ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway.
Apoptosis
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Mice
Electron-Transferring Flavoproteins
/ genetics
Animals
Neuronal Outgrowth
Iron-Sulfur Proteins
/ genetics
Mutation
Humans
Oxidoreductases Acting on CH-NH Group Donors
/ genetics
Multiple Acyl Coenzyme A Dehydrogenase Deficiency
/ genetics
Ubiquinone
/ analogs & derivatives
Signal Transduction
Cell Line
Apoptosis
Bcl-2
Carnitine
Coenzyme Q10
ETFDH
MOMP
Multiple acyl-coenzyme A dehydrogenase deficiency
Neuropathy
Riboflavin
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
23
03
2024
accepted:
03
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
The most common mutation in southern Chinese individuals with late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD; a fatty acid metabolism disorder) is c.250G > A (p.Ala84Thr) in the electron transfer flavoprotein dehydrogenase gene (ETFDH). Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. Given that axonal degeneration and neuronal apoptosis may be regulated by B-cell lymphoma (BCL)-2 family proteins and mitochondrial outer membrane permeabilization through the activation of proapoptotic molecules, we measured the expression levels of proapoptotic BCL-2 family proteins (e.g., BCL-2-associated X protein and p53-upregulated modulator of apoptosis), cytochrome c, caspase-3, and caspase-9 in NSC-34 cells carrying the most common ETFDH mutation. The levels of these proteins were higher in the mutant cells than in the wide-type cells. Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. These results suggest that the activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway promotes apoptosis in cellular models of MADD and that coenzyme Q10 can reverse this effect. Our findings aid the development of novel therapeutic strategies for reducing axonal degeneration and neuronal apoptosis in MADD.
Identifiants
pubmed: 39455656
doi: 10.1038/s41598-024-75286-4
pii: 10.1038/s41598-024-75286-4
doi:
Substances chimiques
Proto-Oncogene Proteins c-bcl-2
0
Electron-Transferring Flavoproteins
0
Iron-Sulfur Proteins
0
electron-transferring-flavoprotein dehydrogenase
EC 1.5.5.1
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
Ubiquinone
1339-63-5
coenzyme Q10
EJ27X76M46
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25374Subventions
Organisme : Kaohsiung Medical University Chung-Ho Memorial Hospital
ID : KMUH-106-6R46.
Organisme : Chi-Mei Medical Center and Kaohsiung Medical University, Taiwan
ID : 108CM-KMU-08
Organisme : Chi-Mei Medical Center and Kaohsiung Medical University, Taiwan
ID : 108CM-KMU-08
Informations de copyright
© 2024. The Author(s).
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