First published September 30

Abstract

. Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase. Am J Physiol Heart Circ Physiol 290: H1289 -H1297, 2006. First published September 30, 2005 doi:10.1152/ajpheart.00811.2005.-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 Ϫ/Ϫ mice showed elevated levels of the uncoupling protein isoforms and peroxisome proliferator-activated receptor-␣. Biochemical assessment of the VLCAD Ϫ/Ϫ mice BAT showed increased oxygen consumption, attributed to uncoupled respiration in the absence of stress. ADP-stimulated respiration was 23.05 (SD 4.17) and 68.24 (SD 6.3) nmol O2⅐min Ϫ1 ⅐mg mitochondrial protein Ϫ1 for VLCAD ϩ/ϩ and VLCAD Ϫ/Ϫ mice, respectively (P Ͻ 0.001), and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated respiration was 35.9 (SD 3.6) and 49.3 (SD 9) nmol O2⅐min Ϫ1 ⅐mg mitochondrial protein Ϫ1 for VLCAD ϩ/ϩ and VLCAD Ϫ/Ϫ mice, respectively (P Ͻ 0.20), but these rates were insufficient to protect them in the cold. We conclude that disturbed mitochondrial bioenergetics in BAT 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. genetics; inborn errors; acyl-coenzyme A dehydrogenase; cardiomyopathy; hypothermia; hypoglycemia; bradycardia INBORN ERRORS OF METABOLISM affecting mitochondrial fatty acid oxidation are recessively inherited and account for a substantial number of cases of sudden infant death There are a number of theorized mechanisms proposed as the causes of death in VLCAD deficiency. These include energy starvation, metabolic acidosis, generalized or organspecific metabolic failure, lipotoxicity, and cardiac rhythm abnormalities. Previous work has shown that mice lacking the mitochondrial acyl-CoA dehydrogenases are cold sensitive MATERIALS AND METHODS VLCAD-deficient mice. VLCAD-deficient mice were generated as described previously (11). The VLCAD gene was inactivated by homologous recombination such that exons 1 through 7 were replaced with a neomycin resistance gene. Male 129sv/C57/BL6 VLCADdeficient mice 2 mo of age were used in this study. These experiments Address for reprint requests and other correspondence: V. Exil, Vanderbil