Mitochondrial calcium uniporter deficiency in dentate granule cells remodels neuronal metabolism and impairs reversal learning

The regulatory roles of the mitochondrial Ca2+ uniporter (MCU) on neuronal metabolism and function remain a puzzle. We found that MCU deficiency increases the net oxidative capacity of dentate granule cells in the hippocampus. The metabolic remodeling of these neurons also involves decreased levels of enzymes from lower glycolysis and diminished cellular antioxidant defenses. Ultimately, chronic MCU deficiency appears to lead to impaired cognitive flexibility in mice. Overall, our results reveal novel aspects of the regulation of neuronal physiology by MCU and provide evidence for its implication in learning and memory (Graphic created with BioRender.com). AbstractThe mitochondrial calcium uniporter (MCU) is the main route of calcium (Ca2+) entry into neuronal mitochondria. This channel has been linked to mitochondrial Ca2+ overload and cell death under neurotoxic conditions, but its physiologic roles for normal brain function remain poorly understood. Despite high expression of MCU in excitatory hippocampal neurons, it is unknown whether this channel is required for learning and memory. Here, we genetically down-regulated theMcu gene in dentate granule cells (DGCs) of the hippocampus and found that this manipulation increases the overall respiratory activity of mitochondrial complexes I and II, augmenting the generation of reactive oxygen species in the context of impaired electron transport chain. The metabolic remodeling of MCU-deficient neurons also involved changes in th...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research