| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Pediatrics, Vanderbilt University, Nashville, TN, USA
2 Medicine, Vanderbilt University, Nashville, TN, USA
3 Medicine, Washington University, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: vernat.exil{at}vanderbilt.edu.
Mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is associated with severe hypoglycemia, cardiac dysfunction, and sudden death in neonates and children. Sudden death is common, but the underlying mechanisms are not fully understood. We report on a mouse model of VLCAD deficiency with a phenotype induced by the stresses of fasting and cold, which includes hypoglycemia, hypothermia, and severe bradycardia. The administration of glucose did not rescue the mice under stress conditions, but rewarming alone consistently led to heart rate recovery. Brown adipose tissue (BAT) from the VLCAD -/- mice showed elevated levels of the uncoupling protein isoforms and peroxisome proliferator-activated receptor alpha. Biochemical assessment of the VLCAD-/- mice BAT showed increased O2 consumption, due to uncoupled respiration in the absence of stress. ADP-stimulated respiration was 23.05 ± 4.17 for VLCAD +/+ and 68.24 ± 6.3 VLCAD -/- mice (p<0.001) and FCCPstimulated respiration was 35.9 ± 3.6 for the VLCAD +/+ mice and 49.3 ± 9 for the VLCAD -/- mice (p<0.20), but these were insufficient to protect them in the cold. We conclude that disturbed mitochondrial bioenergetics in brown adipose tissue is a critical contributing factor for the cold sensitivity in VLCAD deficiency. Our observations provide insights into the possible mechanisms of stress-induced death in human newborns with abnormal fat metabolism and elucidate targeting of specific substrates for particular metabolic needs.
This article has been cited by other articles:
|
|
 |
|
  F. ter Veld, S. Primassin, L. Hoffmann, E. Mayatepek, and U. Spiekerkoetter Corresponding increase in long-chain acyl-CoA and acylcarnitine after exercise in muscle from VLCAD mice J. Lipid Res., August 1, 2009; 50(8): 1556 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Leatherbury, Q. Yu, B. Chatterjee, D. L. Walker, Z. Yu, X. Tian, and C. W. Lo A novel mouse model of X-linked cardiac hypertrophy Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2701 - H2711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Werdich, F. Baudenbacher, I. Dzhura, L. H. Jeyakumar, P. J. Kannankeril, S. Fleischer, A. LeGrone, D. Milatovic, M. Aschner, A. W. Strauss, et al. Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2202 - H2211. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
