PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Schiff, M.* ; Haberberger, B. ; Xia, C.P.* ; Mohsen, A.W.* ; Goetzman, E.S.* ; Wang, Y.* ; Uppala, R.* ; Zhang, Y.* ; Karunanidhi, A.* ; Prabhu, D.* ; Alharbi, H.* ; Prochownik, E.V.* ; Haack, T.B. ; Häberle, J.* ; Munnich, A.* ; Rotig, A.* ; Taylor, R.W.* ; Nicholls, R.D.* ; Kim, J.J.* ; Prokisch, H. ; Vockley, J.*

Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency.

Hum. Mol. Genet. 24, 3238-3247 (2015)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Acyl-CoA dehydrogenase 9 (ACAD9) is an assembly factor for mitochondrial respiratory chain Complex I (CI), and ACAD9 mutations are recognized as a frequent cause of CI deficiency. ACAD9 also retains enzyme ACAD activity for long-chain fatty acids in vitro but the biological relevance of this function remains controversial partly because of the tissue-specificity of ACAD9 expression: high in liver and neurons and minimal in skin fibroblasts. In this study, we hypothesized that this enzymatic ACAD activity is required for full fatty acid oxidation capacity in cells expressing high levels of ACAD9, and that loss of this function is important in determining phenotype in ACAD9 deficient patients. First, we confirmed that HEK293 cells express ACAD9 abundantly. Then, we showed that ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation along with Cl, both of which were rescued by wild-type ACAD9. Further, we evaluated whether the loss of ACAD9 enzymatic fatty acid oxidation affects clinical severity in patients with ACAD9 mutations. The effects on ACAD activity of 16 ACAD9 mutations identified in 24 patients were evaluated using a prokaryotic expression system. We showed that there was a significant inverse correlation between residual enzyme ACAD activity and phenotypic severity of ACAD9 deficient patients. These results provide evidence that in cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation which contributes to the severity of the phenotype in ACAD9 deficient patients. Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunctions.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
6.393
1.477
23
24
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Acyl-coa Dehydrogenase; Mitochondrial Complex; Isovaleric Acidemia; Beta-oxidation; Phenotypic Heterogeneity; Scad Deficiency; Mutations; Gene; Cardiomyopathy; Defects
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Zeitschrift Human Molecular Genetics
Quellenangaben Band: 24, Heft: 11, Seiten: 3238-3247 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
PubMed ID 25721401
DOI 10.1093/hmg/ddv074
WOS ID WOS:000355674000020
Scopus ID 84930729271
Erfassungsdatum 2015-03-01
[➜Korrektur melden]