Cellular Metabolism in Lung Health and Disease

Abstract

The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant. While many extrapulmonary diseases are now linked to abnormalities in cellular metabolism, the pulmonary community has only recently embraced the concept of metabolic dysfunction as a driver of respiratory pathology. Herein, we provide an overview of the major metabolic pathways in the lung and discuss how cells sense and adapt to low-energy states. Moreover, we review some of the emerging evidence that links alterations in cellular metabolism to the pathobiology of several common respiratory diseases.

Keywords: cellular metabolism; energy; glycolysis; lung; mitochondria; respiratory disease.

Figure 1

Major metabolic pathways. Glycolysis is a 10-step reaction that converts glucose into pyruvate; pyruvate is then converted into lactate or enters the tricarboxylic acid (TCA) cycle as acetyl-CoA to yield NADH and FADH₂. NADH and FADH₂ are used by the electron transport chain (ETC) to generate ATP. Metabolic intermediates derived from glycolysis can also be diverted to the pentose phosphate pathway (PPP) to generate NADPH and ribose-5-phosphate. Fatty acid synthesis occurs in the endoplasmic reticulum and requires both NADPH and ATP from other metabolic pathways. During periods of energy deprivation, fatty acids are metabolized in mitochondria via β-oxidation, yielding large amounts of NADH and FADH₂ for ATP synthesis in the ETC.

Figure 2

End products of glucose metabolism based on carbon atoms recovered during perfusion of isolated whole lung tissues. The data are represented as percent of total recovery. Data from Reference .

Figure 3

Mechanisms for generating membrane and surfactant lipids in type II alveolar epithelial cells. These cells can engage in the de novo synthesis of lipids by utilizing pyruvate from glucose, or citrate from the TCA cycle. Mitochondrial citrate is mobilized to the cytoplasm and converted to acetyl-CoA by the enzyme ATP-citrate lyase. Acetyl-CoA undergoes carboxylation to malonyl-CoA by the enzyme acetyl-CoA carboxylase and subsequent steps require repetition of a 4-step reaction known as condensation, reduction, dehydration, and reduction. Fatty acyl chains can then undergo elongation and/or desaturation before being added to glycerol molecules to synthesize membrane and surfactant phospholipids. Fatty acyl chains for phospholipids can also be acquired from dietary sources or from the extracellular surfactant lipid pool. These diverse mechanisms are believed to explain how alveolar epithelial type II cells can maintain precise control over their surfactant lipid pool under a wide range of stress conditions. Abbreviations: ACLY, ATP-citrate lyase; FAS, fatty acid synthesis; TCA, tricarboxylic acid.

Figure 4

Metabolic reprogramming of activated lung fibroblasts. Activated lung fibroblasts utilize aerobic glycolysis (Warburg effect) over mitochondrial glucose oxidation. Although this metabolic reprogramming event generates less ATP than mitochondrial respiration, it also supplies various biosynthetic intermediates for activated myofibroblasts. This includes the production of glucose-6-P, which is diverted to the pentose phosphate pathway for the production of NADPH and ribose-5-P, and the production of glycerate-3-P, which is diverted to the de novo serine and glycine synthesis pathway. Aerobic glycolysis also yields large amounts of lactate acid, which serves to activate latent TGF-β1 by reducing extracellular pH. By-products of aerobic glycolysis can also feed the TCA cycle, leading to an increase in succinate production. Succinate stabilizes HIF-1α, which then amplifies glycolysis by inducing the expression of various glycolytic genes and promotes myofibroblast differentiation via the induction of α-SMA expression. Activated myofibroblasts also exhibit enhanced glutaminase activity, leading to augmented glutaminolysis, which in turn promotes the conversion of glutamine to glutamate. Glutamine metabolism via the TCA cycle can yield high levels of α-KG, which activates mTOR, leading to increased transcription, translation, and hydroxylation of collagen. Abbreviations: α-KG, alpha-ketoglutarate; α-SMA, alpha-smooth muscle actin; GLUT1, glucose transporter 1; HIF-1α, hypoxia-induced factor-1 alpha; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin; P, phosphate; PHGDH, phosphoglycerate dehydrogenase; PPP, pentose phosphate pathway; TCA, tricarboxylic acid; TGF-β1, transforming growth factor-beta 1.