Calcium homeostasis and excitotoxicity


KEYWORDS

  • Neurons

  • Oligodendrocytes

  • Mitochondria and ER


TECHNIQUES

  • Live imaging

  • Calcium dynamics

  • Proteomics

The role of mitochondria and ER during neuronal and glial Ca2+ homeostasis disruption

Calcium homeostasis disruption is a hallmark of most CNS diseases and therefore a research field of high therapeutic interest. In particular, overactivation of glutamate ionotropic receptors produces a cytosolic calcium overload that causes excitotoxic death of neurons and oligodendrocytes and contributes to acute and neurodegenerative disorders such as stroke and Alzheimer´s disease. As a part of the Laboratoy of Neurobiology, we are focused on the role of both mitochondria and endoplasmic reticulum (ER), which are critically involved in these pathological conditions. These organelles are the most important cytoplasmic Ca2+ stores inside the cell and therefore directly impact Ca2+ homeostasis. In addition, Ca2+ homeostasis disruption itself induces ER stress and mitochondrial dysfunction, leading to neuronal and glial cell loss. Using live-cell imaging and molecular biology techniques we study how (i) mitochondrial Ca2+ dynamics and function and (ii) ER stress and related UPR (unfolded protein response) contribute to excitotoxicity, and whether they can be modulated to provide neuroprotection.

Deconvolved confocal micrograph of astrocytic mitochondria (Cytochrome C labelling)

Publications related to this topic

  • Ruiz A, Quintela-López T, Sánchez-Gómez MV, Gaminde-Blasco A, Alberdi E, Matute C. Mitochondrial division inhibitor 1 disrupts oligodendrocyte Ca2+ homeostasis and mitochondrial function. Glia 2020; 68: 1743–1756. [LINK]

  • Ruiz A, Alberdi E, Matute C. Mitochondrial Division Inhibitor 1 (mdivi-1) Protects Neurons against Excitotoxicity through the Modulation of Mitochondrial Function and Intracellular Ca2+ Signaling. Front Mol Neurosci 2018; 11: 3. [LINK]

  • Ruiz A, Alberdi E, Matute C. CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death Dis 2014; 5: e1156. [LINK]

  • Ruiz A, Matute C, Alberdi E. Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes. Cell Death Dis 2010; 1: e54. [LINK]

  • Ruiz A, Matute C, Alberdi E. Endoplasmic reticulum Ca(2+) release through ryanodine and IP(3) receptors contributes to neuronal excitotoxicity. Cell Calcium 2009; 46: 273–281. [LINK]