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Mitochondrial Dysfunction Overview
Symptoms - Causes - Treatments
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What  you need to know about Mitochondria
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Symptoms
Symptoms include poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction and dementia.
 
Characteristics
The effects of mitochondrial disease can be quite varied. Since the distribution of the defective mitochondrial DNA may vary from organ to organ within the body, and each mutation is modulated by other genome variants, the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.
 
Mitochondrial diseases as a rule are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves, because these cells use more energy than most other cells in the body. Although mitochondrial diseases vary greatly in presentation from person to person, several major clinical categories of these conditions have been defined, based on the most common phenotypic features, symptoms, and signs associated with the particular mutations that tend to cause them.
 
An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences. The research on this website supports this hypothesis.
 
Causes
Mitochondrial disorders may be caused by mutations, acquired or inherited, in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes.
 
Nuclear DNA has two copies per cell (except for sperm and egg cells), one copy being inherited from the father and the other from the mother. Mitochondrial DNA, however, is strictly inherited from the mother and each mitochondrial organelle typically contains multiple mtDNA copies. During cell division the mitochondrial DNA copies segregate randomly between the two new mitochondria, and then those new mitochondria make more copies. If only a few of the mtDNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria. Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression".
 
Mitochondrial DNA mutations occur frequently, due to the lack of the error checking capability that nuclear DNA has (see Mutation rate). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial DNA replication (all of which are encoded for by genes in the nuclear DNA) may also cause mitochondrial DNA mutations.
 
Most mitochondrial function and biogenesis is controlled by nuclear DNA. Human mitochondrial DNA encodes only 13 proteins of the respiratory chain, while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and neuro-developmental disorders.
 
Treatment
Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited. Membrane penetrating antioxidants have the most important role in improving mitochondrial dysfunction.
 
Spindle transfer, where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is a potential treatment procedure that has been successfully carried out on monkeys Using a similar pronuclear transfer technique, researchers at Newcastle University successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. In September 2012 a public consultation was launched in the UK to explore the ethical issues involved. Human genetic engineering is already being used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.
 
Statistics
About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.
 
Many diseases of aging are caused by defects in mitochondrial function. Since the mitochondria are responsible for processing oxygen and converting substances from the foods we eat into energy for essential cellular functions, if there are problems with the mitochondria, it can lead to many defects for adults. These include Type 2 diabetes, Parkinson's disease, atherosclerotic heart disease, stroke, Alzheimer's disease, and cancer.

Many medicines can also injure the mitochondria as noted in the clinical study below.
 
Prescribed Drugs are a major cause of Mitochondrial damage
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Molecular Nutrition & Food Research
Medication-induced mitochondrial damage and disease
John Neustadt,  Steve R. Pieczenik

Published: July 14, 2008
 
Abstract
 
Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis.
 
Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have statin medications, analgesics such as acetaminophen, and many others.
 
While targeted nutrient therapies using antioxidants or their prescursors (e. g., N-acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects.
 
 
 Overview and List of Drugs that damage Mitochondria
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Mechanisms of Action
Anything can be toxic if it inhibits the electron transport chain.  Oxidative-phosphorylation disease is affected by any disruption in the ETC.  What appears to be a necessity , ie, oxygen, can in itself be damaging. There are many ways that free radicals can be formed and these free oxygen radicals can be toxins if not handled appropriately. Free radical damage can cause increased energy needs with a cascading effect of further damage.  The key is to attempt to balance the treatment needs with the side effects of the treatment.
 
The pathobiology of mitochondrial toxicity is not well understood.  Toxicity may be exacerbated by other problems and treatments, so always be watchful and observant of all symptoms. Mitochondrial function needs to be supported, not impeded. The types of toxic agents include: pharmaceutical products (medications), anesthesia, surgery, environmental agents, diet, stress related endogenous agents, and  mitochondrial cofactors. A table of the various agents discussed here will be included as an attachment to this summary.
 
Pharmaceutical products
Establishing mitochondrial toxicity is not an FDA requirement for drug approval, so there is no real way of knowing which agents are truly toxic. Nor is there an absolute contraindication against any particular agent, BUT there are those that we know should be avoided.  Some agents have been shown (either through research studies or anecdotal evidence) to have direct toxicity to the mitochondria. These agents directly inhibit or disrupt the ETC, protein production, DNA transcription, etc. Agents that cause indirect toxicity are those that increase free radicals, decrease the production of endogenous antioxidants, or deplete nutrients that are needed.
 
Anticonvulsants
Specifically, most anticonvulsants are well tolerated except  valproate (Depakote).  This drug can inhibit many mitochondrial functions.  It is known to play important role in carnitine utilization by the mitochondria and has been shown to particularly inhibit complex IV. It can also cause liver dysfunction. This does not mean it should never be used, but caution needs to be taken regarding liver function. If used, plasma carnitine levels need to be monitored and maintained carefully.
 
Psychotropics
Certain psychotrophic drugs have been shown to be potentially toxic.  Certain antidepressants such as Prozac, Elavil, and Cipramil can cause autonomic dysfunction. Other psychotropic drugs such as antipsychotics, barbituates, and antianxiety medications also inhibit various mitochondrial functions.
 
Cholesterol Medications
Cholesterol lowering drugs (especially statins) have been shown to reduce endogenous CoEnzynme Q10 is produced in the same metabolic pathway as  cholesterol, so in this way these drugs can be said to be potentially toxic. Other cholesterol medications such as cholestyramine that bind to bile acids can distrupt the ETC.
 
Analgesics  and Anti-inflammatories
Pain relievers such as acetimenophen (sp?), Indocin,  naproxen, Aspirin and the NSAIDS (non steriodal anti inflammatory drugs), all  increase oxidative stress, and therefore could potentially be toxic. Aspirin is contraindicated for children, but it can be harmful for patients with mitochondrial disease as well because of the potential for Reye Syndrome (acute liverfailure). However, patients should keep in mind that it is important to avoid fevers in Mito patients. Therefore, the benefits of some of these medications as fever-reducers may outweigh their potential side-effects.
 
Antibiotics
Antibiotics, (specifically tetracycline, minocycline, chloramphenical, and aminoglycosides), can be harmful to the mitochondria because they inhibit mtDNA translation and protein synthesis. They can cause hearing loss as well as cardiac and renal toxicity. 
 
Steroids
Steroids may reduce transmembrane mitochondrial potential. However, steroids used in local delivery (such as inhaled steroids that only target lungs or injected steroids that target specific locations) are generally recognized as safe.
 
Other drugs which are used less by the Mito population but have potential toxicity include amiodarone which is used as an anti-arrhythmic (rapid heart rate), antivirals like interferon, antiretrovirals (used for  HIV/AIDS), and cancer drugs.  Metformin, used for diabetes, is also considered toxic to mitochondria.
Beta blockers could have possible toxicity due to increased oxidative stress, and may also contribute to feelings of fatigue.
Diuretics are usually not harmful to the mitochondria themselves, but they may cause fluid imbalances.
 
In all cases of the drugs mentioned here, the objective is to balance the need for use of these drugs with the damage they may cause.
 
Anesthesia 
In mitochondrial disease, there seems to be an increased sensitivity to anesthesia, especially the volatile drugs (ie, those inhaled). For this reason, there should be very close management of any anesthesia used even when IV (for example, propofal).  Often  a decreased dosage is adequate.  The smallest dose over the shortest period of time should be the goal of all anesthesia for mitochondrial disease patients. Patients with mitochondrial diseases should make sure that their anesthesiologist is informed and knowledgeable about their condition so that they use the upmost caution and safety while using anesthetics.
 
Mitochondrial dysfunction implicated in nearly all diseases
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Experimental and Molecular Pathology
Mitochondrial dysfunction and molecular pathways of disease

Steve R. Pieczenik, John Neustadt
Received 30 August 2006
Available online 18 January 2007
 
Abstract

"Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health, disease, and aging. “

If in the next 50 years advances in mitochondrial treatments match the immense increase in knowledge about mitochondrial function that has occurred in the last 50 years, mitochondrial diseases and dysfunction will largely be a medical triumph.”
 
A wide range of seemingly unrelated disorders, such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis have underlying pathophysiological mechanisms in common, namely ROS production, the accumulation of mtDNA damage, resulting in mitochondrial dysfunction.”

 

"Mitochondrial dysfunction has been implicated in nearly all pathologic and toxicologic conditions."

"Antioxidant therapies hold promise for improving mitochondrial performance."
 
 
 

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