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Editors Selection IGR 24-4

Basic Science: Glaucoma and metabolic dysfunction under pressure

Comment by Robert Casson on:

116853 Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia, Langbøl M; Rovelt J; Saruhanian A et al., International journal of molecular sciences, 2023; 25:

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Langbøl et al. hypothesized that certain features of an individual's metabolism, in particular their response to bioenergetic stress, may contribute to the relative sensitivity/ resilience of the retinal ganglion cell axons in normal tension glaucoma (NTG) and ocular hypertension (OHT), respectively. To test this, they conducted an interesting metabolomics experiment: humans with NTG, OHT, and controls were exposed to normobaric hypoxia for two hours, followed by a 30-min recovery period in normobaric normoxia; blood samples were collected at baseline, during hypoxia and in recovery. Samples were analyzed with a non-targeted metabolomics approach using liquid chromatography coupled to high-resolution mass spectrometry.

In individuals with NTG, hypoxia did not appreciably alter metabolites that were affected in controls, from which the authors infer a dysregulated metabolism in NTG. In individuals with OHT, certain metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while tryptophan was downregulated. Given that tryptophan is involved in nicotinamide synthesis, one might expect downregulation to enhance axonal sensitivity;^1,2 nevertheless, the authors ascribe potential positive effects of tryptophan downregulation. The authors draw the strong conclusion that: "the metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production."

The data do not support this conclusion

Untargeted metabolomics is a powerful tool, but the generated data are complex and the small sample size in each group in this study make the results difficult to interpret. Only ten patients were included in each group and the initial principal components analysis (an 'unsupervised' statistical approach to obtain unbiased information about group separation) showed only noise. Although the subsequent 'supervised' statistical approach using orthogonal partial to least squares-discriminant analysis had relatively high predictive scores (Q²), this statistical method is sensitive to overfitting and high Q² values can result from complicated models that fit noise rather than underlying patterns. The authors note that there were no significant differences between the groups in response to hypoxia and that no metabolites were significantly regulated in the groups when comparing levels from hypoxia to recovery.

The study motivates further research, but larger samples would be required to provide robust evidence of differential metabolic regulation in individuals with OHT and NTG.

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