Recent Advances in Pulmonary Hypertension

1691 Mitochondria are central to cellular metabolism. The metabolic pathways of mitochondria include fatty acid oxidation, glucose oxidation, and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate (Figure 1). 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). Under pathological 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 and the developmental stage of the organism and pathological 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 phenomenon. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, socalled aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg, who first described the phenomenon in cancer cells. Warburg et al noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells. They also observed, but could not explain, accumulation of ammonia in their 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 1 or more mitochondrial enzymes, most often inhibition of PDH by PDH kinases (PDKs). These acquired changes in metabolism alter the bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis, and contractility of the cell. Importantly, the metabolic choices of the cell can be pharmacologically manipulated, offering the potential for metabolic therapies. In addition to generating ATP, mitochondria are constantly dividing and joining together. These highly conserved and regulated processes are called fission and fusion, respectively. These noncanonical mitochondrial functions (fission and fusion), as well as migration, are called mitochondrial dynamics. Mitochondrial dynamics are important in physiology, participating in oxygen sensing and distributing mitochondria to daughter cells during mitosis. 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 injury. 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 (RV).