Necrosis

Non programmed cell death. Differs from programmed cell death (apoptosis). Apoptosis enable individual cells to commit suicide when they are dysfunctional. During apoptosis, the dying cells.

Necrosis is caused by accidental damage of a cell, does not follow a specific cellular program. Membrane integrity is lost and the cell body swells then bursts, this can cause inflammation, which can be damaging to the body. Disruption of essential functions leads to necrosis, the 2 most problematic areas is ATP generation and protein synthesis.

The 3 primary causes of necrosis are:

ATP-depletion- ATP is both a source of energy and a precursor in many synthetic reactions. Four key mechanisms by which ATP can be depleted: inhibition of the ETC, inhibition of oxygen deliver, inhibition of ADP phosphorylation, damage to mitochondria. One of the main consequences of ATP depletion is the loss of control of ion gradients. This is a pos feedback loop, as more Na+ and Ca2+ enters the cell, more voltage gated channels open and more ions enter. This causes loss of volume, swelling and water influx, eventually cell swells and dies.

Excitotoxicity- Ca2+ is involved. Intracellular calcium levels are heavily regulated. Difference in conc between intra and extra environment upto 10,000 fold. Cell membrane is impermeable to ca2+, specific transport mechanisms remove Ca2+. Can also be stored in the ER or SR. Calcium Is toxic to the cell is present at high levels in the cytoplasm. For this reason there are many mechanisms for its removal: Extracellular C2+ ATPase, ER ca2+ ATPase, Extracellular Na/Ca exchanger, mitochondrial ca2+ uniporter. Consequences of increased intracellular Ca2+ is excitotoxicity. Depletion of ATP, activation of Ca2+ dependent hydrolytic enzymes, production of RO and N species, microfilament dysfunction.

Oxidative stress- Within the cell there is a carefully maintained balance between oxidants and antioxidants. Oxidants are things that accept electrons Oxidative stress occurs when the balance is disrupted, meaning more oxidants are present. Oxidative stress is caused by ROS and RNS. Increase intracellular calcium activates dehydrogenases in the TCA cycles, increasing electron output Activation of Ca2+ dependent proteases, Activation of constitutively expressed nitric oxide synthases in neuronal and endothelial cells.  Production of ROS and RNS also causes ATP depletion. ROS can mutate DNA. ROS and RNS also cause lipid peroxidation, cell swelling and cell lysis. Enzymes can quench activity of oxidative stress. Superoxide dismutase (SOD) uses metals. Catalase degrades peroxide to oxygen and water.

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