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Pyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics

Abstract

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up.

Key messages

  • Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development.

  • Lactate is a relevant and functional metabolite correlated with AMD progression.

  • Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression.

  • Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD.

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Data availability

The metabolomics and all the data reported in this paper are available on demand from the Laboratory of Biology and Tumor Development and the Metabolomics Group of the University of Liège.

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Acknowledgments

We gratefully acknowledge the medical and technical assistance of M. Dumez, N. Marenne, C. Noel, A. Oger, C. Rogister, B. Detry, C. Fink, M. Dehuy, I. Dassoul, P. Roncarati, J. Parotte, J. Lhoest, G. Musso, and C. Benveniste. We thank the GIGA (Groupe Interdisciplinaire de Génoprotéomique Appliquée, University of Liège, Belgium) for the access to the several platforms (GIGA-Imaging and Flow Cytometry platform and GIGA-Mouse facility and Transgenics platform) and the Center for Interdisciplinary Research on Medicines (CIRM) for the access to the NMR-Santé platform.

Funding

This work was supported by grants from the Fonds de la Recherche Scientifique FNRS (F.R.S.-FNRS, Belgium), the Fonds spéciaux de la Recherche (University of Liège), the Fondation Hospitalo Universitaire Léon Fredericq (FHULF, University of Liège), the REGION WALLONNE (Direction Générale Opérationnelle de l’Economie, de l’Emploi et de la Recherche, SPW, Belgium), and the FEDER project No. DMLA-AB/ULG (Fonds européen de développement régional). P. de Tullio is a Research Director of the F.R.S.-FNRS.

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Contributions

V.L. designed the study, performed the in vivo experiments, collected human and murine data with SH, CY, and J. Lecomte. M.S. and J. Leenders performed the metabolomics studies and analyzed the data. M.H. and P.H. performed the assays using macrophages; S.B. performed the computer-assisted quantifications; O.C. performed the bone marrow isolation; P.B., E.D., B.L., and M.T. contributed to patient recruitment and ophthalmic examinations. E.C. and A.G. performed human blood sample analyses; P.d.T. and B.G. performed statistical analyses on metabolomics assays; J-M.R. contributed to the design of the clinical study, data analyses, and manuscript preparation; A.N. designed and supervised the study, analyzed, and interpreted the experimental data, and P.d.T. designed the project, supervised the study, and performed the metabolomics study. A.N. and P.d.T wrote the manuscript and gathered manuscript modifications from the authors. All authors revised the manuscript.

Corresponding author

Correspondence to Pascal de Tullio.

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Competing interests

The authors declare that they no competing interests.

Ethics

Animal experiments were performed in compliance with the Animal Ethical Committee of the Liège University (Liège, Belgium) after the approval of the local Animal Ethical Committee. The human study was conducted under protocols approved by the Ethical Committee of the University Hospital of Liège, B7072006295 (Belgium). Informed consent was obtained from all study subjects before participation.

Code availability

Metabolomics data were processed using Bruker Topspin 3.5 and AMIX 3.9 software. Metabolomics analyses were performed using SIMCA 14.1 software. Statistical analyses were performed using GraphPad Prism 7.0 software.

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Agnès Noel and Pascal de Tullio equally supervised this paper

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Lambert, V., Hansen, S., Schoumacher, M. et al. Pyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics. J Mol Med 98, 1737–1751 (2020). https://doi.org/10.1007/s00109-020-01994-9

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Keywords

  • Neovascular AMD
  • Metabolomics
  • Inflammation
  • Angiogenesis
  • Therapeutic target
  • Lactate