Dataset Information


MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A.

ABSTRACT: Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser378 Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94?Gln94 and MFN2 Thr105?Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105?Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.


PROVIDER: S-EPMC6109362 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC2785744 | BioStudies
2020-01-01 | S-EPMC7655101 | BioStudies
2018-01-01 | S-EPMC6122517 | BioStudies
2019-01-01 | S-EPMC6522073 | BioStudies
2008-01-01 | S-EPMC2409111 | BioStudies
2007-01-01 | S-EPMC2063976 | BioStudies
2017-01-01 | S-EPMC5226824 | BioStudies
2020-01-01 | S-EPMC7039061 | BioStudies
2018-01-01 | S-EPMC6073211 | BioStudies
2019-01-01 | S-EPMC6820788 | BioStudies