The topic of mitochondrial damage is gaining more and more press as a potential side effect of anti-HIV medication. Simply put, the mitochondria are the "energy factories" of the cell -- the tiny, rod-shaped structures, or "organelles," within each cell responsible for producing roughly 90 percent of all the energy that cell needs in order to survive. The number of mitochondria in a particular cell is based upon the energy needs of that cell and can range from 200 to 2,000.
About 80 percent of the energy generated by mitochondria is created through a cellular aerobic (meaning requiring oxygen) process called oxidative phosphorylation, which creates adenosine triphosphate, or ATP. Creating ATP includes an intricate series of steps that involve five multi-subunit enzymes or complexes. Each complex has a different nutritional and chemical need in order to function properly. This is important to remember when exploring the nature of treatment for mitochondrial damage.
As mitochondria produce ATP, they simultaneously yield reactive oxygen species (ROS), which are harmful free radicals that circulate throughout the cell, the mitochondria, and the body, causing more damage. The circulation of ROS leads to the activation of reactive nitrogen compounds, which in turn induce, or activate, genes in the DNA that are associated with many degenerative diseases such as Alzheimer's, Parkinson's, strokes, and multiple sclerosis. The term "mitochondrial toxicity," therefore, is a misnomer and actually refers to the process of mitochondrial damage.
The DNA for each mitochondrion (mtDNA) remains unprotected within the membrane of the mitochondrion itself. In comparison to the DNA in the nucleus of the cell (nDNA), mtDNA is easily damaged by free radicals and the ROS that they produce. Freely floating mtDNA lacks protective measures associated with nDNA, and therefore mtDNA suffers from multiple mutations. It has been estimated that this lack of protective measures results in mutations to mtDNA occurring 10 to 20 times more frequently than mutations to nDNA. The mitochondria that are produced have decreased ability to function, resulting in the inability to utilize fatty acids for energy production, and therefore a decreased ability to store fat in muscle tissue.
In order for mitochondria to reproduce themselves, a specific enzyme called gamma-DNA-polymerase, or "pol gamma" is required. Many medications have been found to interrupt pol gamma. Studies suggest that virtually all the nucleoside analog reverse transcriptase inhibitors (NARTIs) -- such as AZT, 3TC, ddI, ddC, d4T, and abacavir -- interrupt pol gamma to some extent. This disruption prevents the transport of long-chain fatty acids from being transported the membrane wall into the mitochondria, where they are used as primary fuel and energy sources. As a result, fatty acids are dysfunctionally deposited and accumulated in muscle tissue. Without the cell's main source of energy, the number of newly formed mitochondria drops, and therefore, cell function decreases, and possibly even cells die (or apoptosis). Symptoms developed by an individual would depend upon the type of cell affected. However, the most common symptom is generalized, overall fatigue.
Test tube (in vitro) studies have demonstrated that ddC, ddI, and d4T are the most potent inhibitors of pol gamma, although the other NARTIs exert some influence as well. To date, researchers have not studied the extent of mitochondrial damage when anti-HIV medications are combined, which is standard practice for most individuals currently on anti-HIV therapy. Moreover, the effect of combining NARTIs with other anti-HIV medications, such as protease inhibitors, is not known. However, one study demonstrated a reduction in number of mitochondria produced in a cell in people taking d4T. Data from yet another small study suggested that HIV-positive individuals taking any of the NARTIs had up to 44 percent fewer mitochondria per cell than those individuals who are either not taking NARTIs or are HIV-negative. One study demonstrated that those taking AZT had significant depletion of mitochondrial DNA in muscle tissue.
In a study examining the number of mitochondria per cell, participants were separated into four groups: (1) HIV-positive individuals who were on medications and had fat loss/wasting, (2) HIV-positive individuals on medications without signs of fat redistribution, (3) HIV-positive individuals who had not taken anti-HIV drugs and (4) individuals who were HIV-negative. The group with the greatest decrease in mitochondria in cells was the group with fat loss/wasting, followed by the HIV-positive group on medications yet without signs of lipodystrophy. The latter two groups showed no difference in the number of mitochondria. The conclusion drawn is that anti-HIV medications do interfere with the production and lifecycle of mitochondria.
It has been postulated that mitochondrial damage is always present, but the question is to what extent. Mitochondrial damage is poorly diagnosed, and when symptoms do occur, they can run the range from mild, to severe, to life-threatening. For instance, common symptoms include fatigue, muscle weakness (myopathy), peripheral neuropathy, and pancreatitis. However, some researchers suggest that regardless of HIV serostatus, damage to mitochondria can be a possible factor in low platelet count (thrombocytopenia), anemia, and low neutrophil count (neutropenia). Furthermore, there is a significant link between damaged and dysfunctional mitochondria and the development of Type II diabetes in adults, again, regardless of HIV serostatus.
With early enough detection, many of these symptoms and conditions are reversible by altering therapy. This may include stopping medication, or significantly reducing dose. However, people considering such a course of action should first consult with their healthcare provider to identify the specific cause for the symptom.
How can mitochondrial damage be detected? The easiest way is through a blood test that measures lactate levels in the blood. Lactate is a natural byproduct from the breakdown of glucose and fat in the mitochondria. The sore and tired feeling in the muscles following rigorous exercise is a result of the body shifting to "anaerobic respiration" that leads to a buildup of lactic acid. When the mitochondria are damaged, lactate levels rise in the bloodstream and lead to lactic acidosis. This increase in the acidity in the blood is life threatening and must be dealt with immediately. Lactic acid level in the blood should be measured (without a tourniquet, if possible) after a person has been resting for at least 5 minutes, and has refrained from vigorous activity and alcohol consumption for 24 hours.
Early symptoms of lactic acidosis are severe fatigue, nausea, vomiting, shortness of breath, abdominal pain, rapid weight loss, muscle cramps and aches, muscle numbness and tingling, and rapid and progressive muscle weakness. As the severity increases and lactate levels rise over 5 mmol/liter (the normal value is less than 2), mitochondria lose their ability to produce energy, leading to potentially irreversible organ damage and death.
At present, there are no comprehensive studies presenting clear treatment strategies for dealing with mitochondrial damage associated with HIV. Extrapolation can, however, be made from the knowledge available about treatment of mitochondrial damage associated with other diseases. First and foremost is to identify and treat the cause. For many, however, this option may be limited. If it is true that the main associated factors are the NARTIs, then switching to another therapy might be suggested. Eliminating this entire class of HIV medication from treatment options leads to a whole host of medical and health-related issues. It does seem, at this time, that ddI, ddC, and d4T are the most potent inhibitors of pol gamma. This should be considered for those suffering from mitochondrial damage. The availability of Viread (tenofovir) has provided a good alternative to other NRTIs for many people, and Viread does not appear to affect mitochondrial function.
Finally, several nutrients have been studied for their ability to decrease damage to the mitochondria. In the current literature regarding mitochondrial damage and HIV therapies, some mention has been made about carnitine, coenzyme Q10, and riboflavin (B2). Most of these are being studied in isolation and not in conjunction with one another. Although the approach is to determine whether or not each particular nutrient is beneficial in the treatment of mitochondrial damage, the flaw in this approach stems from the fact that each of the five complexes in the oxidative phosphorylation process requires different and varying nutrients simultaneously. Other nutrients that support mitochondrial function are alpha lipoic acid, NAC (N-acetyl-cysteine), vitamin E, and essential fatty acids, to name a few.
Carnitine is a natural substance found in food, mainly meat and dairy products, that can be quickly absorbed in the small intestines. The standard American diet contains roughly between 10 to 100 milligrams of carnitine. The body can synthesize carnitine from the essential amino acid, lysine, with vitamin C, niacin, vitamin B6, iron, and the amino acid methionine as necessary cofactors. Carnitine is vital to the life of the cell since it is required for the transport of long-chain fatty acids into the mitochondria. Regarding supplementation, two forms of carnitine have been used, either L-carnitine or acetyle carnitine. Studies show that supplementation with L-carnitine decreases the percentage of both CD4 and CD8 cells undergoing cell death (apoptosis.) Furthermore, supplementation with L-carnitine has been successfully used in the treatment of mitochondria-induced muscle weakness and degeneration. Studies with patients taking AZT reveal low levels of carnitine found in their muscle tissues. Several studies explored the use of 6 grams of L-carnitine daily intravenously. The results revealed a reduction in serum triglyceride levels, an increase in peripheral blood mononuclear cell-associated cermainde (an intercellular messenger of apoptosis), and a decrease in tumor necrosis factor (a cytokine that is produced as a result of infection, which intensifies viral replication). Another study, in which HIV-positive patients with severe neuropathy were given daily intramuscular injections of 1 gram of acetyl-carnitine (the form of carnitine more easily absorbed in the intestines), showed decrease in patient report of pain and improved movement and mobility. Overall, carnitine is necessary to keep mitochondria alive and functioning well, thereby resulting in proper nerve and muscle function, fatty-acid synthesis, and energy production.
No RDA (recommended daily allowance) has been established for carnitine. Studies range in the amounts used for mitochondrial and neurological benefits. No side effects have been reported, but this author has had patients report slight gastrointestinal pain within a half hour of taking carnitine orally. Current trends recommend between 1,000 to 4,000 mg of L-carnitine or acetyl carnitine in divided doses daily. Because carnitine is an amino acid, it is best absorbed on an empty stomach.
Carnitine works synergistically with another nutrient, the fat-soluble vitamin-like compound called coenzyme Q10 (CoQ10), also known as ubiquinone. CoQ10 is an essential factor in the electron transport chain, the pathway from which ATP and metabolic energy is derived, which occurs within the mitochondria. CoQ10 is a strong antioxidant that resides in the lipid membrane surrounding the mitochondria and protects it against free radical damage. Although the body can generate its own CoQ10, supplementation has been shown to be warranted in persons with HIV. CoQ10 is synthesized in the cells of every living organism in nature. The body produces CoQ10 in a 17-step process that requires riboflavin (B2), niacinamide (B3), pantothenic acid (B5), pyridoxine (B6), cobalamine (B12), folic acid, vitamin C, and other trace minerals. Due to its complex and intricate requirements, nutritional deficiencies with any one of these vitamins can disrupt mitochondrial energy production. Generally, symptoms of CoQ10 deficiency affect cardiovascular health in the form of congestive heart failure, stroke, arhythmias, high blood pressure, mitral valve prolapse, and cardiomyopathy. Additionally, lack of energy, gingivitis, and overall weakened immunity are symptoms of CoQ10 deficiency.
Many medications directly deplete the body of CoQ10. While antiretrovirals have not been studied for their effect on CoQ10 levels, both antiretrovirals and antibiotics, such as Bactrim and Dapson, deplete the body of the B-vitamin family. Other medications, specifically cholesterol-lowering medications, anti-hypertensive medications like beta-blockers, and some tricyclic antidepressants like amitriptyline (at times used for treatment of neuropathy) all directly deplete the body of CoQ10, and thereby negatively impact the mitochondria. Studies of HIV-positive individuals who are either on antiretroviral medications or are drug naive reveal CoQ10 deficiencies. Supplementation with CoQ10 has shown decreased incidence of opportunistic infections and improved immune parameters, measured by a reduction in symptoms such as night sweats, fever, diarrhea, weight loss, and lymphadenopathy.
Again, no RDA has been established for CoQ10; yet, current recommendations range from 30 to 120 mg per day, depending upon the severity of symptoms and health status. No side effects have been reported for CoQ10.
Riboflavin or B2, is a water-soluble vitamin, that, like other B vitamins, is not stored well in the body so must be ingested daily. Riboflavin belongs to a category of yellow colored pigments called flavins (the reason urine changes color when taking B vitamin supplements). When riboflavin interacts with phosphoric acid it becomes a part of two essential enzymes. These enzymes are necessary for the conversion of carbohydrates to energy in the form of ATP within the mitochondria of the cell. Furthermore, deficiencies in riboflavin will exacerbate CoQ10 deficiencies. For these reasons, riboflavin supplementation has been considered in the treatment of mitochondrial damage. Many medications, such as antiretrovirals, antibiotics, oral contraceptives, and the tricyclic antidepressant noritriptiyline result in direct riboflavin deficiencies. No major studies have demonstrated a direct improvement in mitochondrial health with supplement of riboflavin. However, since multiple cofactors are required in energy production in the mitochondria, studies of riboflavin alone may be misguided.
Typical symptoms of frank riboflavin deficiencies are inflamed mucous membranes, chelosis (cracks in the corners of the mouth), soreness and burning of lips, tongue, and mouth, burning, itching and tearing eyes, eczema of skin and genitals, light sensitivity, dry and itching scalp, nerve damage, depression and hysteria.
RDA for riboflavin is approximately 1.7 mg per day. For pregnant women, nursing mothers and heavy exercises, higher doses are recommended. Several studies have used dosages in the range of 2 to 100 mg per day.
Several other nutrients, which are beneficial to the health of the mitochondria and immune system, need mention here. The first, alpha lipoic acid, is a powerful antioxidant. Alpha lipoic acid is found in highest concentration within the mitochondria, and helps protect against damage to the cell's membranes. In vitro, alpha lipoic acid has been demonstrated to inhibit tumor necrosis factor, NF-kappa B, the on-off switch for activation of HIV, and tat gene activity In Europe, alpha lipoic acid has been used successfully for the treatment diabetic neuropathy, leading to its study in the efficacy of treatment for HIV-related neuropathy either as a result of medication or the virus itself. Because of its ability to cross the blood brain barrier, alpha lipoic acid has been recommended as a potential treatment for cognitive disorders as well. Alpha lipoic acid has been shown to heal liver cells, decrease elevated liver enzymes, and lower high blood glucose. An added benefit of alpha lipoic acid is its ability to recycle vitamin C and vitamin E, and to increase blood levels of glutathione. No RDA exists for alpha lipoic acid, but use ranges between 100 to 1,200 mg per day. However, one study postulated that high doses (above 1,200 mg daily) may result in thrombocytopenia, decrease in platelet counts, but this has not be replicated. Standard practice often recommends 200 mg twice a day.
One of the most significant benefits N-acetyl-cysteine (NAC), the sulfur-containing amino acid, is its reported ability to raise glutathione levels. Glutathione is the primary antioxidant system within the body, thus aiding the body against free radical damage. While the literature is still unclear as to whether or not supplementation with oral glutathione will in fact raise tissue stores of glutathione, the majority of studies do conclude that NAC supplementation will raise glutathione levels. Many medications and substances deplete glutathione, such as acetaminophen, sulphamethoxazole (Bactrim), and alcohol, and protease inhibitors deplete liver stores of glutathione, thus the recommendation that those with HIV infection refrain from using large amounts of acetaminophen. Additionally, NAC supplementation leads to a "relative" increase in CD4 cells and a reduction in HIV-1 replication in stimulated CD4 cells. Dosage suggestions vary considerably with ranges between 1,000 mg to 8,000 mg per day having been studied. Side effects of higher dosages include gastrointestinal distress that can be alleviated by taking NAC with food. Standard protocols suggest between 1,000 mg and 3,000 mg per day in divided doses.
Finally, dietary fat has a major impact on the health of mitochondria. Trans-fatty acids, fat sources from hydrogenated and partially hydrogenated vegetable oils directly affect the membranes through which fats must be shuttled to be used by the mitochondria for energy. The greater the amounts of trans-fatty acids in the diet, the less fluid can easily pass through. As mentioned earlier, the production of ATP involves five multi-subunit complexes. Studies suggest that trans-fatty acids might inhibit ATP production by inhibiting complex V in the process. Therefore, diets high in saturated fats and trans-fatty acids are to be avoided in order to prevent damage to or improve the function of mitochondria. Rather, essential fatty acids such as flaxseed oil and fish oils should be recommended ensure healthy membranes surrounding mitochondria.
Mitochondria are sensitive organelles whose function and health can be easily disrupted. In searching for "treatments" for mitochondrial damage, many researches continually focus on one nutrient or one substance to restore balance. Since the ATP system is complex and requires a large number of nutrients, such a singular search will often fail to yield a significant result. For this reason, a series or group of nutrients needs to be explored. L-carnitine (acetyl-carnitine), CoQ10, and B vitamins would be an excellent starting point for someone suffering with mitochondrial damage. Since all nutrients have multiple benefits, those interested in expanding their protocol should consult about any supplementation program with a qualified healthcare provider well versed in HIV medications as well as diet and nutrition.
Brad S. Lichtenstein, N.D. is licensed naturopathic physician, personal trainer, and yoga and meditation teacher. In private practice, he specializes in HIV care, counseling, and yoga therapy.