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Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms

Lookup NU author(s): Dr Jack Collier, Dr Oliver Russell, Dr Charlotte Alston, Professor Bobby McFarlandORCiD, Professor Robert Taylor, Dr Monika Olahova



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 Nolden et al. 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.

Publication metadata

Author(s): Nolden KA, Egner JM, Collier JJ, Russell OM, Alston CL, Harwig MC, Widlansky ME, Sasorith S, Barbosa IA, Douglas AG, Baptista J, Walker M, Donnelly DE, Morris AA, Tan HJ, Kurian MA, Gorman K, Mordekar S, Deshpande C, Samanta R, McFarland R, Hill RB, Taylor RW, Olahova M

Publication type: Article

Publication status: Published

Journal: Life Science Alliance

Year: 2022

Volume: 5

Issue: 12

Online publication date: 01/08/2022

Acceptance date: 07/07/2022

Date deposited: 17/08/2022

ISSN (electronic): 2575-1077

Publisher: Life Science Alliance


DOI: 10.26508/lsa.202101284

PubMed id: 35914810


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
MR/S005021/1Medical Research Council (MRC)
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award