Differential expression of the mitochondrial calcium uniporter in hippocampal neurons attunes mitochondrial calcium handling and bioenergetics

Abstract

Mitochondria are precisely positioned throughout neuronal axons and dendrites to meet unique energy demands across functionally distinct compartments. Dendritic mitochondria can be molecularly, structurally, and functionally distinct depending on the neuron type, supporting the diversity of synaptic functions and connectivity patterns across brain areas. A better understanding of how heterogeneous properties, such as mitochondrial morphology, dynamics, and function, converge to support cell- and compartment-specific metabolic demands, is crucial for elucidating how mitochondrial heterogeneity affects intact circuits. We found that the mitochondrial calcium uniporter (MCU) is endogenously enriched in the distal apical dendrites of CA2, precisely where CA2 neurons receive entorhinal cortical inputs carrying social information. Mitochondrial calcium uptake is tightly coupled with neuronal activity and stimulates the TCA cycle by activating calcium-dependent enzymes that are important for oxidative phosphorylation. Given the substantial energetic demand on neuronal mitochondria, we hypothesized that the enrichment of MCU in distal dendrites indicated mitochondria with a greater capacity to meet energy demand. To determine whether mitochondria enriched with MCU exhibited enhanced bioenergetic properties, we assessed whether MCU overexpression increased mitochondrial calcium uptake and respiration. We report enhanced mitochondrial calcium uptake rates in hippocampal mitochondria overexpressing MCU without increased sensitivity to calcium overload. Moreover, we reveal that the efficiency of mitochondrial respiration scales proportionally with bioenergetic demand. These findings suggest that differential expression of MCU can modulate mitochondrial calcium uptake and respiration under increasing demand and that mitochondria in CA2 distal dendrites have faster rates of calcium uptake without increased sensitivity to overload and synthesize ATP most efficiently under high energetic demand. These findings help expand our understanding of how mitochondrial adaptations support differences in neuronal bioenergetics, which may be critical for understanding cell-type-specific vulnerability to mitochondrial dysfunction in the brain.