The burst of mitochondrial diseases: neurons and calcium.

In the last decade there has been a tremendous burst of publications on mitochondrial diseases. In the past 5 years alone more than 5,000 articles have appeared on this subject [Figure 1]. We would like to restrict this review to two aspects: mitochondrial diseases of the nervous system, and their connection to intracellular calcium. Most of the diseases are due to neuronal cell death and are related to mitochondria and calcium dysregulation [1]. In some cases faulty intracellular regulation of calcium is the primary cause of cell death, but in others is secondary to genetic defects. We will focus on five diseases; two of them are fairly common: Parkinson's disease and Alzheimer's disease, while the other three are quite rare: Huntington's disease, Leber's hereditary optic neuropathy, and amyotrophic lateral sclerosis. Ca ions are of great importance in the normal function of the nervous system. They are involved in a large number of important cellular processes such as transmitter release [2,3], action potential conduction [4], and gene expression [3]. Large increases in the free intracellular calcium concentration ([Ca2+]in) cause cell death (apoptosis) [1]. There is a large number of cellular organelles that control [Ca2+]in [for review see ref. 5]. These include, among others, the surface membrane [6,7], endoplasmic reticulum [8], nucleus [8], and secretory vesicles [9]. Of special importance in the context of this review is the regulation of intracellular calcium by the mitochondria. This was suggested more than 30 years ago [10], including their involvement in the function of the nervous system, by one of us [2,11]. However, this notion was not immediately accepted and only in the past decade has the basic importance of the mitochondrion in regulation of the intracellular calcium and neuronal function been shown [12]. Mitochondria are also involved in the generation of ATP [13], in intermediary metabolism, in building and recycling molecular building blocks [6], in protecting the cells from oxidative stress