Energy metabolism - Part 4: Fatty acids and carnitine transporter
Have you ever weighed yourself in the morning and were frustrated with the scales?
Well, if that’s the case, then your body may just be well prepared for bad times.
After all, fatty acids represent the body’s main energy store.
Their breakdown helps overcome prolonged periods of fasting.
To provide energy, fatty acids are activated, especially in liver and muscle cells, and
subsequently transported into the mitochondrial matrix.
Once inside, the long linear molecules are cleaved into short C2 units of acetyl-CoA.
This cleaving process is called beta-oxidation.
Afterwards, acetyl-CoA can, for example, enter the citric acid cycle, which also takes place
in the mitochondrial matrix.
To help you understand the reactions during beta-oxidation in the following episode of
this course, let’s freshen up the most important facts about fatty acids: Fatty acids from
foods or the body’s fat deposits are usually present as triacylglycerols, in short TAG.
These are also termed triglycerides.
To be broken down, fatty acids must first be released from triacylglycerol.
Here’s an example of a free saturated fatty acid with 16 carbon atoms, palmitic acid.
Like all fatty acids, it has a polar carboxylic acid group, which is called the head, and
an apolar hydrocarbon chain, termed the tail.
To localize structural changes in the long hydrocarbon chain, the carbon atoms are numbered
consecutively, starting with the carbon atom at the head.
Alternatively, the carbon atoms can be labeled with lower-case Greek letters.
However, when using this nomenclature, the carbon atom of the head group is not included.
The alpha carbon atom is C2, the beta carbon atom is C3, and so on.
You've probably figured it out already but that’s how beta-oxidation obtained its name:
During the breakdown of fatty acids, the beta carbon of the fatty acid is oxidized.
Palmitic acid is a saturated fatty acid and does, therefore, not contain double bonds
in the hydrocarbon chain.
Unsaturated fatty acids contain one or more double bonds.
Their breakdown slightly differs from regular beta-oxidation.
We’ll be showing you these differences in episode 5 of this Chalk Talk series.
For now, let’s focus on how to correctly describe the position of a double bond in
the fatty acid molecule: To denote the double bond’s position in relation to the head,
a capital delta is used.
Following this symbol, the position of the first carbon atom involved in each double
bond is placed as a superscript.
For example, a delta-3 indicates the presence of a double bond between C3 and C4.
Now, let’s move on to how fatty acids are prepared for their breakdown.
In many metabolic pathways, the first step involves substrate activation, which is mainly
achieved by adding a phosphate group.
You’ve already seen this in glycolysis, in which glucose is phosphorylated.
In contrast, fatty acids are activated by forming a thioester at the head group.
This reaction consumes ATP, while the relatively complex coenzyme A molecule binds via a sulfur
atom to the fatty acid’s head.
To make things simpler, you’ll find coenzyme A usually abbreviated as CoA.
The collective term for activated fatty acids is, accordingly, acyl-CoA.
This term comprises fatty acids of different chain lengths and saturation states.
However, acyl-CoA shouldn’t be confused with the similar sounding acetyl-CoA.
The latter exclusively refers to acetic acid activated with coenzyme A. It’s the C2 unit
we already heard of earlier.
Acetyl-CoA is an energy-rich molecule produced in glycolysis and fatty acid degradation,
and can be further broken down in the citric acid cycle.
While activation takes place in the cytosol, fatty acid degradation occurs in the mitochondria.
The enzymes involved aren’t specific to any particular fatty acid but can degrade
various acyl-CoA molecules.
Though, mitochondrial enzymes preferably use short and medium chain fatty acids.
Fatty acids with a long hydrocarbon chain, which is longer than 20 C atoms, need to be
broken down initially in peroxisomal beta-oxidation.
These shortened fatty acids later enter the mitochondria, to be broken down completely.
We’ll get back to this in episode 5 of this Chalk Talk series.
Since fatty acids are activated in the cytosol, the acyl-CoA formed needs to be transported
into the mitochondrial matrix for degradation.
The outer mitochondrial membrane is highly permeable through porins, whereas the inner
membrane isn’t.
Therefore, acyl-CoA needs to be translocated across the inner membrane by a transport system,
termed the carnitine shuttle.
In preparation for transport, the coenzyme-A is exchanged for carnitine by a carnitine
palmitoyltransferase, while the molecule still is located in the cytosol.
The formed acylcarnitine enters the intermembrane space and is subsequently shuttled across
the inner membrane into the matrix via carnitine-acylcarnitine translocase.
Inside the matrix, carnitine is exchanged for coenzyme A again regaining acyl-CoA.
While carnitine is transported back into the cytosol, the acyl-CoA can now enter the beta-oxidation
cycle.
As you can see, carnitine plays a very important role in fatty acid breakdown.
If carnitine levels in the body aren’t sufficient, the clinical effects are quite prominent:
Let’s look at an example.
Individuals with primary carnitine deficiency are afflicted during early childhood with
extremely low levels of ketone bodies and glucose.
They develop hypoketotic hypoglycemia.
Some of the effects include failure to thrive, hypotonia, and cardiomyopathy.
If left untreated, the disease can be fatal.
However, the condition is easily treated through a lifelong, oral supplementation of carnitine.
Now, let’s summarize the most important take-home points.
Fatty acids need to be initially released from triacylglycerols for degradation.
Fatty acids are converted to coenzyme A thioesters and are thereby activated.
Beta-oxidation occurs primarily in the mitochondria of muscle and liver cells.
Acyl-CoA is transported across the inner mitochondrial membrane into the matrix by a carnitine-acylcarnitine
translocase.
Long-chain fatty acids are shortened in the peroxisomes before their final degradation
in the mitochondria.
In the next episode of this course on energy metabolism, we’ll delve into the reactions
of the beta-oxidation process.
See you then!