Makrecka-Kuka 2018 MiPschool Tromso E1

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Marina Makrecka-Kuka
Cardiac fatty acid oxidation: from in vitro to in vivo.

Link: MitoEAGLE

Makrecka-Kuka M, Liepinsh E (2018)

Event: MiPschool Tromso-Bergen 2018

COST Action MitoEAGLE

Fatty acid oxidation (FAO) plays an essential role in heart bioenergetics and provides 60-95% of necessary ATP for normal heart function. Thus, impairment in FAO results in significant disturbances in cardiac function.

Before being oxidized fatty acids are activated to acyl-CoAs via long-chain acylCoA synthase. Before entering the β-oxidation pathway, acyl-CoAs have to be transported into the mitochondria. In contrast to medium- and short- chain acyl-CoAs, long-chain acyl-CoAs cannot directly pass the inner mitochondrial membrane, and their mitochondrial uptake is mediated by the carnitine-dependent transport system, which is rate-limiting step in FAO. As the first step, acyl-CoAs are converted to respective acylcarnitines by carnitine palmitoyltransferase I (CPT I). Formed acylcarnitines are subsequently transported into the mitochondria, where they are converted back to the respective acyl-CoAs by carnitine palmitoyltransferase II (CPT II) in the mitochondrial matrix. Moreover, the measurements of fatty acid oxidation in mitochondria are highly dependent on addition of co-factors like malate, carnitine and BSA.

Overall, different activated fatty acids can be used to characterize various steps in FAO processes in cardiac mitochondria. However, it is important to interpretate results with caution, taking into account FAO biochemical pathway.

Long-chain fatty acids are inert molecules, but their intermediates, acyl-CoAs and acylcarnitines, could actively participate in the regulation of cardiac mitochondrial bioenergetics. Interestingly that long-chain acylcarnitines, but not long-chain acyl-CoAs, are able to reduce the pyruvate oxidation rate in mitochondria and induce insulin resistance [1,2]. The accumulation of long-chain fatty acids activated intermediates, is observed in the ischemic myocardium after acute ischemia-reperfusion. Both long-chain acyl-CoAs and acylcarntines decreased OXPHOS-dependent mitochondrial respiration in dose-dependent manner. However, the content of long-chain acyl-CoAs was up to 50-fold lower than the measured acylcarnitine content in ischemic mitochondria. Our results demonstrate that long-chain acylcarnitines inhibit oxidative phosphorylation in cardiac mitochondria, thus, inducing mitochondrial membrane hyperpolarization and stimulating the production of reactive oxygen species, which can lead to the cell death [3]. The increase in long-chain acylcarnitine content induced an increase in infarct size, while pharmacological reduction of long-chain acylcarnitine content decreases ischemia-reperfusion induced mitochondrial dysfunction and significantly decreases infarct size [3,4].

Overall, present results demonstrate that long-chain acylcarnitines, but not long-chain acyl-CoAs, orchestrate mitochondrial energy metabolism pattern and determine ischemia-reperfusion induced damage in cardiac mitochondria.


Bioblast editor: Beno M, Plangger M O2k-Network Lab: LV Riga Makrecka-Kuka M


Affiliations

Latvian Inst Organic Synthesis, Lab Pharmaceutical Pharmacology, Riga, Latvia. - makrecka@farm.osi.lv

References

  1. Makrecka M, Kuka J, Volska K, Antone U, Sevostjanovs E, Cirule H, Grinberga S, Pugovics O, Dambrova M, Liepinsh E (2014) Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria. Mol Cell Biochem 395:1-10.
  2. Liepinsh E, Makrecka-Kuka M, Makarova E, Volska K, Vilks K, Sevostjanovs E, Antone U, Kuka J, Vilskersts R, Lola D, Loza E, Grinberga S, Dambrova M (2017) Acute and long-term administration of palmitoylcarnitine induces muscle-specific insulin resistance in mice. Biofactors 43:718-30.
  3. Liepinsh E, Makrecka-Kuka M, Volska K, Kuka J, Makarova E, Antone U, Sevostjanovs E, Vilskersts R, Strods A, Tars K, Dambrova M (2016) Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria. Biochem J 473:1191-202.
  4. Kuka J, Makrecka-Kuka M, Cirule H, Grinberga S, Sevostjanovs E, Dambrova M, Liepinsh E (2017) Decrease in long-chain acylcarnitine tissue content determines the duration of and correlates with the cardioprotective effect of methyl-GBB. Basic Clin Pharmacol Toxicol 121:106-12.


Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion 

Tissue;cell: Heart 


Regulation: Fatty acid 


HRR: Oxygraph-2k  Event: E1