Functional redundancy of mitochondrial enoyl-CoA isomerases in the oxidation of unsaturated fatty acids.
Mitochondrial enoyl-CoA isomerase (ECI1) is an auxiliary enzyme involved in unsaturated fatty acid oxidation. In contrast to most of the other enzymes involved in fatty acid oxidation, a deficiency of ECI1 has yet to be identified in humans. We used wild-type (WT) and Eci1-deficient knockout (KO) mice to explore a potential presentation of human ECI1 deficiency. Upon food withdrawal, Eci1-deficient mice displayed normal blood β-hydroxybutyrate levels (WT 1.09 mM vs. KO 1.10 mM), a trend to lower blood glucose levels (WT 4.58 mM vs. KO 3.87 mM, P=0.09) and elevated blood levels of unsaturated acylcarnitines, in particular C12:1 acylcarnitine (WT 0.03 μM vs. KO 0.09 μM, P<0.01). Feeding an olive oil-rich diet induced an even greater increase in C12:1 acylcarnitine levels (WT 0.01 μM vs. KO 0.04 μM, P<0.01). Overall, the phenotypic presentation of Eci1-deficient mice is mild, possibly caused by the presence of a second enoyl-CoA isomerase (Eci2) in mitochondria. Knockdown of Eci2 in Eci1-deficient fibroblasts caused a more pronounced accumulation of C12:1 acylcarnitine on incubation with unsaturated fatty acids (12-fold, P<0.05). We conclude that Eci2 compensates for Eci1 deficiency explaining the mild phenotype of Eci1-deficient mice. Hypoglycemia and accumulation of C12:1 acylcarnitine might be diagnostic markers to identify ECI1 deficiency in humans.
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases (F0-222), Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Michel
M
van Weeghel
Heleen
H
te Brinke
Henk
H
van Lenthe
Wim
W
Kulik
Paul E
PE
Minkler
Maria S K
MS
Stoll
Jörn Oliver
JO
Sass
Uwe
U
Janssen
Wilhelm
W
Stoffel
K Otfried
KO
Schwab
Ronald J A
RJ
Wanders
Charles L
CL
Hoppel
Sander M
SM
Houten
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019748:Carbon-Carbon Double Bond Isomerases / Q000235:genetics / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D064006:Dodecenoyl-CoA Isomerase; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction
D001786:Blood Glucose; D005231:Fatty Acids, Unsaturated; C116917:acylcarnitine; D019748:Carbon-Carbon Double Bond Isomerases; D064006:Dodecenoyl-CoA Isomerase; C576298:ECI1 protein, human; C119738:ECI2 protein, human; C576299:Eci1 protein, mouse; D002331:Carnitine