Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
received:
01
11
2021
revised:
07
07
2022
accepted:
07
07
2022
entrez:
1
8
2022
pubmed:
2
8
2022
medline:
4
8
2022
Statut:
epublish
Résumé
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 <i>DNM1L</i>, 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 <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.
Identifiants
pubmed: 35914810
pii: 5/12/e202101284
doi: 10.26508/lsa.202101284
pmc: PMC9354038
pii:
doi:
Substances chimiques
Microtubule-Associated Proteins
0
Mitochondrial Proteins
0
GTP Phosphohydrolases
EC 3.6.1.-
DNM1L protein, human
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Banques de données
GENBANK
['NM_012062.5']
PDB
['5WP9', '4BEJ', '3W6P', '3W6O']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCATS NIH HHS
ID : TL1 TR001437
Pays : United States
Organisme : Medical Research Council
ID : MR/S005021/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL128240
Pays : United States
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800674
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD025036
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM067180
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM080202
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2022 Nolden et al.
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