In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk and loss of store-operated Ca2+ entry (SOCE) in rat hippocampal neurons

Abstract

Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to subcellular Ca²⁺ homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated Ca²⁺ entry (SOCE). In addition, Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria sustains energy production but mitochondrial Ca²⁺ overload promotes apoptosis. We have addressed whether SOCE and ER-mitochondria Ca²⁺ transfer are influenced by culture time in long-term cultures of rat hippocampal neurons, a model of neuronal aging. We found that short-term cultured neurons show large SOCE, low Ca²⁺ store content and no functional coupling between ER and mitochondria. In contrast, in long-term cultures reflecting aging neurons, SOCE is essentially lost, Stim1 and Orai1 are downregulated, Ca²⁺ stores become overloaded, Ca²⁺ release is enhanced, expression of the mitochondrial Ca²⁺ uniporter (MCU) increases and most Ca²⁺ released from the ER is transferred to mitochondria. These results suggest that neuronal aging is associated to increased ER-mitochondrial cross talking and loss of SOCE. This subcellular Ca²⁺ remodeling might contribute to cognitive decline and susceptibility to neuron cell death in the elderly.

Keywords: Aging; ER-mitochondria cross talking; Hippocampal neurons; Orai1; Stim1; Store-operated calcium entry.