The citric acid cycle (also known as the Krebs Cycle) is actually a part of the much larger process called cellular respiration, the process where your body harvests energy from the food you eat. Yes, the citric acid cycle has the same citric acid found in oranges and other citrus fruits!
Where does the citric acid cycle fit into cellular respiration?
  1. Glycolysis, where the simple sugar glucose is broken down, occurs in the cytosol.
  2. Pyruvate, the product from glycolysis, is transformed into acetyl CoA in the mitochondria for the next step.
  3. The citric acid cycle, where acetyl CoA is modified in the mitochondria to produce energy precursors in preparation for the next step.
  4. Oxidative phosphorylation, the process where electron transport from the energy precursors from the citric acid cycle (step 3) leads to the phosphorylation of ADP, producing ATP. This also occurs in the mitochondria.
The citric acid cycle captures the energy stored in the chemical bonds of acetyl CoA (processed glucose) in a step-by-step process, trapping it in the form of high-energy intermediate molecules. The trapped energy from the citric acid cycle is then passed on to oxidative phosphorylation, where it is converted to a usable form of cellular energy, ATP (adenosine triphosphate). We can then use that energy to move, breathe, make our hearts beat, and think (among other things)!

How does it happen?

The molecules that enter and circulate through the citric acid cycle are made mostly of carbon atoms. To understand how the citric acid cycle works, we need to follow how the carbon atoms are rearranged through the cycle. Molecules, called electron shuttles, accept the energy released by stepwise rearrangements and the subtraction of carbons in the form of electrons. Electron shuttles are small organic molecules, such as NAD+^\text{+} and FADH, that transport high energy electrons to where they need to be by gaining electrons (through “reduction”) and losing electrons (through “oxidation”). The electrons transported by electron shuttles will later be used to generate ATP.
Aside from following how the carbons are rearranged in the cycle, you will also need to know where high energy molecules are formed.
Let’s describe some of our key players in the citric acid cycle:
Energy shuttles:
  1. NADH: An energy shuttle which delivers high energy electrons to the electron transport chain where they will eventually power the production of 2 to 3 ATP molecules. When this electron shuttle is not carrying high energy electrons, meaning it has been oxidized (lost its electrons), it is left with a positive charge and is called NAD+^\text{+}.
  2. FADH2_{2}: Another energy shuttle that carries high energy electrons to the electron transport chain, where they will ultimately drive production of 1 to 2 ATP molecules. The oxidized form of FADH2_{2} is FAD and happens just like in NADH.
High energy molecules:
  1. ATP: The basic energy currency of the cell. It’s a form of energy that cells can use right away.
  2. GTP: Similar to ATP, GTP can be easily converted to ATP in the cell.
Figure of the 4 step citric acid cycle
Step 1: Glycolysis
A 6-carbon glucose molecule is split into two 3-carbon molecules called pyruvates. Pyruvate is needed in order to create acetyl CoA.
Step 2: The transformation of pyruvate to acetyl CoA
This is a very short step in between glycolysis and the citric acid cycle. The 3-carbon pyruvate molecule made in glycolysis loses a carbon to produce a new, 2-carbon molecule called acetyl CoA. The carbon that is removed takes two oxygens from pyruvate with it, and exits the body as carbon dioxide (CO2_{2}). CO2_{2} is the waste product that you release when you exhale.
Step 3: The citric acid cycle
The citric acid cycle is called a cycle because the starting molecule, oxaloacetate (which has 4 carbons), is regenerated at the end of the cycle. Throughout the citric acid cycle, oxaloacetate is progressively transformed into several different molecules (as carbon atoms are added to and removed from it), but at the end of the cycle it always turns back into oxaloacetate to be used again. Energy can be captured from this cycle because several of the steps are energetically favourable. When a step is favoured, it means that the products of the reaction have lower energy than the reactants. The difference in energy between the products and the reactants is the energy that is released when the reaction takes place (see enzyme kinetics). The released energy is captured as the electron shuttles (NAD+^\text{+} and FAD) are reduced to NADH and FADH2_{2} .
To start the cycle, an enzyme fuses acetyl CoA and oxaloacetate together so that citric acid is formed (a 2-carbon molecule + a 4-carbon molecule = a 6-carbon molecule!). This is the first molecule that is made in the cycle and is where the cycle gets its name. Enzymes then proceed to speed up (or “catalyze”) a sequence of rearrangements that convert the newly made citric acid molecule into a series of slightly different molecules. These enzymes only change the rate that these rearrangements occur, not the outcome.
  1. An enzyme rearranges the atoms in the citric acid molecule (6 carbons) into a new 6-carbon arrangement.
  2. Energy is released when the 6-carbon arrangement is oxidized, causing one carbon to be removed. The removed carbon molecule combines with oxygen to produce CO2_{2}. Some of the energy, in the form of electrons, is captured in formation of high-energy compound, NADH. (Recall that some of the energy released from the cycle is used to reduce NAD+^\text{+} to create NADH.) The high energy electrons that are handed to NAD+^\text{+} for reduction come from the oxidation (loss of electrons) from the carbon molecule here.
  3. Next, the same type of reaction happens again. Another carbon is cleaved off the 5-carbon molecule, leaving a 4-carbon molecule and CO2_{2}, and some of the energy released is used to reduce NAD+^\text{+} to NADH.
  4. Rearrangement occurs, allowing the 4-carbon molecule to find a more comfortable configuration (one that doesn’t use require a lot of energy or structural strain, and one that allows each bond to be satisfied). During this rearrangement, non-carbon groups are added to and removed from the molecule. GTP and FADH2_{2} are made in these steps.
  5. The 4-carbon molecule rearranges its carbons one last time, producing oxaloacetate. Remember that oxaloacetate will be used again in the next cycle. Once again, some of the energy released is transferred to reduce NAD+^\text{+} to NADH.
The products of the citric acid cycle:
From one citric acid cycle, the following products are formed:
  • 1 GTP
  • 3 NADH
  • 1 FADH2_{2}
  • 2 CO2_{2}
  • Regenerated oxaloacetate
The CO2_{2} that is released during the transformation step (step 2) and the two CO2_{2} that are made during the citric acid cycle are the same three carbons that came from the initial pyruvate (made at the end of step 1 of cellular respiration). After two rounds of the citric acid cycle, we have completely oxidized one molecule of glucose to CO2_{2} and captured its energy in a series of steps. These products from the citric acid cycle are made in the mitochondria of your cells..
Step 4: Oxidative phosphorylation
During oxidative phosphorylation, NADH and FADH2_{2} are transported to the electron transport chain, where their high energy electrons will ultimately drive synthesis of ATP.

Consider the following:

What types of foods do we need to be eating in order to fuel our citric acid cycles? Our bodies are capable of digesting complex carbs, proteins, and fats to provide energy for the citric acid cycle. Carbs can be broken down into glucose, the first molecule used during glycolysis. Similarly, proteins can be broken down into their basic parts to form acetyl CoA, the molecule that enters the citric acid cycle. Components of many fats can be transformed into acetyl CoA, or converted to glucose so they can enter the citric acid cycle as well. Essentially, all of the different types of food we eat can end up in the citric acid cycle.


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