The Highs and Lows of Memantine—An Autophagy and Mitophagy Inducing Agent That Protects Mitochondria

Memantine is an FDA-approved, non-competitive NMDA-receptor antagonist that has been shown to have mitochondrial protective effects, improve cell viability and enhance clearance of Aβ(42) peptide. Currently, there are uncertainties regarding the precise molecular targets as well as the most favourable treatment concentrations of memantine. Here, we made use of an imaging-based approach to investigate the concentration-dependent effects of memantine on mitochondrial fission and fusion dynamics, autophagy and mitochondrial quality control using a neuronal model of CCCP-induced mitochondrial injury so as to better unpack how memantine aids in promoting neuronal health. GT1-7 murine hypothalamic cells were cultured under standard conditions, treated with a relatively high and low concentration (100 µM and 50 µM) of memantine for 48 h. Images were acquired using a Zeiss 780 PS1 platform. Utilising the mitochondrial event localiser (MEL), we demonstrated clear concentration-dependent effects of memantine causing a protective response to mitochondrial injury. Both concentrations maintained the mitochondrial network volume whilst the low concentration caused an increase in mitochondrial number as well as increased fission and fusion events following CCCP-induced injury. Additionally, we made use of a customised Python-based image processing and analysis pipeline to quantitatively assess memantine-dependent changes in the autophagosomal and lysosomal compartments. Our results revealed that memantine elicits a differential, concentration-dependent effect on autophagy pathway intermediates. Intriguingly, low but not high concentrations of memantine lead to the induction of mitophagy. Taken together, our findings have shown that memantine is able to protect the mitochondrial network by preserving its volume upon mitochondrial injury with high concentrations of memantine inducing macroautophagy, whereas low concentrations lead to the induction of mitophagy.