Cardiolipin is the fat “signature” of your mitochondria. Although you’ve probably never heard of it before, cardiolipin is a key player in producing energy and maintaining mitochondrial health. This article breaks down the latest cardiolipin research and its implications for a wide range of diseases.

What is Cardiolipin?

Cardiolipin is the “signature” fat of the mitochondria that plays an essential role in energy production. This unique compound is found only in the inner membrane of the mitochondria; there it is made, used, broken down, and once again re-created [1].

Chemically speaking, cardiolipin is a phospholipid – a fat attached to phosphate groups, similar to lecithin [1].

The “cardio” part of cardiolipin is due to its discovery in the heart. The heart uses an immense amount of energy and is abundant in mitochondria. For this reason, your heart contains a lot of cardiolipin [2].

Cardiolipin is a key player in producing ATP – your body’s main energy currency – in the mitochondria. It also helps eliminate potentially dangerous cells by activating programmed cell death (apoptosis) [1].

And that’s not all.

Cardiolipin can combat oxidative stress and excessive platelet clotting. In turn, it protects the heart and blood vessels. Cardiolipin can also protect the brain and support cognitive function [1].

Scientists are just tapping into how cardiolipin maintains health and what can go wrong if it starts to malfunction.

Structure of Cardiolipin

Mitochondria need the unique and adaptable properties of cardiolipin to work properly.

What makes cardiolipin so unique?

For one, it contains more fatty acids than other phospholipids (it has a double glycerophosphate backbone with four fatty acid side chains). The fatty acids make cardiolipin cone-shaped, allowing it to interact with many proteins [2].

Thanks to its structure, cardiolipin can make mitochondrial membranes more fluid: it reduces their rigidity and density. And more fluid mitochondrial membranes mean less oxidative damage and a healthier heart [3, 4].

What’s more, the mitochondria can produce cardiolipin as-needed: to fit the specific functions and demands of different tissues and cells. Over one hundred different types of cardiolipin exist, which vary in their fatty acid (side chain) profile [5].

Snapshot

PROS

  • Essential for optimal mitochondrial function
  • Protects from many age-related diseases
  • May be increased/regenerated with certain supplements

CONS

  • Few human studies
  • Most studies only deal with correlation

Cardiolipin Antibodies

Cardiolipin antibodies mistakenly target and damage the body’s own cardiolipins.

Specifically, cardiolipin antibodies can be high in people with [6, 7, 8]:

  • Increased risk of excessive blood clotting
  • Autoimmune diseases
  • Bacterial infections (Lyme disease, syphilis, tuberculosis)
  • Viral infections (hepatitis, HIV, Epstein-Barr)
  • Women with recurrent miscarriages or pregnancy complications
  • In response to some medications (amoxicillin, hydralazine, propranolol, clozapine)

When a person experiences symptoms and has an autoimmune response against phospholipids (including cardiolipin), this is called antiphospholipid syndrome. About 40% of people with this syndrome have lupus [9].

Test

A cardiolipin test examines cardiolipin antibody levels in the blood. Similar to other blood tests, a sample is taken from a vein in the arm.

Your doctor may request this test if you experience unexplained blood clots, recurrent miscarriages, or autoimmune disease symptoms [9, 6].

Although this test can be useful, it is far from ideal. No “gold standard” exists to compare it to, while the procedures among different labs vary greatly. This test is also not specific: it can point to a wide array of diseases. Plus, about 1 – 5% of healthy people have cardiolipin antibodies [6].

We’ve compiled the normal range from the literature below. However, have in mind that the normal range is poorly defined [6].

Antibody Normal Range

Cardiolipin Antibody Reference Ranges [10]:

  • Negative: <5 to 10 GPL/MPL
  • Low positive: 5 – 10 to 20 GPL/MPL
  • Moderate positive: 20 to 40 – 80 GPL/MPL
  • High positive: > 40 to 80 GPL/MPL

A negative result indicates normal cardiolipin antibodies. If high antibody levels are discovered in the first test, the test is repeated 12 weeks later to determine whether the antibodies are temporary or chronic.

Note: Test results are provided as 1 microgram of IgG antibody (GPL) and 1 microgram of IgM antibody (MPL). Normal ranges vary by lab, but the above ranges are the same for both IgM and IgG antibodies.

Role in Autoimmunity

The autoimmune attack against cardiolipin has been researched for decades. It is widely accepted in the medical community.

In two studies of 500 people in total, anticardiolipin antibody levels were elevated in those with Crohn’s disease and ulcerative colitis, compared to healthy individuals [11, 12].

In a different study, 12% of 168 patients with autoimmune thyroid disorders had anticardiolipin antibodies, compared to 0% in healthy people [13].

Additionally, 21% of people with Hashimoto’s disease had anticardiolipin antibodies in another study. However, two earlier studies failed to show a difference between healthy people and those with Hashimoto’s [14, 15, 16].

Antiphospholipid Syndrome

Antiphospholipid syndrome is an autoimmune disease. The autoimmune attack is directed against phospholipids, including cardiolipin. It often results in unexplained blood clotting and pregnancy complications. People with this disorder have anticardiolipin and/or anti-beta-2-glycoprotein I antibodies [17, 18].

The syndrome is most common in people with lupus, but it may be related to other autoimmune disorders as well [17, 18].

HIV

People with HIV can experience autoimmunity. Many human studies reveal that people with HIV have high anticardiolipin antibodies [19, 20, 21, 22, 23, 24].

In a study of 67 people with untreated HIV, cardiolipin antibodies were also linked to increased virus replication and immune cell activation [25].

Chronic Fatigue Syndrome

Mitochondrial dysfunction and high oxidative stress are common in chronic fatigue syndrome. Cardiolipin changes may impair energy use in chronic fatigue, especially coupled with an autoimmune response [26, 27].

In one study, 95% of patients with chronic fatigue syndrome had high anticardiolipin IgM antibodies [28].

Miscarriages

Recurrent spontaneous miscarriage (when a woman has at least 3 miscarriages with the same partner) affects 1-2% of women. While many factors can affect it, immune imbalances may be an important one [29].

In a large study of 565 women, those with recurrent spontaneous miscarriages had high cardiolipin antibodies (IgG and IgM). In women with this condition, heparin and aspirin may improve the birth rate. How these treatments affect cardiolipin autoimmunity, though, is unclear [30, 31, 32].

Bottom Line

Although it’s been accepted that anticardiolipin antibodies play some role in various autoimmune diseases, much has yet to be uncovered and explained.

Cardiolipin Affects the Function of Mitochondria

Cardiolipin maintains the function of proteins that act as transporters; these proteins carry substances involved in energy use into and out of the mitochondria [1].

For example, the transfer of pyruvate into the mitochondria is the first step for energy production. Proteins that transfer pyruvate require cardiolipin [33, 34].

Without cardiolipin, many protein complexes that play a role in energy production break down and lose function. The lack of cardiolipin can decrease the energy-producing activity of the mitochondria by 50% [1, 35, 36].

These so-called mitochondrial protein complexes work best when grouped in “supercomplexes,” which streamline energy flow and capacity. Cardiolipin increases their assembly. As a result, more ATP is released (at least 35% more) [1, 37, 38].

Importantly, mildly damaged mitochondria have to be recycled and repaired – a process termed “mitophagy.” Cardiolipin senses mitochondrial damage. It then helps destroy severely damaged structures and repair salvageable ones [39].

Similarly, cells in the body can be recycled via autophagy, while the damaged ones are broken down via apoptosis. Cardiolipin is involved in many of the mitochondrial-dependent steps of apoptosis [40, 39].

Once cardiolipin senses mitochondrial damage, it can activate an inflammatory response (via Nlrp3) [41].

In a nutshell, cardiolipin ensures mitochondria stay healthy and produce energy efficiently.

Oxidative Stress

Oxidative stress can disrupt cardiolipin. Cardiolipin is particularly susceptible to oxidative stress because it contains many unsaturated fatty acids. Plus, it is located close to the mitochondria’s main reactive oxygen species production site [42].

Damage to and loss of cardiolipin can cause mitochondrial dysfunction and cell death. The mitochondria have their own “cardiolipin pool.” Any alteration to it can cause damage and has been linked to numerous diseases [43].

Once the mitochondria sense stress, cardiolipin moves from the inner to the outer mitochondrial membrane. It takes a strategic location to tackle the problem. There it serves as a messenger, communicating with various important proteins and molecules. A 2017 study outlines its crucial role in apoptosis, autophagy, and inflammation [44].

In fact, changes in the cardiolipin pool (and the resulting mitochondrial dysfunction) have been linked to [44, 45, 46, 47, 48, 49]:

  • Heart disease
  • Muscle Wasting
  • Slow development in children
  • Low neutrophils (neutropenia)
  • Low thyroid (hypothyroidism)
  • Parkinson’s disease
  • Alzheimer’s disease
  • Non-alcoholic fatty liver disease

What’s more, the damage, oxidized form of cardiolipin has been linked to aging and worse outcomes after traumatic brain injury [50, 51, 52].

You have a right to be surprised that you never heard of cardiolipin before, given its role in so many diseases!

Most of the research we outline here was published in the last couple of years (2016 – 2019). Large-scale clinical studies have yet to be carried out. Thus, knowledge about the possible relevance of cardiolipin hasn’t made it into the medical community yet. In medicine, cardiolipin is only mentioned in the context of its antibodies and some autoimmune disorders.

But there’s so much more to it. Let’s dive into the emerging science behind it.

“Leaky Mitochondria”

Cardiolipin
Pathological remodeling of CL as a common denominator of mitochondrial dysfunction in metabolic and aging-related diseases.

You’ve heard of “leaky gut” (and maybe even “leaky brain”) but we bet you’ve never heard of “leaky mitochondria.” And no – it’s not a fad name invented by popular health blogs. In 2010, an eminent scientist, Dr. Shi from Pennsylvania State University, explained this concept in his research paper [53].

He proposed that a process called “pathological remodeling of cardiolipin” underlies mitochondrial dysfunction in metabolic, brain, and aging-related diseases. These diseases are all marked by oxidative stress, which damages cardiolipin: it turns “good” cardiolipin to “bad cardiolipin” [53].

“Bad” cardiolipin is, as you would guess, less functional. It can’t form tight junctions in the mitochondrial membrane. As a result, the mitochondrial membrane becomes leaky and mitochondrial dysfunction follows [53].

A vicious cycle starts to unfold: dysfunctional mitochondria worsen diseases symptoms even further and generate even more oxidative stress [53].

According to Dr. Shi’s research, the rise in “bad” cardiolipin might be common to all aging-related diseases. He thinks that new treatments should target and block the enzymes that turn cardiolipin “bad” [53].

Aging

As mentioned, aging is marked by a drop in healthy cardiolipin and a spike in oxidized, “bad” cardiolipin in the mitochondria. Oxidized cardiolipin reduces the activity of the mitochondria, further impairing energy production [50, 51].

Raising mitochondrial cardiolipin may reverse some aspects of aging, such as fatigue and inactivity. In aged rats, restoring cardiolipin levels in the mitochondria increased their activity to that of young rats [54, 42].

Since the brain uses a large amount of energy, cardiolipin may be especially important for brain health in aging [42, 54].

Thyroid Health

Back in 1997, one study revealed that rats with low thyroid (hypothyroidism) have lower heart cardiolipin levels. Adding cardiolipin to their mitochondria restored normal energy production [45, 46].

On the other hand, the heart is especially sensitive to the oxidative stress that hyperthyroidism can cause. In one older study with hyperthyroid rats, cardiolipin and phosphatidylserine were increased in heart mitochondria by more than 50%. Since this study is older, it’s quite possible that only the “bad” cardiolipin increased [55, 56].

High thyroid hormone levels do increase the “bad” cardiolipin. Recent research only highlights that oxidative stress in hyperthyroidism is likely to cause a deficiency in healthy cardiolipin [53, 53].

Parkinson’s Disease

Patients with Parkinson’s disease have reduced cardiolipin activity, which is associated with oxidative stress and poor energy use [47].

In Parkinson’s disease, a protein called alpha-synuclein builds up in the brain. Low cardiolipin brain levels promote its build up, suggesting that healthy cardiolipin levels may play a role in disease prevention [57].

Alzheimer’s Disease

In an early study, patients with Alzheimer’s didn’t have different brain cardiolipin (levels or quality) than healthy people [58].

However, a recent study counters these findings. Mice with Alzheimer’s disease had lower cardiolipin in their synapses, which allow brain cell communication. Their brain cardiolipin was also poorly organized. These changes occurred alongside mitochondrial dysfunction in the early stages of Alzheimer’s disease [48].

Thus, cardiolipin loss may be an early sign of Alzheimer’s [48].

Traumatic Brain Injury

Cardiolipin allows the brain mitochondria to recover after damage, restoring cognitive function. It also helps sense which mitochondria are damaged beyond repair. Cardiolipin activates their recycling to prevent brain cell death and cognitive impairment. If cardiolipin is damaged, however, the whole brain cells can die, instead of just the mitochondria being recycled [52].

Cardiolipin is supposed to stay in cells. Its presence in the blood points to cell death. The cells that die from brain injury, the more cardiolipin floods the bloodstream. This cardiolipin is often of the “bad”, oxidized type. Its release disrupts the blood-brain barrier, causing blood clotting changes and worsening leakage [59].

Drugs that block the production of “bad” cardiolipin increase brain cell survival and recovery after stroke in animals [60].

Non-alcoholic Fatty Liver Disease

In rats with non-alcoholic fatty liver disease, liver cardiolipin decreased by 38% while “bad” cardiolipin increased. This was linked to a 35% drop in the mitochondria’s energy-producing activity [49].

When healthy cardiolipin was added back to the animals, mitochondrial activity was restored. This study adds to the theory that “bad” cardiolipin underlies mitochondrial dysfunction in non-alcoholic fatty liver disease [49].

Heart Disease

Cardiolipin is extremely important for heart health. It owes its name to its initial discovery in heart cells, which is how it got its name [61].

Cardiolipin keeps the heart mitochondria running smoothly, satisfying the heart’s high energy demands. In fact, mitochondria take up one-third of a heart cell. We already know that oxidative stress plays a large role in heart disease, but cardiolipin may have been the missing piece to tie the story together [62, 63].

Cardiolipin also supports the action of ubiquinone, CoQ10’s active form [64, 65].

Unsurprisingly, people with heart failure have low heart cardiolipin. A deficiency in cardiolipin causes mitochondrial dysfunction, which worsens oxidative stress [62, 66, 67].

Excessive oxidative stress then damages blood vessels and energy-sensitive heart cells, leading to many of the typical symptoms of heart disease. It also increases “bad” cardiolipin, which makes everything even worse, increasing inflammation and plaque formation in the arteries. Plaque buildup clogs the arteries and reduces their elasticity, triggering atherosclerosis [62, 66, 67].

Diabetes

In mice, diet-induced obesity increased cardiolipin’s sensitivity to oxidative damage, causing mitochondrial dysfunction and insulin resistance [68].

In mice, type 2 diabetes onset was linked with a steep drop in heart cardiolipin levels, as well as the buildup of “bad” cardiolipin. An antidiabetic drug (rosiglitazone) restored cardiolipin levels [69, 70, 71].

Cancer

Cardiolipin deficits impair energy use and may play a role in cancer [72].

One theory (the Warburg theory) suggests that mitochondrial damage is the first step to cancer development. According to this theory, the main cause of cancer is impaired energy metabolism. In line with it, “leaky mitochondria” and the rise in “bad” cardiolipin may make cells more prone to cancerous changes [73, 74, 72].

Additionally, low or damaged cardiolipin increases reactive oxygen species during tumor progression. This can impair genome stability and turn off cancer-fighting genes [72, 75, 76, 77].

In patients with leukemia, cardiolipin changes in lymphocytes are associated with increased cancer growth [78].

Genetic Disorders

Barth Syndrome

Barth syndrome is an X-linked genetic disorder of cardiolipin formation caused by mutations of the tafazzin (TAZ) gene. Symptoms include heart and muscle weakness, low neutrophils, and stunted growth [79].

Patients with Barth syndrome have 20% lower muscle cardiolipin and 80% lower heart cardiolipin levels, compared with healthy people. As a result, people with this syndrome have poorly functioning mitochondria and impaired energy productions [80].

Tangier Disease

Tangier disease is caused by defects in the ABCA1 gene. It leads to very low levels of the “good” HDL cholesterol and increases the risk of heart disease [81].

Cardiolipin levels are higher than normal Tangier disease. It’s unknown whether the rise in cardiolipin is helpful (to compensate for impaired cholesterol level) or harmful [82].

How to Boost or Regenerate Cardiolipin

No human studies have yet looked into cardiolipin-boosting substances. Animal and cell-based research gives us some clues as to what might help.

Blocking the FAS gene (fatty acid synthase or FASH) increased cardiolipin in one study [65].

Some natural FAS inhibitors include [83, 84]:

Additionally, melatonin injected into heart cells prevented cardiolipin oxidation and mitochondrial damage [85].

MitoQ increases cardiolipin in the livers of rats fed high-fat diets [86].

Plastoquinones, antioxidants found in chlorophyll, were particularly effective at preventing cardiolipin oxidation in the mitochondria [87].

In rats with heart failure, diets with linoleic acid preserved cardiolipin in the heart and reduced mitochondrial dysfunction [88].

Ubiquinol and similar antioxidants that can target the mitochondria protect cardiolipin from damage. Fat-soluble antioxidants, such as vitamin E, don’t work as well [89].

Having all the above in mind, reducing your oxidative stress, in general, is crucial. Lower oxidative stress load will reduce the chance of cardiolipin damage and “leaky mitochondria.”

Read more about the mitochondria and how to improve mitochondrial function.

Limitations and Caveats

Cardiolipin research is in its exciting but early stages. Most studies have been conducted in cells and animals. Whether the findings will translate to humans remains to be seen.

It’s still not completely clear whether cardiolipin underlies or results from mitochondrial dysfunction.

The evidence to support cardiolipin’s causal role in many diseases is lacking. Future research will help clarify the many things we don’t yet know about cardiolipin. Or, as one article put it: “the best is yet to come” [90].

Resources

SelfHacked Secrets contain a chapter specifically dedicated to improving mitochondrial function.

Lab Test Analyzer allows you to analyze your lab test results and optimize your health based on them.

Are you genetically predisposed to problems with cardiolipin? Upload your DNA file to SelfDecode and check out these pages:

This section contains sponsored links, which means that we may receive a small percentage of profit from your purchase, while the price remains the same to you. The proceeds from your purchase support our research and work. Thank you for your support.

Takeaway

The mitochondria, the energy powerhouses of your cells, are crucial to a healthy, long life. But we should even talk about the mitochondria without mentioning cardiolipin. This small fatty molecule forms the mitochondrial blueprint, ensuring proper energy use.

People with various autoimmune issues may have antibodies directed against cardiolipin.

Scientists have only recently realized that cardiolipin deficiency or damage underlies many diseases, especially age-related ones.

Natural strategies that may boost your cardiolipin levels include ubiquinol, NAC, EGCG from green tea, and plant antioxidants like resveratrol and quercetin.

About the Author

Matt Lehrer, PhD

PhD (Behavioural Health, Nutritional Sciences)

Matt is a PhD candidate at The University of Texas at Austin and has a MS from The University of Texas at Austin.

As a scientist, Matt believes his job is not only to produce knowledge, but to share it with a wide audience. He has experience in nutritional counseling, personal training, and health promotion.

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