Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers.
Acyl-CoA Dehydrogenase, Long-Chain
/ deficiency
Adenosine Triphosphate
/ metabolism
Antioxidants
/ pharmacology
Apoptosis
/ drug effects
Cell Survival
/ drug effects
Congenital Bone Marrow Failure Syndromes
/ etiology
Electron Transport
/ drug effects
Endoplasmic Reticulum
/ metabolism
Energy Metabolism
/ drug effects
Lipid Metabolism, Inborn Errors
/ etiology
Membrane Potential, Mitochondrial
/ drug effects
Mitochondria
/ drug effects
Mitochondrial Diseases
/ etiology
Mitochondrial Dynamics
/ drug effects
Muscular Diseases
/ etiology
Oxidation-Reduction
/ drug effects
Oxygen Consumption
Reactive Oxygen Species
/ metabolism
Signal Transduction
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
06
08
2018
revised:
12
11
2018
accepted:
13
11
2018
pubmed:
18
11
2018
medline:
10
3
2020
entrez:
17
11
2018
Statut:
ppublish
Résumé
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid β-oxidation. Patients present with heterogeneous clinical phenotypes affecting heart, liver and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD-deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain (RC) function, increased reactive oxygen species (ROS) production and altered mitochondrial function and signaling pathways in a variety of VLCAD-deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved RC function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD-deficient patients.
Identifiants
pubmed: 30445591
pii: 5185121
doi: 10.1093/hmg/ddy403
pmc: PMC6400046
doi:
Substances chimiques
Antioxidants
0
Reactive Oxygen Species
0
Adenosine Triphosphate
8L70Q75FXE
Acyl-CoA Dehydrogenase, Long-Chain
EC 1.3.8.8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
928-941Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK078775
Pays : United States
Organisme : NIEHS NIH HHS
ID : R33 ES025606
Pays : United States
Informations de copyright
© The Author(s) 2018. Published by Oxford University Press.
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