahorse? essays. The present work has benefited from Imagerie-Gif core facility supported by I?Agence Nationale de la Recherche (ANR-11-EQPX-0029, ANR-10-INBS-04, ANR-11-IDEX-0003-02). F.G and L.R. were supported by ANR Jeune Chercheur (ANR0015TD), ATIP-Avenir Program. Work in A.R.?s laboratory was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)?Projektnummer 240245660?SFB 1129 TP13. RN acknowledges BSF (Binational Science Foundation (BSF) Grant No. 2015831). This work was supported by institutional funding from INSERM (U1151SE19KA and U115120K), University de Paris (16CONV30UPDE and L17V22CONV02) and grants from ANR (ANR-17-CE14-0030-02 and ANR-17-CE13-0015-003), to P.C. and E.Mo.
Publisher Copyright:
© 2020 The Authors
Keywords
- NEET proteins
- contact sites
- mitochondria
- morphodynamics
- virus
