RT Journal Article
SR Electronic
T1 Novel <em>DNM1L</em> variants impair mitochondrial dynamics through divergent mechanisms
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101284
DO 10.26508/lsa.202101284
VO 5
IS 12
A1 Nolden, Kelsey A
A1 Egner, John M
A1 Collier, Jack J
A1 Russell, Oliver M
A1 Alston, Charlotte L
A1 Harwig, Megan C
A1 Widlansky, Michael E
A1 Sasorith, Souphatta
A1 Barbosa, Inês A
A1 Douglas, Andrew GL
A1 Baptista, Julia
A1 Walker, Mark
A1 Donnelly, Deirdre E
A1 Morris, Andrew A
A1 Tan, Hui Jeen
A1 Kurian, Manju A
A1 Gorman, Kathleen
A1 Mordekar, Santosh
A1 Deshpande, Charu
A1 Samanta, Rajib
A1 McFarland, Robert
A1 Hill, R Blake
A1 Taylor, Robert W
A1 Oláhová, Monika
YR 2022
UL http://www.life-science-alliance.org/content/5/12/e202101284.abstract
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.