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Lactate: More Than Merely a Metabolic Waste Product in the Inner Retina

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Abstract

The retina is an extension of the central nervous system and has been considered to be a simplified, more tractable and accessible version of the brain for a variety of neuroscience investigations. The optic nerve displays changes in response to underlying neurodegenerative diseases, such as stroke, multiple sclerosis, and Alzheimer’s disease, as well as inner retinal neurodegenerative disease, e.g., glaucoma. Neurodegeneration has increasingly been linked to dysfunctional energy metabolism or conditions in which the energy supply does not meet the demand. Likewise, increasing lactate levels have been correlated with conditions consisting of unbalanced energy supply and demand, such as ischemia-associated diseases or excessive exercise. Lactate has thus been acknowledged as a metabolic waste product in organs with high energy metabolism. However, in the past decade, numerous beneficial roles of lactate have been revealed in the central nervous system. In this context, lactate has been identified as a valuable energy substrate, protecting against glutamate excitotoxicity and ischemia, as well as having signaling properties which regulate cellular functions. The present review aims to summarize and discuss protective roles of lactate in various model systems (in vitro, ex vivo, and in vivo) reflecting the inner retina focusing on lactate metabolism and signaling in inner retinal homeostasis and disease.

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Funding

The work is carried out as a part of the BRIDGE–Translational Excellence Programme (bridge.ku.dk) at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (Grant agreement no. NNF18SA0034956).

Supplementary description of methods.

The human Müller cell line, MIO-M1, was cultured to 90% confluence and scraped off after treatment with 10 mM L-Lactate in the presence and absence of 6 mM glucose in the media (DMEM A1443001, Gibco). The cells were centrifuged at 550 g for 5 minutes at 4 °C. Supernatants were discarded and cells were lysed in radioimmune precipitation assay (RIPA) buffer (Sigma-Aldrich), which also included protease cocktail inhibitor 1 and 2 (Sigma-Aldrich). Protein lysates were centrifuged at 8000 g for 10 minutes at 4 °C. The samples containing 22 μg proteins were loaded onto gels to investigate protein expression of MCT-1 and GPR81 by the use of an MCT-1 antibody (cat no. AB3538P, Millipore) and GPR81 antibody (cat. no. SAB1300090, Sigma-Aldrich). The blots were pre- incubated for 1 hour with Tris-buffered saline (TBS) (20 mM Tris-HCl, 150 mM NaCl) containing 5% nonfat dry milk. Afterwards, the blots were incubated with a primary antibody against either MCT-1 (dilution 1:500) or GPR81 (dilution 1:200) in TBS 1% nonfat dry milk over night at 4 °C. The blots were washed in TBS and incubated with the secondary antibody goat anti- rabbit IgG alkaline phosphatase conjugated secondary antibody (Jackson ImmunoResearch, West Grove, PA, USA) followed by visualization using BCIP/NBT (5-bromo-4-chloro- 3-indoyl phosphate-nitroblue tetrazolium) substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD, USA). To ensure that equal amounts of protein were loaded in each lane, the membranes were incubated with GAPDH at dilution 1:1000 (Cell Signaling Technologies, Danvers, MA, USA). Bands were quantified by densitometry through the use of Fiji; ImageJ software (National Institutes of Health, Bethesda, MD, USA). The density of each band was normalized to its own GAPDH band.

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  1. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Rupali Vohra & Miriam Kolko

  2. Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark

    Rupali Vohra

  3. Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark

    Miriam Kolko

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Vohra, R., Kolko, M. Lactate: More Than Merely a Metabolic Waste Product in the Inner Retina. Mol Neurobiol 57, 2021–2037 (2020). https://doi.org/10.1007/s12035-019-01863-8

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