Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury

Dambrova, Maija; Zuurbier, Coert J.; Borutaitė, Vilmantė; Liepinsh, Edgars; Makrecka-Kūka, Marina

doi:10.1016/j.freeradbiomed.2021.01.036

Cited by 96 publications

(69 citation statements)

References 162 publications

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“…In the present study, circulating medium- and long-chain acylcarnitines, especially C6:0, C8:0, C8:1, C12:1, C14:1, C16:0, C16:1, C18:1, and C20:4, were found to be elevated in CAD patients. This accumulation could be explained by a dysregulation in carnitine shuttle enzymes and by an inefficient beta-oxidation as previously demonstrated ( 34 , 38 , 40 , 44 , 56 , 87 – 90 ). The main carnitine shuttle enzymes are carnitine palmitoyltransferase 1 (CPT1) and carnitine palmitoyltransferase 2 (CPT2), which are responsible for the conversion of acyl-CoA and carnitine to free CoA and acylcarnitine and the opposite reaction, respectively.…”

Section: Discussionsupporting

confidence: 54%

“…In ischemic conditions, CPT1 activity is increased and CPT2 activity decreased, leading to an accumulation of medium- and long-chain acylcarnitines ( Figure 5 ) ( 87 ). Furthermore, ischemia leads to an altered beta-oxidation, which may be attributed to impaired function of fatty acid oxidation enzymes or increased fatty acid oxidation relative to tricarboxylic acid (TCA) flux ( 12 , 38 ), both leading to accumulation of acyl-CoA ( 12 , 34 , 47 , 88 , 91 , 92 ). Excess acyl-CoA can be retroconverted to acylcarnitine, which can then be excreted via blood and urine, thus detoxifying mitochondria of excess carbons ( Figure 5 ) ( 37 , 39 , 88 , 93 ).…”

Section: Discussionmentioning

confidence: 99%

“…These are then transported through the inner mitochondrial membrane by the carrier carnitine/acylcarnitine translocase (CACT). Once inside the mitochondrion, the enzyme carnitine palmitoyltransferase 2 (CPT2) converts acylcarnitines back to their corresponding acyl-CoAs, which will then undergo beta-oxidation to produce acetyl-CoA ( 34 – 36 ). Beyond fuel trafficking, acylcarnitines also defend against mitochondrial stress by buffering the intracellular free CoA to acyl-CoA ratio ( 37 – 39 ).…”

Section: Discussionmentioning

confidence: 99%

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Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights

Gander

Carrard

Gallart-Ayala

et al. 2021

Front. Cardiovasc. Med.

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Coronary artery disease (CAD) remains the leading cause of death worldwide. Expanding patients' metabolic phenotyping beyond clinical chemistry investigations could lead to earlier recognition of disease onset and better prevention strategies. Additionally, metabolic phenotyping, at the molecular species level, contributes to unravel the roles of metabolites in disease development. In this cross-sectional study, we investigated clinically healthy individuals (n = 116, 65% male, 70.8 ± 8.7 years) and patients with CAD (n = 54, 91% male, 67.0 ± 11.5 years) of the COmPLETE study. We applied a high-coverage quantitative liquid chromatography-mass spectrometry approach to acquire a comprehensive profile of serum acylcarnitines, free carnitine and branched-chain amino acids (BCAAs), as markers of mitochondrial health and energy homeostasis. Multivariable linear regression analyses, adjusted for confounders, were conducted to assess associations between metabolites and CAD phenotype. In total, 20 short-, medium- and long-chain acylcarnitine species, along with L-carnitine, valine and isoleucine were found to be significantly (adjusted p ≤ 0.05) and positively associated with CAD. For 17 acylcarnitine species, associations became stronger as the number of affected coronary arteries increased. This implies that circulating acylcarnitine levels reflect CAD severity and might play a role in future patients' stratification strategies. Altogether, CAD is characterized by elevated serum acylcarnitine and BCAA levels, which indicates mitochondrial imbalance between fatty acid and glucose oxidation.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights

Gander

Carrard

Gallart-Ayala

et al. 2021

Front. Cardiovasc. Med.

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“…Since it has been shown that the accumulation of LCAC in ischaemic cardiac mitochondria promotes ROS production due to the inhibition of oxidative phosphorylation [ 30 , 46 ], the observed prevention of oxidative stress in ischaemic hearts by methyl-GBB treatment is more likely associated with the prevention of LCAC accumulation during ischaemia. Moreover, activation of mitochondrial respiration and FA oxidation decreases lipotoxicity [ 47 ], and it has been suggested that stimulation of fatty acid oxidation during reperfusion could be beneficial against I/R-induced oxidative stress [ 48 ]. Treatment with methyl-GBB increases mitochondrial fatty acid oxidation after ischaemia, thus ensuring effective utilization of accumulated fatty acid intermediates and subsequent reduction of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia‐Reperfusion Injury in Zucker Rats

Kuka

Makrecka-Kūka

Vilks

et al. 2021

Oxidative Medicine and Cellular Longevity

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Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are known to induce cardiometabolic benefits, but the metabolic pathways of their biosynthesis ensuring sufficient bioavailability require further investigation. Here, we show that a pharmacological decrease in overall fatty acid utilization promotes an increase in the levels of PUFAs and attenuates cardiometabolic disturbances in a Zucker rat metabolic syndrome model. Metabolome analysis showed that inhibition of fatty acid utilization by methyl-GBB increased the concentration of PUFAs but not the total fatty acid levels in plasma. Insulin sensitivity was improved, and the plasma insulin concentration was decreased. Overall, pharmacological modulation of fatty acid handling preserved cardiac glucose and pyruvate oxidation, protected mitochondrial functionality by decreasing long-chain acylcarnitine levels, and decreased myocardial infarct size twofold. Our work shows that partial pharmacological inhibition of fatty acid oxidation is a novel approach to selectively increase the levels of PUFAs and modulate lipid handling to prevent cardiometabolic disturbances.

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“…During ischemia, anaerobic glycolysis of glucose produces excessive lactic acid in the ischemic cells and ultimately causes acidification in the heart ( 61 ). When oxidative phosphorylation is not supported by sufficient oxygen, ATP production is largely reduced, leading to the dysfunction of Na + -K + -ATPase and the elevation of intracellular calcium, sodium, and hydrogen concentration ( 62 , 63 ). Subsequently, cells swell while the activities of cytoplasmic enzymes are impaired.…”

Section: Sumoylation In the Pathophysiological Process Of Myocardial Infarctionmentioning

confidence: 99%

SUMOylation as a Therapeutic Target for Myocardial Infarction

Zhao

Zhang

2021

Front. Cardiovasc. Med.

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Myocardial infarction is a prevalent and life-threatening cardiovascular disease. The main goal of existing interventional therapies is to restore coronary reperfusion while few are designed to ameliorate the pathology of heart diseases via targeting the post-translational modifications of those critical proteins. Small ubiquitin-like modifier (SUMO) proteins are recently discovered to form a new type of protein post-translational modifications (PTM), known as SUMOylation. SUMOylation and deSUMOylation are dynamically balanced in the maintenance of various biological processes including cell division, DNA repair, epigenetic transcriptional regulation, and cellular metabolism. Importantly, SUMOylation plays a critical role in the regulation of cardiac functions and the pathology of cardiovascular diseases, especially in heart failure and myocardial infarction. This review summarizes the current understanding on the effects of SUMOylation and SUMOylated proteins in the pathophysiology of myocardial infarction and identifies the potential treatments against myocardial injury via targeting SUMO. Ultimately, this review recommends SUMOylation as a key therapeutic target for treating cardiovascular diseases.

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Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury

Cited by 96 publications

References 162 publications

Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights

Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights

Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia‐Reperfusion Injury in Zucker Rats

SUMOylation as a Therapeutic Target for Myocardial Infarction

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