Electron Transport Chain and Oxidative Phosphorylation

 
Similarly to how ATP is a “universal energy source”, NADH is a sort of “universal electron carrier” Nicotinamide Adenine Dinucleotide (NAD⁺) and it’s cousin NADP⁺ (just add phosphate) can accept electrons (get reduced) to become NADH and NADPH. It might look like the big difference between NAD⁺ and NADH is a hydrogen (H), but the real difference is “unspoken” – it’s the electrons! When NAD⁺ picks up that H, it picks it up as something called a HYDRIDE, which is an H with 2 electrons instead of its usual 1. Hydrogen atoms only have 1 proton & 1 electron & they often leave that electron behind when they go, so all they’re left with is a H⁺, so we often call H⁺ a proton but when H’s have 2 electrons we call it a hydride 
 
NADH makes a great carrier because it wants electrons, but not desperately, so it’s willing to give and take. Some molecules want electrons more than others – and if something which doesn’t want or only kinda wants an electron (has a lower reduction potential) gives an electron to something that’s happier with it than it is (has a higher reduction potential) you get a net gain in happiness. And when you make molecules happier, they release energy (I like to think of it as them not having to fidget as much to get comfy so they can relax). So you can pass electrons from things with low reduction potential (like NADH) to things with high reduction potential (like O₂), and release little bits of energy as you do, which you can put to use - including to make ATP! 
 
Electron-to-ATP conversion occurs in a process called OXIDATIVE PHOSPHORYLATION, which takes place in a secret club house in your cells called the mitochondrion (your cells actually have lots of mitochondria because of their important roles as cellular powerhouses). Unlike some other organelles (membrane-bound compartments inside your cells) like the endoplasmic reticulum (involved in protein processing), mitochondria have double membranes because they come from an ancient ancient ancient cell swallowing a bacteria and then adapting that bacteria to suit its needs, specializing in energy production through oxidative phosphorylation (oxphos). 
 
OXIDATIVE PHOSPHORYLATION consists of an ELECTRON TRANSPORT CHAIN (ETC) and CHEMIOSMOSIS. The electron transport chain (ETC) occurs at the inner membrane (between the inner matrix & intermembrane space). Starting with NADH (or FADH₂), the original electron carrier transfers its electrons to another molecule that wants them more which passes them to another molecule that wants them even more . . . until they reach oxygen which wants them the most. Each of those pass-offs releases a little energy and that energy is used to pump protons out of the inner room of the mitochondria (mitochondrial matrix) into the outer room of the mitochondria (intermembrane space), creating a proton gradient where there are more protons in the intermembrane space than there are in the matrix.  
 
Only one way back in is provided – through the ATP-making factory, ATP synthase, or as I like to call it, the ATP ATM. ATP synthase is seriously one of the most incredible machines ever made, able to harness the power of flowing protons similarly to how a hydrolytic dam harnesses the power of flowing water, in order to turn a molecular crank and turn ADP + Pi into ATP. It’s way more efficient than any man-made machine - and way way tinier. For each NADH that goes in, ~10 protons get pumped out, and it takes 4 protons coming in for 1 ATP to be made. 10/4= 2.5, so you get ~2 and a half ATP per NADH.  
 
Pretty cool, eh? But you have to get the NADH in there (into the mitochondrial matrix) and spoiler alert - you can’t… At least not directly - but you can pass along the electrons its holding onto for you (which is the main thing you care about anyway). And then you can use those electrons to reduce more NAD⁺ inside the matrix so you end up with NADH in there without it ever crossing the inner mitochondrial matrix - sneaky, eh?  
 
finished in comments

[healthbabe]

This is one of my favorite lectures that discusses the grand details of this molecular machinery. NADH getting inside the matrix by the disassembling and reassembling the NADH molecule is fascinating process and I would do more reading on it to gain better understand. Thanks for your dedication.

[thebumblingbiochemist]

Why can’t you just take the NADH in from where it’s made in the early breakdown steps of food? For example, in the early sugar breakdown process glycolysis, which takes place in the cytoplasm, you get 2 molecules of NADH (from NAD⁺). But you can’t ship them in because it’s purposefully hard to get into the mitochondrial matrix. You can’t just let any ole molecule in, or else what’s the point of having a compartment anyway, right? So the inner mitochondrial membrane (IMM) is selective about what it lets in (it’s much more selective than the outer mitochondrial membrane so molecules that can pass through generic pores in the outer mitochondrial membrane (OMM) need specialized channels to get through the inner one). But the membrane only has control at the import/export stage - it can choose what to let through but can’t police what the molecules do once they’re in or out…  
 
So your cells find a way to to get those electrons in without taking in NADH itself. Malate dehydrogenase in the cytoplasm transfers electrons generated in the cytoplasm (such as by glycolysis) from NADH to oxaloacetate. Going back to OIL RIG, we can say NADH got oxidized (lost electrons to become NAD⁺) and oxaloacetate got reduced (gained electrons to become malate. This has the effect of transferring 2 electrons (and a H⁺) from NADH (which can’t cross the IMM) to something that can (malate).  
 
So malate enters, and it does so through an antiporter - a type of membrane passageway that does a swap where one thing comes in in exchange for another going out. In this case, malate comes in and alpha-ketoglutarate leaves. So you’ve gotten malate into the mitochondrial matrix - the next goal is to get the electrons it’s transporting to the ATP ATM. And that factory wants those electrons to come from NADH, so now you have to reverse what you had to do to get in. With the help of malate dehydrogenase (the mitochondrial type this time) you take those electrons back out of malate and plop them back onto NAD⁺ (a different copy of it of course, but there’s tons floating around) to give you NADH. This NAD⁺ reduction generates oxaloacetate again. 
 
The NADH is now in the proper location for getting to the ATP factory, so it goes off and gets converted into ATP via oxidative phosphorylation. And now you’re left with the “leftovers” as oxaloacetate. It’s not useful in the matrix, but it can be reused out in the cytosol to transfer electrons again. So you want to ship it out there. But you have a similar problem to the one you had in the beginning. Oxaloacetate can’t get through, so you have to convert it to something that can get through.  
 
This time, instead of converting it to malate, you convert it to aspartate, getting the amino group from the amino acid glutamate. When you take away glutamate’s amino group you get alpha-ketoglutarate (this is the molecule we can exchange malate for in the first swap). This time, in the aspartate swap, we use a different antiporter - the glutamate-aspartate antiporter. It brings in glutamate when you send out aspartate (which is good because we need to replenish the glutamate!) 
 
But the cytoplasm might not want aspartate - and if it does use aspartate for something else, you’re not regenerating the oxaloacetate. So, if you want to keep the cycle going strong you can use cytosolic aspartate aminotransferase to deaminate aspartate back to oxaloacetate, plopping the amino group off onto alpha-ketoglutarate to replenish your glutamate. So basically this malate-aspartate shuttle allows you to interconvert over and over again between the same molecules, with only electrons really getting used up (because they get taken out of the cycle to be used for oxphos). This malate-aspartate shuttle is the main way of moving electrons from NADH into the mitochondria in the liver, heart, & kidneys. Some tissues use other ways.  
 
Awesome right?