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Neuroprotection of the inner retina: Müller cells and lactate

Müller cells: The neglected neighbor: Müller cells constitute the majority of retinal glial cells and offer more alternating functions than any other cell of the retina. Uniquely, Müller cells cover the complete thickness of the retina, and their roles therefore differ correspondingly to the retinal segment in which they are located. In the inner retina, Müller cells are crucial in taking up toxic molecules, such as excessive glutamate from the synapses between bipolar cells and retinal ganglion cells (RGCs), thereby preventing glutamate-induced excitoxic RGC death (Bringmann et al., 2009; Skytt et al., 2016; Toft-Kehler et al., 2016; Vohra et al., 2017) (Figure 1). Additionally, Müller cells are crucial in maintaining ion balances and have also been suggested to secrete essential neuroprotective factors as well as to buffer energy sources to the neighboring cells (Bringmann et al., 2006, 2009). Despite being over looked for decades Müller cells have now been proven essential in overall retinal maintenance, and increasing attention and acknowledgement has been attributed to their mere presence and function. In general, Müller cells contain elevated amounts of mitochondria and are known to be extremely resistant to various forms of pathogenic conditions, such as hypoxia, hypoglycemia and oxidative stress (Toft-Kehler et al., 2016; Vohra et al., 2017), indicating that the Müller cells’ defense towards toxic stress might be defined by their energy metabolism and increased adenosine triphosphate (ATP) turnover. However, in the case of excessive stress or multiple toxic factors, the defense mechanisms may diminish and result in dysfunctional Müller cells (Toft-Kehler et al., 2016; Vohra et al., 2017). As a compensatory self defensive mechanism, the Müller cells might take up alternate energy substrates, such as glutamate, to accommodate the need for a greater energy consumption (Skytt et al., 2016; Toft-Kehler et al., 2016, 2017) (Figure 1). Recently, Müller cells were proposed to take up lactate from the outer retina and merely transfer lactate to inner retinal neurons as an alternate energy substrate (Hurley et al., 2015). However, we challenge this assumption by arguing that Müller cells may in fact metabolize lactate (Vohra et al., 2018), which during compromised glucose availability may be essential in upholding their protection of inner retinal neurons. Although human peripheral blood lactate levels lie between 1–2 mM, physiological levels of retinal lactate extend up to 5–50 mM depending on the species. Certainly, these high levels of lactate must play a role in maintaining retinal function and survival (Kolko et al., 2016). In line with this, our previous studies have shown increased uptake of radioactively marked glutamate by the human Müller cell line, MIO-M1 in response to 10 mM of extracellular L-lactate (Vohra et al., 2018), thus verifying a boosted Müller cell function in the presence of lactate. Moreover, our recent paper highlighted numerous novel features of lactate uptake in Müller cells such as sustained glycogen storage and increased survival, indicating a shift in scientific reasoning towards lactate being more than merely a metabolic waste product. The present perspective article aims to highlight the importance of Müller cell energy metabolism with special attention to lactate-linked neuroprotection in the inner retina.