Iron Transport and Storage

00:02 Now iron is very important for many things.

00:05 And with respect to heme, of course it's central, no pun intended, with respect to making the heme function.

00:13 It is therefore important that we understand the movement and storage of iron in the human body.

00:20 Iron is a limiting micro-nutrient.

00:22 That's true whether it's in our body.

00:24 That's true whether you're a bacterium floating around in the ocean.

00:27 That's true for almost any organism.

00:29 It's needed for the synthesis of heme for a variety of enzymes for electron transport and also for oxygen transport.

00:38 Iron is problematic because it can gain and lose electrons depending upon its oxidative state.

00:45 That means it can participate in the formation of reactive oxygen species or reactive nitrogen species, and those as we've seen in other lectures are very, very detrimental to the body.

00:57 Iron is therefore very reactive and toxic to cells if it's not managed properly.

01:03 Iron, as I said, can create radicals and these occur via the Fenton reaction as shown in the screen here.

01:09 This involves the reaction to produce the hydroxyl radical on the right side of the equation.

01:15 The uptake of iron into the body is very tightly controlled.

01:17 And the reason for this is because there is no good regulated means of excretion of iron once it has gotten there.

01:24 A disease called "hemochromatosis" occurs with the unregulated uptake of iron.

01:29 The person's body is taking up too much iron.

01:32 And interestingly this disease has a genetic cause and that genetic cause is still present among the population today.

01:40 It's very common among the Irish and the Norwegians.

01:44 And the iron that comes in can cause severe problems for the people who have it.

01:49 About 0.6% of the population has this primary cause of the disease.

01:55 They have inherited it.

01:56 Now, how is it that this disease has been propagated and has continued to exist because it has some very detrimental things associated with it.

02:06 The reason is because this disease, went it arose, gave resistance to the plague that plagued Europe in the 13th century.

02:15 People who had this mutation that today is detrimental, was beneficial because they lived through the plague.

02:23 We are the progeny of those people who lived with this disease.

02:27 There are secondary sources of hematochromatosis and these are acquired not genetic in nature.

02:34 Whether it's primary or it's secondary, the hematochromatosis is a fairly significant disease.

02:40 It can give cirrhosis to the liver.

02:42 It can participate in the formation of diabetes through poisoning the pancreas.

02:49 It can create cardiomyopathies and it can also create arthritis.

02:54 When we hear about the process of bloodletting, which was a way that people used to treat disease back about 300, 400 years ago, that treatment of the disease by bloodletting, which involved the removing of blood from a person's body, helped those who had hemochromatosis and killed those who didn't.

03:14 The iron storage in cells is very carefully regulated for the same reason that iron intake in the body is very carefully regulated.

03:22 That reactive iron has to be managed.

03:25 So the rest of what I'm going to talk about here is how the iron is managed getting into and within the cells.

03:34 So there are iron binding proteins that performs these functions and they keep the iron from doing cellular harm.

03:41 Now, the intracellular form of iron storage is a protein known as ferritin.

03:46 There are extracellular storage form and transport forms that handle iron and they're known as lactoferrin which are found in the secretory fluids and transferrin which is found in the blood plasma.

04:00 Enzymes like catalase and aconitase help monitor the relative levels of iron and give signals to cells whether they have too much or too little.

04:10 Electron transport complexes I, II, III, IV and cytochrome C all need and contain iron.

04:18 And other sources we've seen in other lectures of course include hemoglobin and myoglobin.

04:23 So iron is needed but not too much.

04:26 Now, transferrin is a glycoprotein.

04:28 Remember, it's part of transferring iron to the cells that need it.

04:33 It's found in the blood plasma and it contains iron.

04:37 There is a very small pool of transferrin in the body, but it has a very rapid turnover of iron.

04:42 It's screwing about carrying iron across the body very rapidly.

04:47 It has a very high affinity for iron.

04:49 Each transferrin atom contains -- I'm sorry, each transferrin protein contains two iron atoms.

04:56 It delivers iron from the place of the intestines, the duodenal absorption centers and also for the macrophages and then delivers that iron to the tissues that need it.

05:06 Transferrin carries iron to the cell by binding to a membrane bound transferring receptor.

05:13 So transferrin grabs the iron from the one location of the body, transfers it to target cells and gets the iron into the target cells by binding to a specific transferrin receptor.

05:26 Transferrin is moved into the cell with its iron after binding to the receptor by a receptor-mediated endocytosis of both the receptor and of the transferrin.

05:37 This receptor-mediated endocytosis brings them both into the cytoplasm of the cell.

05:42 Within the cytoplasm of the cell, proton pumps actually bring in protons and lower the pH, so the transferrin lets go of its iron.

05:50 The iron is released into the cell and that free iron is taken up by a protein in the cell known as ferritin.

05:58 Well, to continue this process, we have to get the transferrin back out of the cell.

06:02 So the transferrin and its receptor are both recycled.

06:05 The transferrin receptor is moved to the cell surface where it waits another transferrin coming.

06:11 And the transferrin is dumped out of the cell back into the plasma to go bring back more iron.

06:17 Now, ferritin is a very interesting protein.

06:20 You can see it shown in the structure on the right part of the slide.

06:23 It's an intercellular protein complex of 24 subunits.

06:27 This is a pretty big complex and it's found in almost all cells.

06:31 A small amount of the ferritin is actually found in the serum, but that's not significant.

06:37 The low serum ferritin is linked to anemia though.

06:40 So, if it gets too low, we understand there's a problem.

06:44 Each ferritin complex that you see here stores about 4500 iron atoms.

06:50 Remember that each transferrin was bringing in only two.

06:54 So to get 4500 into one of these takes a lot of transferrin moving iron into the cell.

07:01 Hemosiderin is a large complex of dysfunctional ferritins and other materials sequestering iron.

07:08 And these are ways of dealing with problems that occur with ferrtin.

07:14 Iron is stored in the ferric or plus three state within ferritin.

07:18 That means it has to be converted from the plus two state which is the way that it arrived.

07:23 This reaction is catalyzed by a ferroxidase within ferritin itself.

07:28 So the oxidation of iron is occurring in ferritin.

07:31 If you think about this, this makes good sense because iron plus two, when it gives up an electron can create a radical.

07:39 And rather than allow that to happen in the confines of a cell where anything could happen to that radical.

07:44 This enzyme is located inside of ferritin where the radical and the processes that make it are contained.

07:51 Now, intracellular ferritin concentrations increase on infection, meaning more iron brought in.

07:56 And serum concentrations decrease with some infections, meaning the result of that iron being brought in to the individual cells.

08:05 Now, transferrin receptors are transmembrane glycoproteins.

08:09 They're the third part of this movement of iron that I need to talk about.

08:13 They are the proteins that bring in the transferrin from the serum.

08:19 Low cellular iron levels can increase the expression of the transferrin receptor.

08:24 That makes sense.

08:25 If the cell doesn't have enough iron, it needs to have more receptor to bring more transferrin in.

08:32 If it has too much, then the synthesis of the transferrin receptor needs to decrease.

08:38 Now, one of the ways of monitoring and taking care of the amount of iron that comes into a cell is via secreted glyceraldehyde 3-phosphate dehydrogenase, the glycolysis enzyme, because this enhances the transferrin uptake by cells.

08:53 The signal being, of course, we need more iron.