Mitochondria, calcium-dependent neuronal death and neurodegenerative disease

Michael R Duchen

doi:10.1007/s00424-012-1112-0

Abstract

Understanding the mechanisms of neuronal dysfunction and death represents a major frontier in contemporary medicine, involving the acute cell death in stroke, and the attrition of the major neurodegenerative diseases, including Parkinson's, Alzheimer's, Huntington's and Motoneuron diseases. A growing body of evidence implicates mitochondrial dysfunction as a key step in the pathogenesis of all these diseases, with the promise that mitochondrial processes represent valuable potential therapeutic targets. Each disease is characterised by the loss of a specific vulnerable population of cells—dopaminergic neurons in Parkinson's disease, spinal motoneurons in Motoneuron disease, for example. We discuss the possible roles of cell type-specific calcium signalling mechanisms in defining the pathological phenotype of each of these major diseases and review central mechanisms of calcium-dependent mitochondrial-mediated cell death.

Highlights

The fine spatial and temporal organisation of intracellular calcium signals is fundamental to function in the CNS, perhaps more than in any other tissue
Chronic defects in aspects of mitochondrial biology have been linked with most of the major neurodegenerative diseases. These include a range of genetic diseases— Huntington's disease and Friedreich's ataxia, some of the cerebellar ataxias, and heritable, familial forms of Parkinsons' disease, Motoneuron disease ( known as amyotrophic lateral sclerosis (ALS)) and Alzheimer's disease
Loss of NADH and mitochondrial depolarization were prevented by Ru360, (Fig. 2b) arguing that mitochondrial Ca2+ uptake is an essential step on the pathway to PARP activation and to cell death [2]

Summary

Introduction

The fine spatial and temporal organisation of intracellular calcium signals is fundamental to function in the CNS, perhaps more than in any other tissue. The source specificity of glutamate-induced neuronal damage has been refined more recently to suggest that excessive activation of extrasynaptic receptors may induce toxic Ca2+ loads and mitochondrial Ca2+-dependent injury, whilst activation of synaptic receptors tends to cause smaller Ca2+ elevations that play a prosurvival role [61], suggesting that the balance between these two pathways may be critical in some disease models, in which glutamate ‘overspill’ from synaptic release, glutamate release from glial cells by reversal of the glutamate transporter, or impaired glutamate clearance from synaptic clefts might lead to overactivation of extrasynaptic receptors, causing cell injury.

Results

Conclusion