Pathobiological Links Discovered Between Asthma and Metabolism

Could diet matter?

By Weiling Xu, MD, and Serpil Erzurum, MD

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Clinicians and researchers have long observed a relationship between asthma and obesity. But the nature of the association has been poorly understood. Our recent research sheds light on this perplexing and important relationship and helps to define the role of metabolism in the pathobiology of asthma.

A growing understanding over the last decade is that underlying metabolism contributes in a major way to predisposition to disease, including lung disease. It turns out that your grandmother’s adage, “You are what you eat,” may be true.

Mitochondria of people with asthma are less reliant on glycolysis

We now recognize that nutritional intake, body fat type and the microbiome can all impact asthma risk and control. Epidemiological studies show a very tight link between asthma and obesity, but not causation. Plenty of lean people have asthma, and many people with obesity do not.

Our multisite team has been working for the past seven years to elucidate the asthma-metabolism link. In collaboration with Sruti Shiva, PhD, at University of Pittsburgh, we began our research by studying mitochondrial function in platelets of asthmatic individuals in comparison to healthy individuals.  Mitochondria of asthmatics exhibited decreased reliance on glycolysis and greater tricarboxylic acid cycle (TCA) activity, suggesting that oxidative phosphorylation is more efficient in asthmatic individuals.

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Figure 1. Ultrastructure of mitochondria in asthma airway epithelium. Different mitochondria are shown by arrowheads. B: close-up of A, and C: close-up of B. N, nucleus. All scale bars: 1 μm.

Asthma: an arginine-driven metabolic disorder

Our most recent study of the mechanisms underlying the change in mitochondrial metabolism identified that the alterations in the mitochondria may be the result of increased expression of type II arginase (ARG2). ARG2 is localized within mitochondria and serves to break down arginine to ornithine, which through several transamination reactions can form alpha-ketoglutarate and enter the TCA cycle. The findings showed that the greater levels of mitochondrial ARG2 and arginine flux in asthma accelerate the TCA cycle and cellular respiration.

Interestingly, the ARG2 gene variants lie within an asthma linkage region on chromosome 14q24, and these were some of the earliest and most consistent single nucleotide polymorphisms discovered in genome-wide association studies of asthma. In fact, alterations in the ARG2 gene are strongly linked to asthma and asthma severity. In our recent mechanistic studies, mice genetically deficient in ARG2 had alterations in cellular metabolism and more severe asthma inflammation.


Figure 2. Arginine metabolism and bioenergetics in asthma. (A) Inducible nitric oxide synthase (iNOS) converts arginine to citrulline and nitric oxide (NO). Arginase 2 (ARG2), found in mitochondria, converts arginine to ornithine which is converted to glutamate by ornithine aminotransferase (OAT). α-ketoglutarate (αKG) then enters the tricarboxylic acid (TCA) cycle for electron transport chain (ETC) to generate ATP energy. The TCA cycle in mitochondria is linked to the citrulline-NO cycle in the cytosol. (B) Greater ARG2 expression is found in asthmatic bronchial epithelium. Scale bar: 40 μm.

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These studies and prior work indicate asthma is endotypically an arginine-driven metabolic disorder.

Next questions – new management for asthma?

Our discoveries open new lines of speculation. All studies were performed in lean individuals, so we do not yet know if metabolic effects differ between individuals with asthma with or without obesity.  Drugs that modify mitochondrial bioenergetics are in development, but untested in asthma. Further work is needed to understand if and how mitochondrial targeted therapies and/or diet might impact metabolism and control of asthma.

Dr. Xu is an assistant professor in Pathobiology at the Lerner Research Institute.

Dr. Erzurum is the Alfred Lerner Chair of the Lerner Research Institute; and staff, Pulmonary Medicine, Respiratory Institute.