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Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms

Nolden, Kelsey A; Egner, John M; Collier, Jack J; Russell, Oliver M; Alston, Charlotte L; Harwig, Megan C; Widlansky, Michael E; ... Oláhová, Monika; + view all (2022) Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms. Life Science Alliance , 5 (12) , Article e202101284. 10.26508/lsa.202101284. Green open access

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Abstract

Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene DNM1L, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological DNM1L variants impair mitochondrial network maintenance by divergent mechanisms.

Type: Article
Title: Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.26508/lsa.202101284
Publisher version: https://doi.org/10.26508/lsa.202101284
Language: English
Additional information: © 2022 Nolden et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Keywords: Dynamins, GTP Phosphohydrolases, Humans, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10153626
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