Ischemic neuronal cell death and organellae damage

Abstract

The brain is an organ that consumes much energy. This is partially due to the character of neurons; they possess excitable plasma membrane and a large amount of ATP is indispensable for maintaining ion gradient. Once neurons experience energy failure, calcium accumulates in the intracellular space as a result of disturbed ion homeostasis. This, in turn, activates many cellular processes, which culminate in cell death. In this cellular catastrophic cascade, many organelles play important roles. In addition to the plasma membrane, cytosol is the 'organelle' that first becomes exposed to the increased level of calcium. Many proteases, kinases and lipases are localized here, and are activated directly or indirectly by the ischemic insult. Some enzymes are pro-apoptotic ones, while others are anti-apoptotic. It was reported that neurons that would die later showed activated pro-apoptotic enzymes, but ones that would survive possessed activated anti-apoptotic molecules. Mitochondria is the organelle that plays the central role for intrinsic pathways of apoptosis. The release of cytochrome c from this organelle is the key step in apoptotic cascade in the ischemic neurons. However, the exact molecular mechanism of cytochrome c release remains uncertain. In addition, expression of genes essential for mitochondrial function changes in neurons after ischemia, which further indicates the crucial role of this organelle in cell death. Endoplasmic reticulum (ER) not only mediates proteins processing, but also regulates intracellular calcium homeostasis and cell death signal activation. Recent reports indicate that dysfunction of this organelle occurs at an early stage after ischemia and might be the initial step of apoptotic cascades in neurons. Golgi apparatus and lysosomes are organelles that are involved in apoptotic cell death in some situations. There have been no reports that demonstrated active role of these organelles in ischemic neuronal cell death. Further investigation would be desired about this issue. Nucleus is the organelle that contains genomic DNA. Many studies demonstrated DNA breakage in the neurons that would die later, but whether this is the cause or merely the result of the insult remains uncertain. If the more precise role of each organelle in neuronal cell death are disclosed, we should be able to think about new means of therapy for ischemic stroke.