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 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 O2.min(-1).mg
mitochondrial protein(-1) for
VLCAD+/+ and
VLCAD-/- mice, respectively (P < 0.001), and
carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated respiration was 35.9 (SD 3.6) and 49.3 (SD 9) nmol O2.min(-1).mg
mitochondrial protein(-1) for
VLCAD+/+ and
VLCAD-/- mice, respectively (P < 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.