Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics

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.

Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy

“…We showed a significant reduction of contact sites number and density in electron microscopy ( Fig 2C, 2D and 2E ). The reduction was validated in confocal microscopy experiment where PTPIP51 presence (a contact site resident protein, [ 24 ]) was significantly reduced at the ER/mitochondria interface ( Fig 2F and 2G ).…”

“…In the context of H1N1 viral infection, we thought to evaluate whether the mitochondrial fusion phenotype we just described was required for influenza pathogenesis. We therefore investigated the effects of Mito-C, a molecule recently developed by ENYO Pharma and previously described to induce mitochondria fragmentation on virus replication [ 24 ]. Our hypothesis was that Mito-C could counteract the effects of influenza virus infection on mitochondria fusion, restore a normal phenotype and inhibit influenza replication.…”

“…Indeed, no anti-viral activity is detectable in RIG-I knock-out cells. Together with its anti-Dengue virus activity, this finally suggests that Mito-C compound could have a broad-spectrum activity against viruses that are sensed by RIG-I and that induce mitochondria elongation [ 12 , 24 ]. In the current epidemic context, it is tempting to propose the repositioning of Mito-C against SARS-CoV-2, since SARS-coronavirus ORF9b protein was recently shown to induce mitochondrial network elongation and to inactivate RLR pathway by degrading MAVS signalosome [ 29 ].…”

Alterations in mitochondrial morphology as a key driver of immunity and host defence

“…Recently, it has been shown that the pro‐fission compound Mito‐C has anti‐viral effects on cells through altering mitochondrial morphology to increase mitochondrial‐ER contact sites (Molino et al , 2020 ). Mito‐C was found to promote recruitment of DRP1 to mitochondria‐ER sites to induce mitochondrial fragmentation which inhibited dengue virus replication in host cells.…”

Réponse antivirale

“…Nous avons ensuite évalué l'effet d'une molécule synthétique, MITO-C, sur les modifications de l'appareil mitochondrial induites par le virus. MITO-C est une molécule hétérocyclique de petite taille obtenue en mimant les déterminants des protéines virales impliqués dans leur interaction avec les protéines des cellules hôtes [12]. Les cibles de MITO-C sont les trois protéines de la famille des protéines contenant le motif NEET (Asn-Glu-Glu-Thr) : MitoNEET (CDGSH iron sulfur domain 1), NAF-1 (nutrient-deprivation autophagy factor-1) et MiNT (ou CDGSH iron sulfur domain 3) [13].…”