Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93Amice.

Abstract

Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Caoverload as critical mechanisms in disease pathophysiology. We used MNs from G93Aand nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AMNs compared to nontransgenic MNs but downregulated in MNs from adult G93Amice. Furthermore, cultured embryonic G93Awere rescued from kainate-induced excitotoxicity by the Ca/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AMNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Caactivity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.