Energy Metabolism – Part 4: Fatty Acids & Carnitine Transporter

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!

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