Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria

Abstract

In the heart, a nutritional state (fed or fasted) is characterized by a unique energy metabolism pattern determined by the availability of substrates. Increased availability of acylcarnitines has been associated with decreased glucose utilization; however, the effects of long-chain acylcarnitines on glucose metabolism have not been previously studied. We tested how changes in long-chain acylcarnitine content regulate the metabolism of glucose and long-chain fatty acids in cardiac mitochondria in fed and fasted states. We examined the concentrations of metabolic intermediates in plasma and cardiac tissues under fed and fasted states. The effects of substrate availability and their competition for energy production at the mitochondrial level were studied in isolated rat cardiac mitochondria. The availability of long-chain acylcarnitines in plasma reflected their content in cardiac tissue in the fed and fasted states, and acylcarnitine content in the heart was fivefold higher in fasted state compared to the fed state. In substrate competition experiments, pyruvate and fatty acid metabolites effectively competed for the energy production pathway; however, only the physiological content of acylcarnitine significantly reduced pyruvate and lactate oxidation in mitochondria. The increased availability of long-chain acylcarnitine significantly reduced glucose utilization in isolated rat heart model and in vivo. Our results demonstrate that changes in long-chain acylcarnitine contents could orchestrate the interplay between the metabolism of pyruvate-lactate and long-chain fatty acids, and thus determine the pattern of energy metabolism in cardiac mitochondria.

Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and α-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia

“…A recent study demonstrated that plasma levels of acylcarnitines reflect intracellular levels of these compounds during fasting (Makrecka et al 2014) and may suggest a similar correlation in the present study. Whether this reflects an organismal downregulation or a more prominent localized effect in the arm undergoing RIC maneuver is unknown.…”

“…Whether this reflects an organismal downregulation or a more prominent localized effect in the arm undergoing RIC maneuver is unknown. Being responsible for the transportation of fatty acids into mitochondria for β-oxidation, acylcarnitines play an important role in the energy generation in the heart and other organs (Makrecka et al 2014). During ischemia, long-chain acylcarnitines accumulate in the ischemic tissue, though ischemic conditioning has been proposed to prevent such an accumulation (Ford et al 1996; Simkhovich et al 1993).…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…The shift towards long‐chain acylcarnitine accumulation is a result of unbalanced acylcarnitine synthesis and mitochondrial oxidation rates, which leads to accumulation of long‐chain acylcarnitines in mitochondria—often referred to in the literature as incomplete FAO . In this case, the highest concentrations of long‐chain acylcarnitines are found in the mitochondrial inner membrane and the intermembrane space, but long‐chain acylcarnitines can also escape from mitochondria and inhibit the insulin signalling cascade upstream of protein kinase b (Akt) phosphorylation, favouring FA metabolism at the expense of glucose/pyruvate metabolism . Meanwhile, in cardiac mitochondria, long‐chain acylcarnitines inhibit pyruvate and lactate metabolism even at physiological concentrations .…”

“…In this case, the highest concentrations of long‐chain acylcarnitines are found in the mitochondrial inner membrane and the intermembrane space, but long‐chain acylcarnitines can also escape from mitochondria and inhibit the insulin signalling cascade upstream of protein kinase b (Akt) phosphorylation, favouring FA metabolism at the expense of glucose/pyruvate metabolism . Meanwhile, in cardiac mitochondria, long‐chain acylcarnitines inhibit pyruvate and lactate metabolism even at physiological concentrations . At elevated levels, the accumulation of long‐chain acylcarnitines inhibits OXPHOS, inducing mitochondrial membrane hyperpolarization and stimulating ROS production .…”

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

“…Infusing the heart with palmitoylcarnitine prior to arterial occlusion significantly exacerbated the size of the resulting infarct. In cultured mouse myotubules, acylcarnitines induce insulin resistance, cell membrane permeability, and promote apoptosis [39, 21, 40, 41]. Acylcarnitines can activate NF-κB and promote a pro-inflammatory response [22, 20].…”