PT  - JOURNAL ARTICLE
AU  - Kelsey A Nolden
AU  - John M Egner
AU  - Jack J Collier
AU  - Oliver M Russell
AU  - Charlotte L Alston
AU  - Megan C Harwig
AU  - Michael E Widlansky
AU  - Souphatta Sasorith
AU  - Inês A Barbosa
AU  - Andrew GL Douglas
AU  - Julia Baptista
AU  - Mark Walker
AU  - Deirdre E Donnelly
AU  - Andrew A Morris
AU  - Hui Jeen Tan
AU  - Manju A Kurian
AU  - Kathleen Gorman
AU  - Santosh Mordekar
AU  - Charu Deshpande
AU  - Rajib Samanta
AU  - Robert McFarland
AU  - R Blake Hill
AU  - Robert W Taylor
AU  - Monika Oláhová
TI  - Novel <em>DNM1L</em> variants impair mitochondrial dynamics through divergent mechanisms
AID  - 10.26508/lsa.202101284
DP  - 2022 Dec 01
TA  - Life Science Alliance
PG  - e202101284
VI  - 5
IP  - 12
4099  - https://www.life-science-alliance.org/content/5/12/e202101284.short
4100  - https://www.life-science-alliance.org/content/5/12/e202101284.full
SO  - Life Sci. Alliance2022 Dec 01; 5
AB  - 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.