Does It Make Sense to Replace Linoleic Acid in Cardiolipin?

We already know that in order to maintain a healthy metabolism, we need to keep our mitochondria in very good condition. But how do we do that?

When I tried to find out what the usual composition of cardiolipin, one of the most important phospholipids in a healthy mitochondrial membrane, is, I always found that it contains a high percentage of tetralinoleoyl cardiolipin (4L-CL), i.e. cardiolipin containing four linoleic acid chains. Cis-vaccenic acid (cVA) comes in second, and only further down do we find, for example, DHA (in mitochondria from the heart), oleic acid, or other polyunsaturated fatty acids.

In some studies, researchers have tried to replace linoleic acid with the long-chain fatty acids ARA and DHA, but the results are not particularly encouraging. For example, in this study, they tried to remodel cardiolipin by manipulating the enzyme ALCAT1 and achieved the incorporation of more DHA into cardiolipin, but they obtained the best results after shutting down remodeling via ALCAT1. Linoleic acid simply appears to be the most suitable for cardiolipin.

The diagram shows the causal role of ALCAT1 in mitochondrial dysfunction and insulin resistance. Cardiolipin containing linoleic acid (C18-CL) enriched with DHA omega-3 (DHA-CL) causes mitochondrial dysfunction and insulin resistance.

We need to realize that even if some other fatty acids may appear better at first glance and may provide a faster rate of oxidative phosphorylation, this is not necessarily always a positive change. An unlimited processing rate can sometimes be very problematic, as we have already shown. Burning must take place in a controlled, regulated manner. Once the burning gets out of control and runs at full capacity for a prolonged period, something will always be damaged.

Since we know that during oxidative stress, linoleic acid is released from phospholipids by the enzyme iPLA2γ, most likely specifically from cardiolipin, 4L-CL is apparently also the largest source of the aldehyde HNE, i.e. peroxidized linoleic acid. Is this good or bad?

Oxidative stress releases linoleic acid C18:2 from phospholipids.

Lately, I have been thinking that this is probably intentional: during oxidative stress, it may be beneficial to release linoleic acid from the membrane, oxidize it to HNE, and then, after conversion to HNA, use it to reduce oxidative stress through mitochondrial uncoupling. This lowers the potential across the inner mitochondrial membrane and also reduces oxidative stress. It therefore appears to be part of a regulatory negative-feedback loop that suppresses oxidative stress.

How does it happen that this regulatory loop stops working?

It is enough to suppress the function of the enzyme ALDH2. It is also part of this regulatory loop. The HNE aldehyde does not directly function as an uncoupler; it must be converted to HNA, and only then does it begin to function as an uncoupler even without UCP enzymes. It then functions as a "safety valve releasing excess steam." This is a very useful function that protects mitochondria.

So how does it happen that the ALDH2 enzyme stops working?

For the ALDH2 enzyme to function even in the presence of the HNE aldehyde, hydrogen sulfide H2S must be available. It prevents HNE from attaching to enzymes at sensitive sites; HNE simply likes to "stick" and then prevents many enzymes from functioning. Hydrogen sulfide can prevent this. It is actually quite simple: instead of a thiol group with an -SH bond, it creates an -SSH bond, which protects the given site.

Linoleic acid therefore appears to be not only a problem but, in the case of cardiolipin, also a solution. It just must not be present in excessive amounts. Its excess causes mitochondrial overload and higher oxidative stress, and excess HNE also blocks the enzymes responsible for producing H2S, specifically probably the enzyme CSE, the largest producer of H2S from sulfur-containing amino acids.

In my opinion, therefore, it does not make sense to reduce the amount of LA in cardiolipin or in phospholipids. It even appears that if we replace LA in cardiolipin with longer-chain PUFAs, such as DHA or ARA, we gain nothing and increase the sensitivity of cardiolipin to oxidative stress. But we want the exact opposite; we want to reduce its sensitivity. This could perhaps be achieved, for example, by replacing part of the linoleic acid in 4L-CL with a chain of cis-vaccenic acid (cVA). We have already seen an example here showing that increasing the production of cVA from palmitoleic acid by the enzyme ELOVL5 can improve mitochondrial function. I think this is the right path. And we obtain palmitoleic acid by desaturating palmitic acid C16:0 using the enzyme SCD1.

It is very interesting that the total percentage of unsaturated fatty acids in adipose tissue is maintained remarkably constant. This is not accidental. It is a controlled process governed by feedback mechanisms. If even a low-fat diet provides enough linoleic acid for cardiolipin production, and desaturation of newly formed fats ensures the proper composition of stored fats, then a high-fat diet with the same fat composition must necessarily cause an excess of linoleic acid and suppression of desaturation, i.e. suppression of SCD1 enzyme activity. This probably causes a deficiency of cVA. Even replacing linoleic acid with oleic acid does not necessarily lead to the desired outcome. Excess oleic acid causes desaturation by the SCD1 enzyme to be unnecessary and signals to the body that it should store fat.

Effect of cVA increase following 5-day ELOVL5 activation (Ad-Elovl5)

If mitochondria are to be protected even on a high-fat diet, it is necessary to reduce the amount of polyunsaturated fats of plant origin, limit the rate at which fats are processed in the mitochondria, and specifically slow down the breakdown of long-chain fatty acids into acetyl-CoA. I have already mentioned foods that can do this here. Fish oil, saturated fats with shorter chains, such as MCT oil, and even vinegar can do it, for example.

So, to summarize, the most important thing for mitochondrial health is ensuring the uninterrupted activity of all key enzymes. In addition to the enzymes involved in the TCA cycle and oxidative phosphorylation, these also include other enzymes (ALDH2, SCD1, ELOVL5, etc.). For example, activation of ALDH2 itself using flurbiprofen removes HNE, suppresses obesity, leptin resistance, and ER stress in mice fed a diet high in lard. This does not mean, however, that we are deficient in flurbiprofen. It means that we have accumulated an excess of linoleic acid, so its processing generates a large amount of HNE, which causes enzyme activity to slow down.

ALDH2 activator (+Flu) suppresses mitochondrial damage in mice fed a lard containing high-fat diet


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References:

Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity

Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease

Kinetics of the depletion of linoleic acid in mice


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