Mitochondria cross-section, illustration

The human body works like a well-oiled machine, allowing a million metabolic activities to take place simultaneously in astounding precision and harmony. For example, a simple act of walking down the street, though mundane for most, is actually the coming together of many different processes in the body: muscle function, energy expenditure, coordination between sight and movement, and more.

It is often when something becomes defective in the human body, or if something is lost, that we gain a renewed appreciation of what we once had. It is but human nature for this to occur, but in the race to unearth medical solutions to these problems, a sort of clear-eyed objectivity needs to take over that is almost void of sentimentality, as the work of data generation, comparison of data, and implementation of data findings take place. 

One of the rare diseases that we cover in Rare Disease Advisor is long chain fatty acid oxidation disorder (LCFAOD). It belongs to a group of diseases collectively known as inherited metabolism diseases of mitochondrial fatty acid metabolism. In the simplest of terms, it is a disease that is caused by dysfunctions in the body in coming up with sufficient energy to meet demand.


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Read more about LCFAOD epidemiology

We will take a look at a German study that summarizes our understanding of inherited metabolism diseases of mitochondrial fatty acid metabolism, published in the International Journal of Molecular Sciences, as well as an Australian study that does the same, with an emphasis on insulin resistance, published in the Journal of Endocrinology. 

Mitochondrial β-Oxidation

Before we look at how mitochondrial oxidation can go wrong, let’s quickly recap what goes on when the mitochondrial oxidation process is normal and unhindered. The German researchers presented a simplified version of this very complex process.

As we know, mitochondrial β-oxidation produces energy from fat. Short and medium chain fatty acids participate in the β-oxidation freely as they can cross the mitochondrial membrane easily; this is not the case for long chain fatty acids, which cannot do so without the help of an active transport system. Long chain fatty acids cross the mitochondrial membrane with the help of carnitine palmitoyltransferase I, which is then converted into active acyl-CoA once inside the mitochondria. 

Turner et al elaborated on the differences between short, medium, long, and very long chain fatty acids, writing, “Fatty acids are grouped into short chain (2–6 carbon atoms), medium chain (8–12 carbon atoms), long chain (14–18 carbon atoms) and very long chain (20–26 carbon atoms). The major types of fatty acids in the circulation and in the tissues of mammals are the long-chain and very-long-chain FAs with varying degrees of saturation.” 

Read more about LCFAOD etiology 

This process works smoothly in healthy individuals, but in patients with fatty acid oxidation disorders can cause serious energy deficiencies, resulting in high-mortality conditions, including coma and death. There currently is no definite cure for this problem, but patients with long chain fatty acid disorders are encouraged to avoid fasting and take frequent meals to prevent the catabolic state. 

Would increasing fat oxidation drive an increase in energy expenditure? Existing literature seems to argue this isn’t the case. Based on the analysis of previous studies, Turner et al concluded, “it would appear that apart from theoretical calculations suggesting that increasing fat oxidation will drive increased energy expenditure, there is little experimental evidence to support the idea that energy expenditure can be increased simply by increasing substrate availability or by switching to oxidize fatty acids.” 

Other Contributing Factors 

Moving beyond fixing the mitochondrial energy-producing ability, what other factors worsen the clinical symptoms of patients with long chain fatty acid disorders? Tucci et al list a number of factors that physicians would do well to keep an eye on, such as diet and sex.

With regards to diet, skeletal muscle has particular sensitivity to nutrient availability. When insulin production is stimulated, it drives glucose transport into the cell and the uptake of triglycerides into muscle. At the same time, the rate of fatty acid oxidation decreases and the rate of protein synthesis increases.

A medium chain triglycerides (MCTs) diet is recommended in patients with LCFAOD because MCTs are rapidly hydrolyzed after ingestion, allowing the circulating medium-chain fatty acids to be more easily taken up by peripheral tissue and undergo β-oxidation. Keep in mind that they can cross the mitochondrial membrane without the need for an active transport system. 

The scientific literature around sex is more controversial. However, there is consensus that some differences occur at the level of basal metabolism, especially in experiments with mice models. Studies have isolated higher-efficiency mitochondria from the liver, heart, and skeletal muscles in male mice models. However, mitochondria isolated from the cardiac muscle of female rats are, though fewer in number, morphologically more differentiated than those of male rats, indicating a more efficient mitochondrial electron transport chain and lower H2O2 generation.

In addition, mitochondria from tissues other than cardiac muscles in female mice also demonstrated higher energetic efficiency and mitochondrial oxygen consumption, explaining the higher rate of respiratory rate in fibroblasts from wild-type female mice from another experiment. 

Furthermore, differences between mice models and humans remain. Turner et al commented that “energy metabolism is not constant in animals and humans, but has a substantial diurnal variation that is highly relevant to designing appropriate experiments.” 

References

Tucci S, Alatibi KI, Wehbe Z. Altered metabolic flexibility in inherited metabolic diseases of mitochondrial fatty acid metabolismInt. J. Mol. Sci. Published online April 6, 2021. doi:10.3390/ijms22073799

Turner N, Cooney GJ, Kraegen EW, Bruce CR. Fatty acid metabolism, energy expenditure and insulin resistance in muscleJ Endocrinol. Published online January 15, 2014. doi:10.1530/JOE-13-0397