The heart utilizes primarily
fatty acids for energy production. During
ischemia, however, diminished
oxygen supply necessitates a switch from beta-oxidation of
fatty acids to
glucose utilization and glycolysis. Molecular mechanisms responsible for these alterations in metabolism are not fully understood. Mitochondrial
acyl-CoA dehydrogenase catalyzes the first committed step in the beta-oxidation of
fatty acids. In the current study, an in vivo rat model of
myocardial ischemia was utilized to determine whether specific
acyl-CoA dehydrogenases exhibit
ischemia-induced alterations in activity, identify mechanisms responsible for changes in
enzyme function, and assess the effects on mitochondrial respiration.
Very long chain acyl-CoA dehydrogenase (
VLCAD) activity declined 34% during 30 min of
ischemia. Loss in activity appeared specific to
VLCAD as
medium chain acyl-CoA dehydrogenase activity remained constant. Loss in
VLCAD activity during
ischemia was not due to loss in
protein content. In addition, activity was restored in the presence of the
detergent Triton X-100, suggesting that changes in the interaction between the
protein and inner mitochondrial membrane are responsible for
ischemia-induced loss in activity. Palmitoyl-
carnitine supported
ADP-dependent state 3 respiration declined as a result of
ischemia. When octanoyl-
carnitine was utilized state 3 respiration remained unchanged. State 4 respiration increased during
ischemia, an increase that appears specific to
fatty acid utilization. Thus,
VLCAD represents a likely site for the modulation of substrate utilization during
myocardial ischemia. However, the dramatic increase in mitochondrial state 4 respiration would be predicted to accentuate the imbalance between energy production and utilization.