DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.

Publisher: Company of Biologists Country of Publication: England NLM ID: 0052457 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9137 (Electronic) Linking ISSN: 00219533 NLM ISO Abbreviation: J Cell Sci Subsets: MEDLINE

Publication: Cambridge : Company of Biologists
Original Publication: London.

Dynamins*/genetics ; Dynamins*/metabolism ; Brain Diseases*/genetics ; Brain Diseases*/metabolism; Humans ; Membrane Potential, Mitochondrial/genetics ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Mutation/genetics ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Dynamics/genetics ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism

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.
Competing Interests: Competing interests The authors declare no competing or financial interests.
(© 2023. Published by The Company of Biologists Ltd.)

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RF1 MH123971 United States MH NIMH NIH HHS; R01 GM125844 United States GM NIGMS NIH HHS; 1R35 GM128915-01NIGMS United States NH NIH HHS; S10 OD021630 United States OD NIH HHS; R35 GM128915 United States GM NIGMS NIH HHS; R01 CA208516 United States CA NCI NIH HHS; T32 GM008554 United States GM NIGMS NIH HHS; R21 CA227483 United States CA NCI NIH HHS; R01 AI148190 United States AI NIAID NIH HHS; S10 OD012324 United States OD NIH HHS; R35 CA197532 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute; F99 NS125829 United States NS NINDS NIH HHS

Keywords: Cristae; DRP1; Fibroblast; Glycolysis; Mitochondria; Oxidative phosphorylation; Peroxisome

EC 3.6.5.5 (Dynamins)
EC 3.6.1.- (GTP Phosphohydrolases)
0 (Mitochondrial Proteins)

Date Created: 20230210 Date Completed: 20230214 Latest Revision: 20240211

20240211

PMC10657212

10.1242/jcs.260370

36763487