Mitochondria of neuron

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

Like other cells, a neuron has a nucleus with genetic DNA, although nerve cells cannot divide (replicate) after maturity, and a prominent nucleolus for ribosome synthesis. There are also mitochondria for energy supply as well as a smooth and a rough endoplasmic reticulum for lipid and protein synthesis, and a Golgi apparatus. These are all in a fluid cytosol (cytoplasm), containing enzymes for cell metabolism and NT synthesis and which is surrounded by a phospholipid plasma membrane, impermeable to ions and water-soluble substances. In order to cross the membrane, substances either have to be very lipid soluble or transported by special carrier proteins. It is also the site for NT receptors and the various ion channels important in the control of neuronal excitability. 

Perkins, G.A., Reuken, C., Martone, M.E., Young, S.J. and Frey, T. (1997). Electron tomography of neuronal mitochondria three dimensional structure and organisation of crystae and membrane contacts. J. Struct. Biol., 119, 260-272... 

Mitochondria are the centers for oxidative phosphorylation and the respiratory centers of all cells. While usually aerobic, some mitochondria (e.g. in some bacteria), are known that function anaerobically. These organelles occur ubiquitously in the neuron and its processes (Figs 1-4, 1-6). Their overall shape may change from one type of neuron to another but their basic morphology is identical to that in other cell types. Mitochondria consist morphologically of double-membraned sacs surrounded by protuberances, or cristae, extending from the inner membrane into the matrix space [7]. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

The effect of released norepinephrine wanes quickly, because approx. 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-0-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta-nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-dihydroxymandelic acid). 

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

What are the possible adverse consequences of accumulation of the A(3 protein It may cause inflammation by activation of microglia,1157 which may cause damage by release of NO.1206 A(3 may induce death of neurons by apoptosis.1201 1207-1209 A defect in protesomal degradation may be a factor.1208 Both Ap and the prion protein may promote oxidative damage. The brain derives most of its energy from oxidative metabolism, a major source of damaging radicals. Mitochondria are found in dendrites as well as cell bodies.1210 Methionine residues in glycine-rich parts of the AP and prion proteins are suspected as centers of free radical formation.1202 1211... 

Acetylcholine synthesis. Acetylcholine (ACh) is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA) (Fig. 12—8). Choline is derived from dietary and intraneuronal sources, and AcCoA is synthesized from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase to produce the neurotransmitter ACh. 

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