Compromised mitochondrial fatty acid synthesis in transgenic mice results in defective protein lipoylation and energy disequilibrium.
A mouse model with compromised mitochondrial fatty acid synthesis has been engineered in order to assess the role of this pathway in mitochondrial function and overall health. Reduction in the expression of mitochondrial malonyl CoA-acyl carrier protein transacylase, a key enzyme in the pathway encoded by the nuclear Mcat gene, was achieved to varying extents in all examined tissues employing tamoxifen-inducible Cre-lox technology. Although affected mice consumed more food than control animals, they failed to gain weight, were less physically active, suffered from loss of white adipose tissue, reduced muscle strength, kyphosis, alopecia, hypothermia and shortened lifespan. The Mcat-deficient phenotype is attributed primarily to reduced synthesis, in several tissues, of the octanoyl precursors required for the posttranslational lipoylation of pyruvate and α-ketoglutarate dehydrogenase complexes, resulting in diminished capacity of the citric acid cycle and disruption of energy metabolism. The presence of an alternative lipoylation pathway that utilizes exogenous free lipoate appears restricted to liver and alone is insufficient for preservation of normal energy metabolism. Thus, de novo synthesis of precursors for the protein lipoylation pathway plays a vital role in maintenance of mitochondrial function and overall vigor.
Children's Hospital Oakland Research Institute, Oakland, California, USA. ssmith@chori.org
Stuart
S
Smith
Andrzej
A
Witkowski
Ayesha
A
Moghul
Yuko
Y
Yoshinaga
Michael
M
Nefedov
Pieter
P
de Jong
Dejiang
D
Feng
Loren
L
Fong
Yiping
Y
Tu
Yan
Y
Hu
Stephen G
SG
Young
Thomas
T
Pham
Carling
C
Cheung
Shana M
SM
Katzman
Martin D
MD
Brand
Casey L
CL
Quinlan
Marcel
M
Fens
Frans
F
Kuypers
Stephanie
S
Misquitta
Stephen M
SM
Griffey
Son
S
Tran
Afshin
A
Gharib
Jens
J
Knudsen
Hans Kristian
HK
Hannibal-Bach
Grace
G
Wang
Sandra
S
Larkin
Jennifer
J
Thweatt
Saloni
S
Pasta
D051080:Acyl-Carrier Protein S-Malonyltransferase / Q000235:genetics* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism / Q000648:ultrastructure; D000740:Anemia / Q000235:genetics; D000818:Animals; D019069:Cell Respiration; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D007657:Ketone Bodies / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D054878:Lipoylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D012005:Rectal Prolapse / Q000235:genetics; D015398:Signal Transduction
D005227:Fatty Acids; D007657:Ketone Bodies; D024101:Mitochondrial Proteins; D019344:Lactic Acid; D051080:Acyl-Carrier Protein S-Malonyltransferase