Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice

Neurobiol Aging. 2019 Mar:75:209-222. doi: 10.1016/j.neurobiolaging.2018.11.019. Epub 2018 Nov 23.

Abstract

Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93AhSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AhSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93AhSOD1 mice. Furthermore, cultured embryonic G93AhSOD1 were rescued from kainate-induced excitotoxicity by the Ca2+/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AhSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca2+ activity 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.

Keywords: ALS; Calcium; KN-62; Kaempferol; MCU; SOD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Astrocytes / metabolism*
  • Calcium Channels
  • Disease Models, Animal
  • Glutamic Acid / metabolism
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Motor Neurons / metabolism*
  • Superoxide Dismutase / metabolism

Substances

  • Calcium Channels
  • mitochondrial calcium uniporter
  • Glutamic Acid
  • Superoxide Dismutase