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Stephen L Archer - One of the best experts on this subject based on the ideXlab platform.

  • emerging concepts in the molecular basis of pulmonary arterial hypertension part i metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension
    Circulation, 2015
    Co-Authors: John J Ryan, Stephen L Archer
    Abstract:

    Mitochondria are central to cellular metabolism. The mitochondria’s metabolic pathways include fatty acid oxidation, glucose oxidation and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate1 (Figure 1). Figure 1 Mechanism of impaired glucose oxidation and enhanced aerobic glycolysis in PAH. Changes in redox signaling, such as downregulation of SOD2 and the resultant decrease in H2O2 signaling, can activate transcription factors (i.e. HIF-1α) which in ... Normally, glycolysis is coupled to glucose oxidation, meaning that the pyruvate is transported into the mitochondria where it serves as a substrate for pyruvate dehydrogenase (PDH)3. Under pathologic conditions, such as inhibition of PDH, glycolysis may be uncoupled from glucose oxidation and remain a wholly cytosolic reaction that terminates in the generation of lactate. Metabolism is quite plastic and the relative importance of each pathway can change in response to environmental stimuli, such as substrate availability, the organism’s developmental stage, and pathologic stimuli, such as hypoxia, shear stress, pressure overload, ischemia and hypertrophy. In addition, the activity of one metabolic pathway alters the activity of competing pathways. Examples of this metabolic crosstalk include the reciprocal relationship between fatty acid and glucose oxidation. Fatty acid oxidation suppresses glucose oxidation, through a mechanism called the Randle Cycle (Figure 2), named after Phillip Randle who first described the phenomenon3. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, so called aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg who first described the phenomenon in cancer cells5. Warburg noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells5. He also observed, but could not explain, accumulation of ammonia in his cancer tissue culture. Ultimately this proved to relate to a concomitant upregulation of glutaminolysis in cancer cells. Aerobic glycolysis results in a reliance on glycolysis to produce ATP despite the presence of sufficient oxygen to have allowed pyruvate generation and mitochondrial glucose oxidation. Aerobic glycolysis usually reflects active inhibition of one or more mitochondrial enzymes, notably inhibition of PDH by pyruvate dehydrogenase kinases (PDK). These acquired changes in metabolism alter the cell’s bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis and contractility. Importantly, the cell’s metabolic choices can be pharmacologically manipulated, offering the potential for metabolic therapies. Figure 2 Manipulating fatty acid and glucose oxidation in PAH: The Randle’s Cycle. Randle’s Cycle is the reciprocal relationship between glucose oxidation and fatty acid oxidation. Note how the acetyl CoA and citrate produced by β-oxidation ... In addition to generating adenosine triphosphate (ATP), mitochondria are constantly dividing and joining together6. These highly conserved and regulated processes are called fission and fusion, respectively7. These non-canonical mitochondrial functions (fission, fusion), as well as migration, are called mitochondrial dynamics.8 Mitochondrial dynamics are important in physiology, participating in oxygen sensing9 and the distribution of mitochondria to daughter cells during mitosis10. Mitochondrial dynamics are also involved in cellular quality control, notably participating in mitophagy and apoptosis. Acquired and inherited disorders of mitochondrial dynamics are involved in diseases, including pulmonary arterial hypertension (PAH), cancer, and cardiac ischemia reperfusion injury7. Both metabolic plasticity and mitochondrial dynamics are relevant to the pathogenesis of PAH and offer new therapeutic targets in the pulmonary vasculature and the right ventricle.

  • emerging concepts in the molecular basis of pulmonary arterial hypertension pah part i metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pah
    Circulation, 2015
    Co-Authors: John J Ryan, Stephen L Archer
    Abstract:

    Mitochondria are central to cellular metabolism. The mitochondria’s metabolic pathways include fatty acid oxidation, glucose oxidation and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate1 (Figure 1). Figure 1 Mechanism of impaired glucose oxidation and enhanced aerobic glycolysis in PAH. Changes in redox signaling, such as downregulation of SOD2 and the resultant decrease in H2O2 signaling, can activate transcription factors (i.e. HIF-1α) which in ... Normally, glycolysis is coupled to glucose oxidation, meaning that the pyruvate is transported into the mitochondria where it serves as a substrate for pyruvate dehydrogenase (PDH)3. Under pathologic conditions, such as inhibition of PDH, glycolysis may be uncoupled from glucose oxidation and remain a wholly cytosolic reaction that terminates in the generation of lactate. Metabolism is quite plastic and the relative importance of each pathway can change in response to environmental stimuli, such as substrate availability, the organism’s developmental stage, and pathologic stimuli, such as hypoxia, shear stress, pressure overload, ischemia and hypertrophy. In addition, the activity of one metabolic pathway alters the activity of competing pathways. Examples of this metabolic crosstalk include the reciprocal relationship between fatty acid and glucose oxidation. Fatty acid oxidation suppresses glucose oxidation, through a mechanism called the Randle Cycle (Figure 2), named after Phillip Randle who first described the phenomenon3. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, so called aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg who first described the phenomenon in cancer cells5. Warburg noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells5. He also observed, but could not explain, accumulation of ammonia in his cancer tissue culture. Ultimately this proved to relate to a concomitant upregulation of glutaminolysis in cancer cells. Aerobic glycolysis results in a reliance on glycolysis to produce ATP despite the presence of sufficient oxygen to have allowed pyruvate generation and mitochondrial glucose oxidation. Aerobic glycolysis usually reflects active inhibition of one or more mitochondrial enzymes, notably inhibition of PDH by pyruvate dehydrogenase kinases (PDK). These acquired changes in metabolism alter the cell’s bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis and contractility. Importantly, the cell’s metabolic choices can be pharmacologically manipulated, offering the potential for metabolic therapies. Figure 2 Manipulating fatty acid and glucose oxidation in PAH: The Randle’s Cycle. Randle’s Cycle is the reciprocal relationship between glucose oxidation and fatty acid oxidation. Note how the acetyl CoA and citrate produced by β-oxidation ... In addition to generating adenosine triphosphate (ATP), mitochondria are constantly dividing and joining together6. These highly conserved and regulated processes are called fission and fusion, respectively7. These non-canonical mitochondrial functions (fission, fusion), as well as migration, are called mitochondrial dynamics.8 Mitochondrial dynamics are important in physiology, participating in oxygen sensing9 and the distribution of mitochondria to daughter cells during mitosis10. Mitochondrial dynamics are also involved in cellular quality control, notably participating in mitophagy and apoptosis. Acquired and inherited disorders of mitochondrial dynamics are involved in diseases, including pulmonary arterial hypertension (PAH), cancer, and cardiac ischemia reperfusion injury7. Both metabolic plasticity and mitochondrial dynamics are relevant to the pathogenesis of PAH and offer new therapeutic targets in the pulmonary vasculature and the right ventricle.

John J Ryan - One of the best experts on this subject based on the ideXlab platform.

  • emerging concepts in the molecular basis of pulmonary arterial hypertension part i metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension
    Circulation, 2015
    Co-Authors: John J Ryan, Stephen L Archer
    Abstract:

    Mitochondria are central to cellular metabolism. The mitochondria’s metabolic pathways include fatty acid oxidation, glucose oxidation and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate1 (Figure 1). Figure 1 Mechanism of impaired glucose oxidation and enhanced aerobic glycolysis in PAH. Changes in redox signaling, such as downregulation of SOD2 and the resultant decrease in H2O2 signaling, can activate transcription factors (i.e. HIF-1α) which in ... Normally, glycolysis is coupled to glucose oxidation, meaning that the pyruvate is transported into the mitochondria where it serves as a substrate for pyruvate dehydrogenase (PDH)3. Under pathologic conditions, such as inhibition of PDH, glycolysis may be uncoupled from glucose oxidation and remain a wholly cytosolic reaction that terminates in the generation of lactate. Metabolism is quite plastic and the relative importance of each pathway can change in response to environmental stimuli, such as substrate availability, the organism’s developmental stage, and pathologic stimuli, such as hypoxia, shear stress, pressure overload, ischemia and hypertrophy. In addition, the activity of one metabolic pathway alters the activity of competing pathways. Examples of this metabolic crosstalk include the reciprocal relationship between fatty acid and glucose oxidation. Fatty acid oxidation suppresses glucose oxidation, through a mechanism called the Randle Cycle (Figure 2), named after Phillip Randle who first described the phenomenon3. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, so called aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg who first described the phenomenon in cancer cells5. Warburg noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells5. He also observed, but could not explain, accumulation of ammonia in his cancer tissue culture. Ultimately this proved to relate to a concomitant upregulation of glutaminolysis in cancer cells. Aerobic glycolysis results in a reliance on glycolysis to produce ATP despite the presence of sufficient oxygen to have allowed pyruvate generation and mitochondrial glucose oxidation. Aerobic glycolysis usually reflects active inhibition of one or more mitochondrial enzymes, notably inhibition of PDH by pyruvate dehydrogenase kinases (PDK). These acquired changes in metabolism alter the cell’s bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis and contractility. Importantly, the cell’s metabolic choices can be pharmacologically manipulated, offering the potential for metabolic therapies. Figure 2 Manipulating fatty acid and glucose oxidation in PAH: The Randle’s Cycle. Randle’s Cycle is the reciprocal relationship between glucose oxidation and fatty acid oxidation. Note how the acetyl CoA and citrate produced by β-oxidation ... In addition to generating adenosine triphosphate (ATP), mitochondria are constantly dividing and joining together6. These highly conserved and regulated processes are called fission and fusion, respectively7. These non-canonical mitochondrial functions (fission, fusion), as well as migration, are called mitochondrial dynamics.8 Mitochondrial dynamics are important in physiology, participating in oxygen sensing9 and the distribution of mitochondria to daughter cells during mitosis10. Mitochondrial dynamics are also involved in cellular quality control, notably participating in mitophagy and apoptosis. Acquired and inherited disorders of mitochondrial dynamics are involved in diseases, including pulmonary arterial hypertension (PAH), cancer, and cardiac ischemia reperfusion injury7. Both metabolic plasticity and mitochondrial dynamics are relevant to the pathogenesis of PAH and offer new therapeutic targets in the pulmonary vasculature and the right ventricle.

  • emerging concepts in the molecular basis of pulmonary arterial hypertension pah part i metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pah
    Circulation, 2015
    Co-Authors: John J Ryan, Stephen L Archer
    Abstract:

    Mitochondria are central to cellular metabolism. The mitochondria’s metabolic pathways include fatty acid oxidation, glucose oxidation and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate1 (Figure 1). Figure 1 Mechanism of impaired glucose oxidation and enhanced aerobic glycolysis in PAH. Changes in redox signaling, such as downregulation of SOD2 and the resultant decrease in H2O2 signaling, can activate transcription factors (i.e. HIF-1α) which in ... Normally, glycolysis is coupled to glucose oxidation, meaning that the pyruvate is transported into the mitochondria where it serves as a substrate for pyruvate dehydrogenase (PDH)3. Under pathologic conditions, such as inhibition of PDH, glycolysis may be uncoupled from glucose oxidation and remain a wholly cytosolic reaction that terminates in the generation of lactate. Metabolism is quite plastic and the relative importance of each pathway can change in response to environmental stimuli, such as substrate availability, the organism’s developmental stage, and pathologic stimuli, such as hypoxia, shear stress, pressure overload, ischemia and hypertrophy. In addition, the activity of one metabolic pathway alters the activity of competing pathways. Examples of this metabolic crosstalk include the reciprocal relationship between fatty acid and glucose oxidation. Fatty acid oxidation suppresses glucose oxidation, through a mechanism called the Randle Cycle (Figure 2), named after Phillip Randle who first described the phenomenon3. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, so called aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg who first described the phenomenon in cancer cells5. Warburg noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells5. He also observed, but could not explain, accumulation of ammonia in his cancer tissue culture. Ultimately this proved to relate to a concomitant upregulation of glutaminolysis in cancer cells. Aerobic glycolysis results in a reliance on glycolysis to produce ATP despite the presence of sufficient oxygen to have allowed pyruvate generation and mitochondrial glucose oxidation. Aerobic glycolysis usually reflects active inhibition of one or more mitochondrial enzymes, notably inhibition of PDH by pyruvate dehydrogenase kinases (PDK). These acquired changes in metabolism alter the cell’s bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis and contractility. Importantly, the cell’s metabolic choices can be pharmacologically manipulated, offering the potential for metabolic therapies. Figure 2 Manipulating fatty acid and glucose oxidation in PAH: The Randle’s Cycle. Randle’s Cycle is the reciprocal relationship between glucose oxidation and fatty acid oxidation. Note how the acetyl CoA and citrate produced by β-oxidation ... In addition to generating adenosine triphosphate (ATP), mitochondria are constantly dividing and joining together6. These highly conserved and regulated processes are called fission and fusion, respectively7. These non-canonical mitochondrial functions (fission, fusion), as well as migration, are called mitochondrial dynamics.8 Mitochondrial dynamics are important in physiology, participating in oxygen sensing9 and the distribution of mitochondria to daughter cells during mitosis10. Mitochondrial dynamics are also involved in cellular quality control, notably participating in mitophagy and apoptosis. Acquired and inherited disorders of mitochondrial dynamics are involved in diseases, including pulmonary arterial hypertension (PAH), cancer, and cardiac ischemia reperfusion injury7. Both metabolic plasticity and mitochondrial dynamics are relevant to the pathogenesis of PAH and offer new therapeutic targets in the pulmonary vasculature and the right ventricle.

Rui Curi - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms underlying skeletal muscle insulin resistance induced by fatty acids importance of the mitochondrial function
    Lipids in Health and Disease, 2012
    Co-Authors: Amanda R Martins, Rui Curi, Renato Tadeu Nachbar, Renata Gorjao, Marco Aurelio Ramirez Vinolo, William T Festuccia, Rafael Herling Lambertucci, Maria Fernanda Curyboaventura, Leonardo R Silveira, Sandro Massao Hirabara
    Abstract:

    Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle Cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.

  • palmitate acutely raises glycogen synthesis in rat soleus muscle by a mechanism that requires its metabolization Randle Cycle
    FEBS Letters, 2003
    Co-Authors: Sandro M Hirabara, Carla Roberta De Oliveira Carvalho, J R Mendonca, E P Haber, Luiz Claudio Fernandes, Rui Curi
    Abstract:

    The acute effect of palmitate on glucose metabolism in rat skeletal muscle was examined. Soleus muscles from Wistar male rats were incubated in Krebs–Ringer bicarbonate buffer, for 1 h, in the absence or presence of 10 mU/ml insulin and 0, 50 or 100 μM palmitate. Palmitate increased the insulin-stimulated [14C]glycogen synthesis, decreased lactate production, and did not alter D-[U-14C]glucose decarboxylation and 2-deoxy-D-[2,6-3H]glucose uptake. This fatty acid decreased the conversion of pyruvate to lactate and [1-14C]pyruvate decarboxylation and increased 14CO2 produced from [2-14C]pyruvate. Palmitate reduced insulin-stimulated phosphorylation of insulin receptor substrate-1/2, Akt, and p44/42 mitogen-activated protein kinases. Bromopalmitate, a non-metabolizable analogue of palmitate, reduced [14C]glycogen synthesis. A strong correlation was found between [U-14C]palmitate decarboxylation and [14C]glycogen synthesis (r=0.99). Also, palmitate increased intracellular content of glucose 6-phosphate in the presence of insulin. These results led us to postulate that palmitate acutely potentiates insulin-stimulated glycogen synthesis by a mechanism that requires its metabolization (Randle Cycle). The inhibitory effect of palmitate on insulin-stimulated protein phosphorylation might play an important role for the development of insulin resistance in conditions of chronic exposure to high levels of fatty acids.

Sandro Massao Hirabara - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms underlying skeletal muscle insulin resistance induced by fatty acids importance of the mitochondrial function
    Lipids in Health and Disease, 2012
    Co-Authors: Amanda R Martins, Rui Curi, Renato Tadeu Nachbar, Renata Gorjao, Marco Aurelio Ramirez Vinolo, William T Festuccia, Rafael Herling Lambertucci, Maria Fernanda Curyboaventura, Leonardo R Silveira, Sandro Massao Hirabara
    Abstract:

    Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle Cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.

Zeng Kui Guo - One of the best experts on this subject based on the ideXlab platform.

  • pyruvate dehydrogenase Randle Cycle and skeletal muscle insulin resistance
    Proceedings of the National Academy of Sciences of the United States of America, 2015
    Co-Authors: Zeng Kui Guo
    Abstract:

    The letters of Constantin-Teodosiu et al. and Petersen et al. debate whether the glucose-fatty acid Cycle (Randle Cycle) operates in skeletal muscle (1, 2). Both groups cited some data of the original study (3) to support their points. However, the well-known skeletal muscle heterogeneity was not mentioned, which seems critical to the point. Skeletal muscle consists of three types: red slow oxidative, white fast glycolytic, and fast oxidative-glycolytic with various degrees of reddish color, depending on the ratio of oxidative fibers (type I, red) to glycolytic fibers (type II, pale). These muscle types differ markedly in substrate metabolism (4), among many other differences. Compared with red muscle (e.g., … [↵][1]1Email: guo.zengkui{at}mayo.edu. [1]: #xref-corresp-1-1