DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
Cristae
DRP1
Fibroblast
Glycolysis
Mitochondria
Oxidative phosphorylation
Peroxisome
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
01 02 2023
01 02 2023
Historique:
received:
27
06
2022
accepted:
22
12
2022
pmc-release:
10
02
2024
entrez:
10
2
2023
pubmed:
11
2
2023
medline:
15
2
2023
Statut:
ppublish
Résumé
Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.
Identifiants
pubmed: 36763487
pii: 286985
doi: 10.1242/jcs.260370
pmc: PMC10657212
pii:
doi:
Substances chimiques
Dynamins
EC 3.6.5.5
GTP Phosphohydrolases
EC 3.6.1.-
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIMH NIH HHS
ID : RF1 MH123971
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM125844
Pays : United States
Organisme : NIH HHS
ID : 1R35 GM128915-01NIGMS
Pays : United States
Organisme : NIH HHS
ID : S10 OD021630
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128915
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208516
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008554
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA227483
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148190
Pays : United States
Organisme : NIH HHS
ID : S10 OD012324
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197532
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NINDS NIH HHS
ID : F99 NS125829
Pays : United States
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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