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 .
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 .
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) .
And that’s not all.
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 .
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 .
- Essential for optimal mitochondrial function
- Protects from many age-related diseases
- May be increased/regenerated with certain supplements
- Few human studies
- Most studies only deal with correlation
Cardiolipin antibodies mistakenly target and damage the body’s own cardiolipins.
- 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 .
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.
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 .
We’ve compiled the normal range from the literature below. However, have in mind that the normal range is poorly defined .
Antibody Normal Range
Cardiolipin Antibody Reference Ranges :
- 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 a different study, 12% of 168 patients with autoimmune thyroid disorders had anticardiolipin antibodies, compared to 0% in healthy people .
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 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].
In a study of 67 people with untreated HIV, cardiolipin antibodies were also linked to increased virus replication and immune cell activation .
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].
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 .
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].
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 .
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 .
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].
In a nutshell, cardiolipin ensures mitochondria stay healthy and produce energy efficiently.
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 .
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 .
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 .
- 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
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.
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 .
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” .
“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 .
A vicious cycle starts to unfold: dysfunctional mitochondria worsen diseases symptoms even further and generate even more oxidative stress .
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” .
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].
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].
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 .
In an early study, patients with Alzheimer’s didn’t have different brain cardiolipin (levels or quality) than healthy people .
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 .
Thus, cardiolipin loss may be an early sign of Alzheimer’s .
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 .
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 .
Drugs that block the production of “bad” cardiolipin increase brain cell survival and recovery after stroke in animals .
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 .
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 .
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 .
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].
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].
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].
Cardiolipin deficits impair energy use and may play a role in cancer .
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].
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 .
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 .
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 .
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.
- N-acetyl cysteine (NAC)
- EGCG from green tea
- Antioxidants in olive oil
- Flavonoids from oranges
- Resveratrol from grape skins
- Ginkgo biloba
Plastoquinones, antioxidants found in chlorophyll, were particularly effective at preventing cardiolipin oxidation in the mitochondria .
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.”
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” .
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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.