Re: What are the causes of necrosis?

Necrosis, is simply a cell dying, all of its coordinated activities going wrong and things shut down. Necrosis is best understood if you compare it to another way cells shut down called apoptosis: Cells these days, are seen by biologists as dying in two major ways: necrosis or apoptosis. Cells can undergo programmed cell-death or "apoptosis", where the cell triggers special metabolic, signal transduction and gene regulation pathways or "programs" that systematically shut down and disassemble the cells components. Apoptosis is not death the way necrosis is. If a cell gets too much heat, or is poisoned by a toxic substance or exposed to chemicals that damage its proteins and membranes or radiation that breaks its DNA molecules, that cell can just stop functioning.

In necrosis, the cell dies as damage leads to loss of control of ion gradients between the outside and the inside of the cell, and also loss of the proton gradient across the membranes of mitochondria (where alot of our ATP is made for energy). A toxic insult that damages a cell and causes it to loose energy (ATP levels fall down), and to loose control of ion gradients (Na+ and Ca++, which are low in the cell, rush into the cell and rise in levels), are causing necrosis. In Apoptosis, cells chop up their DNA, disassemble their organelles (mitochondria, ER, golgi) and break themselves up into little peices of cells. But in programmed cell death, apoptosis, this is meant to happen and is under control of the cell...the cell breaks down its proteins and DNA and membranes to eventually be recycled. During apoptosis, in contrast to necrosis, the cell and eventually the fragments of the cell all maintain their ion-gradients and energy levels. In other words, ATP levels are high, and Na+ and Ca++ levels remain low in the cell fragments because the membrane ion pumps are still working (they need ATP for energy). So cells can recycle(die) on purpose by using the apoptosis systems, eventually they fragment into small fragments of cell remains that are phagocytosed (eaten up) by neighboring cells. When tadpoles lose their tails, the tail seems to shrink day after day, that is because the cells are being recycled. Leaves fall from trees in the autumn, because apoptosis shuts the leaves down where they connect to the branch. These are programed cell deaths, and they are good for the organism to develope as it should. In the womb, our hands start off as paddles, and the skin separates into fingers, as the paddles are remodeled by apoptosis. Some cells go away, and new ones are made somewhere else.

In necrosis, damage from toxic compounds or oxidation damage often harms the mitochondria or membrane ion pumps and causes the energy levels in the cells to drop. ATP levels fall and this also means that cell glutathione levels drop (important antioxidant in cells), and a vicious cycle of damage starts. Lower glutathione levels make the mitochondria even sicker and less able to make ATP and on and on. When mitochondria are damaged in the cell electron transport does not work well, and more oxygen reacts at the wrong place in the chain, leading to formation of superoxide. (a very reactive free radical) The cell and mitochondria have superoxide dismutase, to quickly convert this into H2O2 (hydrogen peroxide) which is less reactive (toxic). However, lots of H2O2 can build up, and react with metal ions to create hyroxy radicals .OH that react and damage proteins and membranes. Catalase gets rid of H2O2 to make water, but it can become overwhelmed. If the cell is in a state of lower energy too, it also cannot make more of these proteins to protect itself either. Therefore when cells are undergoing a necrotic type of cell death from some toxic insult, they often show increased oxidation damage etc in the tissue where this is happening.

Ken Mitton, Eye Research Netork

Research Fellow, Kellogg Eye Center, University of Michigan.