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Metabolic Flexibility and Mitochondrial Bioenergetics in the Failing Heart. Therapeutic Approaches

Mariana G. Rosca
Mariana G. Rosca
   | 03. Mai 2022
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Article Category: Review
Online veröffentlicht: 03. Mai 2022
Seitenbereich: 269 - 282
DOI: https://doi.org/10.47803/rjc.2021.31.2.269
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© 2021 Mariana G. Rosca, published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

Major structural, functional, metabolic and bioenergetic features of the failing heart. Heart failure (HF) with preserved ejection fraction and HF with reduced ejection fraction may both evolve to congestive HF. These functional abnormalities are progressively induced by either primary stiffness of the ventricular wall (defect in cardiomyocyte relaxation, interstitial fibrosis and cardiomyocyte hypertrophy) or contractile dysfunction, cardiomyocyte death and eventually chamber dilation. The heart relies on constant ATP supplied by oxidative metabolism. Heart failure is considered a disease of the myocardial energetic metabolism induced by mitochondrial dysfunction leading to energy deficit, increased oxidative stress and altered redox status.
Major structural, functional, metabolic and bioenergetic features of the failing heart. Heart failure (HF) with preserved ejection fraction and HF with reduced ejection fraction may both evolve to congestive HF. These functional abnormalities are progressively induced by either primary stiffness of the ventricular wall (defect in cardiomyocyte relaxation, interstitial fibrosis and cardiomyocyte hypertrophy) or contractile dysfunction, cardiomyocyte death and eventually chamber dilation. The heart relies on constant ATP supplied by oxidative metabolism. Heart failure is considered a disease of the myocardial energetic metabolism induced by mitochondrial dysfunction leading to energy deficit, increased oxidative stress and altered redox status.

Figure 2

Electron microscopy image of the mouse heart.
Electron microscopy image of the mouse heart.

Figure 3

Cardiac oxidative metabolism. Normal adult heart obtains ATP mostly from fatty acid (FA) oxidation with the remaining delivered from glucose, amino acids and ketones (mainly β-hydroxybutyrate, βHB)5. Glucose uptake is mediated by the glucose transporter4 (GLUT4), and follows multiple metabolic pathways including glycolysis and mitochondrial glucose oxidation. For simplicity, other metabolic pathways are not depicted in this figure. The end product of extramitochondrial glycolysis, pyruvate, is converted by mitochondrial pyruvate dehydrogenase (PDH) to acetyl-CoA (Ac-CoA) that enters the tricarboxylic acid (TCA) cycle (Krebs cycle). Long chain FAs are activated to FA-CoAs that enter the mitochondria via carnitine palmitoyltransferases (CPT1 and 2) and are oxidized via FA β-oxidation. The end products of pyruvate and FA β-oxidation spiral are NADH, FADH2 and acetyl-CoA, which are further oxidized by electron transport chain (ETC) complexes or Krebs cycle, respectively, ultimately leading to ATP synthesis via mitochondrial oxidative phosphorylation. FA β-oxidation is inhibited by malonylCoA (formed from AcCoA via AcCoA carboxylase, ACC), FADH2/FAD+ and NADH/NAD+ redox ratios, and acetyl-CoA/CoA ratio. MalonylCoA is degraded by malonylCoA decarboxylase (MCD) thus releasing its inhibitory effect on CPT1. βHB is oxidized within cardiac mitochondria to acetoacetate (AcAc) that is converted to acetyl-CoA for Krebs cycle. Mitochondrial oxidative phosphorylation provides more than 95% of the cardiac ATP, with the remainder derived from glycolysis. While electrons are transferred from the reducing equivalents, NADH and FADH2, to oxygen by the ETC complexes, an electrochemical gradient is developed across the mitochondrial inner membrane (IM), which is used by the ATP synthase (complex V) to form ATP. Mitochondrial generated ATP is transferred to the cytosol by the mitochondrial and cytosolic creatine kinases (CK) for contractile apparatus, sarcoplasmic reticulum Ca2+-ATPase and other ion pumps. The inset represents an electron micrograph of mouse cardiac muscle showing interfibrillar mitochondria.
Cardiac oxidative metabolism. Normal adult heart obtains ATP mostly from fatty acid (FA) oxidation with the remaining delivered from glucose, amino acids and ketones (mainly β-hydroxybutyrate, βHB)5. Glucose uptake is mediated by the glucose transporter4 (GLUT4), and follows multiple metabolic pathways including glycolysis and mitochondrial glucose oxidation. For simplicity, other metabolic pathways are not depicted in this figure. The end product of extramitochondrial glycolysis, pyruvate, is converted by mitochondrial pyruvate dehydrogenase (PDH) to acetyl-CoA (Ac-CoA) that enters the tricarboxylic acid (TCA) cycle (Krebs cycle). Long chain FAs are activated to FA-CoAs that enter the mitochondria via carnitine palmitoyltransferases (CPT1 and 2) and are oxidized via FA β-oxidation. The end products of pyruvate and FA β-oxidation spiral are NADH, FADH2 and acetyl-CoA, which are further oxidized by electron transport chain (ETC) complexes or Krebs cycle, respectively, ultimately leading to ATP synthesis via mitochondrial oxidative phosphorylation. FA β-oxidation is inhibited by malonylCoA (formed from AcCoA via AcCoA carboxylase, ACC), FADH2/FAD+ and NADH/NAD+ redox ratios, and acetyl-CoA/CoA ratio. MalonylCoA is degraded by malonylCoA decarboxylase (MCD) thus releasing its inhibitory effect on CPT1. βHB is oxidized within cardiac mitochondria to acetoacetate (AcAc) that is converted to acetyl-CoA for Krebs cycle. Mitochondrial oxidative phosphorylation provides more than 95% of the cardiac ATP, with the remainder derived from glycolysis. While electrons are transferred from the reducing equivalents, NADH and FADH2, to oxygen by the ETC complexes, an electrochemical gradient is developed across the mitochondrial inner membrane (IM), which is used by the ATP synthase (complex V) to form ATP. Mitochondrial generated ATP is transferred to the cytosol by the mitochondrial and cytosolic creatine kinases (CK) for contractile apparatus, sarcoplasmic reticulum Ca2+-ATPase and other ion pumps. The inset represents an electron micrograph of mouse cardiac muscle showing interfibrillar mitochondria.

Figure 4

The main redox couples governing the redox balance in cardiac mitochondria (NAD+/NADH, NADP+/NADPH, and GSH/GSSG). Normal cardiomyocytes maintain a constant NAD pool. Both oxidized forms, NAD+ and NADP+, are hybrid acceptors, and are converted to the reduced forms, NADH and NADPH. NADH is oxidized by complex I, and therefore, the NADH/NAD+ couple is important for ATP generation. The NADPH/NADP+ redox couple is central to the antioxidant defense by donating electrons to glutathione (GSH/GSSG) that scavenges the hydrogen peroxide (H2O2, a Reactive Oxygen Species, ROS) via the enzymes glutathione reductase (GR), glutathione peroxidase (GPx). H2O2 is generated from superoxide, O•2, by dismutation via the enzyme, superoxide dismutase (SOD). For simplicity, the thioredoxin antioxidant system is not shown. Mitochondrial antioxidant system is mirrored by a similar scavenging mechanism in the cytosol. In these reactions, the reduced and oxidized members of the redox couples interconvert but are not consumed. Catalase also scavenges H2O2.Mitochondrial NADH/NAD+ and NADPH/NADP+ redox couples are linked by the enzyme nicotinamide nucleotide transhydrogenase (NNT) that reduces NADP+ at the expense of NADH oxidation and utilizing the mitochondrial inner membrane proton motive force to drive this process. NNT is a physiologically relevant source of NADPH to drive the enzymatic degradation of H2O2. The figure shows that the mitochondrial redox state of the NADH/NAD+ and NADPH/NADP+ redox couples are maintained different as these nucleotides have different metabolic roles. The NADH/NAD+ pool supports the divergent transfer of electrons from fuel substrates to both the ETC and antioxidant system via NNT, and thus is only partially reduced in comparison to NADPH/NADP+. The cytosolic NADH is imported in mitochondria by redox shuttles, most commonly the malate-aspartate (M-A) and glycerol 3 phosphate shuttles (G3P).
The main redox couples governing the redox balance in cardiac mitochondria (NAD+/NADH, NADP+/NADPH, and GSH/GSSG). Normal cardiomyocytes maintain a constant NAD pool. Both oxidized forms, NAD+ and NADP+, are hybrid acceptors, and are converted to the reduced forms, NADH and NADPH. NADH is oxidized by complex I, and therefore, the NADH/NAD+ couple is important for ATP generation. The NADPH/NADP+ redox couple is central to the antioxidant defense by donating electrons to glutathione (GSH/GSSG) that scavenges the hydrogen peroxide (H2O2, a Reactive Oxygen Species, ROS) via the enzymes glutathione reductase (GR), glutathione peroxidase (GPx). H2O2 is generated from superoxide, O•2, by dismutation via the enzyme, superoxide dismutase (SOD). For simplicity, the thioredoxin antioxidant system is not shown. Mitochondrial antioxidant system is mirrored by a similar scavenging mechanism in the cytosol. In these reactions, the reduced and oxidized members of the redox couples interconvert but are not consumed. Catalase also scavenges H2O2.Mitochondrial NADH/NAD+ and NADPH/NADP+ redox couples are linked by the enzyme nicotinamide nucleotide transhydrogenase (NNT) that reduces NADP+ at the expense of NADH oxidation and utilizing the mitochondrial inner membrane proton motive force to drive this process. NNT is a physiologically relevant source of NADPH to drive the enzymatic degradation of H2O2. The figure shows that the mitochondrial redox state of the NADH/NAD+ and NADPH/NADP+ redox couples are maintained different as these nucleotides have different metabolic roles. The NADH/NAD+ pool supports the divergent transfer of electrons from fuel substrates to both the ETC and antioxidant system via NNT, and thus is only partially reduced in comparison to NADPH/NADP+. The cytosolic NADH is imported in mitochondria by redox shuttles, most commonly the malate-aspartate (M-A) and glycerol 3 phosphate shuttles (G3P).

Figure 5

Mitochondrial redox modulators. Increasing the efficiency of the electron transport chain. The figure shows a proposed mechanism for the NAD+ enhancing and lysine deacetylating effect of methylene blue (MB). A complex I defect causes a decrease in NADH oxidation. In experimental models of complex I defect MB accepts electrons from catalytic subunits of complex I and become reduced (MBH2) whereas cytochrome c reoxidizes MBH2 to MB. Therefore, MB provides an alternative electron route within complex I-deficient cardiac mitochondria and favors NADH oxidation thus increasing NAD+ and SIRT3 activity. The administration of exogenous NAD or precursors (+) improved the mitochondrial NAD pool and cardiac function (discussed in the main text). Idebenone increases the coenzyme Q pool.
Mitochondrial redox modulators. Increasing the efficiency of the electron transport chain. The figure shows a proposed mechanism for the NAD+ enhancing and lysine deacetylating effect of methylene blue (MB). A complex I defect causes a decrease in NADH oxidation. In experimental models of complex I defect MB accepts electrons from catalytic subunits of complex I and become reduced (MBH2) whereas cytochrome c reoxidizes MBH2 to MB. Therefore, MB provides an alternative electron route within complex I-deficient cardiac mitochondria and favors NADH oxidation thus increasing NAD+ and SIRT3 activity. The administration of exogenous NAD or precursors (+) improved the mitochondrial NAD pool and cardiac function (discussed in the main text). Idebenone increases the coenzyme Q pool.
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Medizin, Klinische Medizin, Allgemeinmedizin, Innere Medizin, Kardiologie, Kinder- und Jugendmedizin, Kinderkardiologie, Chirurgie, Herzchirurgie
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