Mitochondrial function in Müller cells - Does it matter?

Growing evidence suggests that mitochondrial dysfunction might play a key role in the pathogenesis of age-related neurodegenerative inner retinal diseases such as diabetic retinopathy and glaucoma. Therefore, the present review provides a perspective on the impact of functional mitochondria in the most predominant glial cells of the retina, the Müller cells. Müller cells span the entire thickness of the neuroretina and are in close proximity to retinal cells including the retinal neurons that provides visual signaling to the brain. Among multiple functions, Müller cells are responsible for the removal of neurotransmitters, buffering potassium, and providing neurons with essential metabolites. Thus, Müller cells are responsible for a stable metabolic dialogue in the inner retina and their crucial role in supporting retinal neurons is indisputable. Müller cell functions require considerable energy production and previous literature has primarily emphasized glycolysis as the main energy provider. However, recent studies highlight the need of mitochondrial ATP production to upheld Müller cell functions. Therefore, the present review aims to provide an overview of the current evidence on the impact of mitochondrial functions in Müller cells.

Disturbed mitochondrial function restricts glutamate uptake in the human Müller glia cell line, MIO-M1.

Using the human Müller cell line, MIO-M1, the aim was to study the impact of mitochondrial inhibition in Müller glia through antimycin A treatment. MIO-M1 cell survival, levels of released lactate, mitochondrial function, and glutamate uptake were studied in response to mitochondrial inhibition and glucose restriction. Lactate release decreased in response to glucose restriction. Combined glucose restriction and blocked mitochondrial activity decreased survival and caused collapse of the respiratory chain measured by oxygen consumption rate and extracellular acidification rate. Mitochondrial inhibition caused impaired glutamate uptake and decreased mRNA expression of the glutamate transporter, EAAT1. Over all, we show important roles of mitochondrial activity in MIO-M1 cell function and survival.

Oxidative Stress-Induced Dysfunction of Müller Cells During Starvation.

PURPOSE: Müller cells support retinal neurons with essential functions. Here, we aim to examine the impact of starvation and oxidative stress on glutamate uptake and mitochondrial function in Müller cells. METHODS: Cultured human retinal Müller cells (MIO-M1) were exposed to H2O2 and additional starvation for 24 hours. Effects of starvation and H2O2 on glutamate uptake and mitochondrial function were assessed by kinetic glutamate uptake assays and Seahorse assays, respectively. Cell survival was evaluated by cell viability assays. mRNA and protein expressions were assessed by quantitative PCR and Western blot. RESULTS: Starvation of Müller cells increased the glutamate uptake capacity as well as the expression of the most abundant glutamate transporter, EAAT1. Mitochondrial and glycolytic activity were diminished in starved Müller cells despite unaffected cell viability. Simultaneous starvation and exposure to oxidative stress resulted in a reduced glutamate uptake and a collapsed mitochondrial function. In Müller cells with intact energy supply, the glutamate uptake and mitochondrial function were unaffected after exposure to oxidative stress. CONCLUSIONS: Here, we identify an increased susceptibility toward oxidative stress in starved Müller cells in spite of unaffected viability and an apparent decreased ability to transport glutamate. Solely exposure to oxidative stress did not affect Müller cell functions. Thus, our study suggests an increased susceptibility of Müller cells in case of more than one cellular stressor. Extrapolating these findings, age-related neurodegenerative retinal diseases may be the result of impaired Müller cell function.

Limited energy supply in Müller cells alters glutamate uptake.

The viability of retinal ganglion cells (RGC) is essential for the maintenance of visual function. RGC homeostasis is maintained by the surrounding retinal glial cells, the Müller cells, which buffer the extracellular concentration of neurotransmitters and provide the RGCs with energy. This study evaluates if glucose-deprivation of Müller cells interferes with their ability to remove glutamate from the extracellular space. The human Müller glial cell line, Moorfields/Institute of Ophthalmology-Müller 1, was used to study changes in glutamate uptake. Excitatory amino acid transporter (EAAT) proteins were up-regulated in glucose-deprived Müller cells and glutamate uptake was significantly increased in the absence of glucose. The present findings revealed an up-regulation of EAAT1 and EAAT2 in glucose-deprived Müller cells as well as an increased ability to take up glutamate. Hence, glucose deprivation may result in an increased ability to protect RGCs from glutamate-induced excitotoxicity, whereas malfunction of glutamate uptake in Müller cells may contribute to retinal neurodegeneration.