Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

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.