MITOCHONDRIAL DYSFUNCTION AND NEURODEGENERATIVE DISEASES, by Zina ...

[Pages:5]MITOCHONDRIAL DYSFUNCTION AND NEURODEGENERATIVE DISEASES, by Zina Kroner, DO

Mitochondria are small structures (called organelles) which are imperative for the health and function of most cells in the body. Frequently referred to as "the power houses of the cell," mitochondria are responsible for generating some 90% of necessary energy. This is important anywhere in the body, but certain cells have to work harder, and any decrease in mitochondrial function impacts these cells and tissues the most. Muscle cells, brain and nerve cells (called neurons), specific cells in the eye, heart muscle cells, liver and digestive organs are some parts of the body that need the most from mitochondria.

Mitochondria make energy in a number of ways; many chemical reactions occur inside them that convert ADP to ATP, which is necessary fuel. The generation of energy via these reactions ultimately produces what are called free radicals. The free radicals, which are similar to those present in pollution, react with natural substances like oxygen to make reactive oxygen species (ROS). These are known to cause cellular damage. If mitochondria produce more free radicals and ROS than they can handle, this is believed to lead to the type of damage seen in many neurodegenerative diseases as well as normal aging.

Even though mitochondria make free radicals and ROS, they are very susceptible to oxidative damage from them. When damaged mitochondria do not function properly, cells do not get enough energy. They can function poorly or even die.

Mitochondrial dysfunction does not only affect the production of ROS and the ability to protect cells from oxidative damage. Poorly functioning mitochondria cannot provide enough energy for cells. They also may be unable to perform other functions including removing areas of cell damage and conducting many other types of chemical reactions. We now know that mitochondria do countless things in addition to supplying energy, and their other functions are also important to keep most cells in the body healthy. When mitochondria are damaged, cells may become unable to replace them with new healthy ones.

The so-called "mitochondrial theory of aging" states that mitochondrial dysfunction and ultimately death (due to ROS) leads to aging of animals and humans. While this theory is simple and elegant, there has been research that argues against one unifying cause. There is evidence that some ROS are necessary. Neither too much nor too little is good for cells. Research is under way trying to determine how ROS can be both beneficial in some circumstances and damaging in others.

One published study explained this well, as follows, "Many lines of evidence suggest that mitochondria have a central role in age-related neurodegenerative diseases. The recent realization that mitochondria are at the intersection of the life and death of a cell, particularly through the involvement of mitochondrial damage in a range of diseases has made mitochondria a promising target for drug discovery and therapeutic interventions." (8)

Mitochondrial diseases

The very rare, inherited diseases that are definitely caused by mitochondrial dysfunction lead to patterns of serious damage and devastating disorders. Some are inherited in a matter called autosomal recessive, meaning that both parents need to pass on a defective gene or genes. Mitochondria, however, are unusual in that they have some of their own DNA found nowhere else in cells. This DNA is passed on only by females. A woman with a mitochondrial DNA abnormality will transmit it to all of her children, but her male children cannot.

Problems observed in patients with mitochondrial diseases have given researchers information about what can happen when mitochondria do not work properly as well as possible targets for treatment. Much of the experimentation has to be done on animals for ethical reasons. Mice and rats have been bred as models of specific human diseases. Some promising and apparently safe drugs have made it to early stages of human trials.

Congenital mitochondrial dysfunction syndromes usually lead to life-threatening abnormalities and severe impairment and/or death at a young age. Here are some examples adapted from the website of the United Mitochondrial Disease Foundation, where much more information is available. This is by no means a comprehensive list.

Beta-oxidation defects (LCAD, LCHAD, MAD, MCAD, SCAD, SCHAD, VLCAD): These involve missing substances or enzymes. Some can be treated with supplements. An example is LCAD which causes encephalopathy, liver dysfunction, cardiomyopathy, and myopathy, also pigmentary retinopathy and peripheral neuropathy. This is an autosomal recessive disease.

Carnitine Deficiency: Symptoms include cardiomyopathy, failure to thrive, and altered consciousness or coma, sometimes hypotonia. Treatment is dietary supplementation with L-Carnitine. This is an autosomal recessive disease.

Co-Enzyme Q10 Deficiency: Symptoms include encephalomyopathy, mental retardation, exercise intolerance, ragged-red (muscle) fibers, and recurrent myoglobin in the urine. Treatment consists of administration of Co-enzyme Q10 or ubiquinol.

Creatine Deficiency Syndromes include GAMT, AGAT, and CRTR. These are caused by inherited abnormalities of creatine metabolism. GAMT and AGAT are thought to be autosomalrecessive traits. CRTR is X-linked. In all of these, there is a severe lack of creatine/phosphocreatine in the brain. Symptoms include mental retardation, speech and language delay, hyperactivity, seizures, autistic-type behavior and abnormal movements. Oral creatine can help GAMT and AGAT especially if started early in live whereas CRTR does not respond as well.

Neurodegenerative diseases and mitochondrial dysfunction

Since the nervous system is so frequently involved in mitochondrial diseases, it makes sense that mitochondrial dysfunction might cause or contribute to the development of degenerative neurologic conditions, including Alzheimer's disease (AD), Parkinson's disease ( PD), amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Huntington's disease (HD). All of these involve the loss of functioning nerves and/or muscles. Research has shown that mitochondrial dysfunction is a part of all of these disorders, although the specific problems vary from illness to illness. Some of these are inherited and others occur sporadically.

Alzheimer's disease is the most common neurodegenerative disease. Parkinson's disease is also common. Mitochondrial defects can cause many symptoms characteristic of both AD and PD. Amyotrophic lateral sclerosis is devastating autosomal-dominant inherited disorder. Huntington's disease which affects both motor nerve cells and muscle cells can be inherited or sporadic.

In known congenital mitochondrial dysfunction syndromes caused by specific deficiencies, replacing needed anti-oxidants or other nutrients does cause improvement. Since mitochondrial dysfunction is suspected or proven to be part of the problem in these neurodegenerative disorders, treatment aimed at reducing free radicals and ROS by giving anti-oxidants could prove helpful, as could anything believed to improve the health and function of mitochondria.

Research on supplements for mitochondrial dysfunction

One reason for the lack of clearly positive results in studies giving supplements to affected individuals is that most antioxidants cannot get into the central nervous system where the damage is taking place. There is something called the blood-brain barrier which is the body's defense system, protecting the brain and the central nervous system from toxins, infections, and other dangers. Various modifications to antioxidants may allow them to get past the barrier, as may taking them with certain carrier molecules.

Some of the more promising compounds include Co-enzyme Q10 which is already used to treat inherited Co-enzyme Q10 deficiency. It has also been useful in mitochondrial dysfunction associated with neurodegenerative disorders and is under active study. It cannot get through the blood-brain barrier easily and researchers are looking for ways to improve its entry into the central nervous system. To date, there has been some success using Co-enzyme Q to treat Parkinson's disease. Some studies have also shown slower deterioration in treated patients with Huntington's disease.

In other research, old rats have been given combinations of acetyl-L-carnitine and lipoic acid. The rats showed decreased evidence of oxidative stress as well as less cognitive impairment, presumably because of improved mitochondrial function.

Lipoic acid is a co-factor, a substance needed for many critical reactions to take place in the mitochondria, and much research has been done showing how this lowers risk of everything from neurodegeneration to cancer.

Carnitine also provides multiple benefits, including improved mitochondrial function. It slows deterioration of memory loss, especially if given early to patients with Alzheimer's disease. This has been demonstrated in both people and animals. It is available in many forms, but acetyl-Lcarnitine is best at crossing the blood-brain barrier.

Current approach to treatment

If the mitochondrial theory of aging is true, the DNA in mitochondria can be damaged by free radicals. With age, the body is less able to make CoQ10. Supplementation with CoQ10 may be able to reverse damage if taken before permanent damage occurs. This supplement may be able to stop mitochondria from aging, and therefore people may live longer and/or suffer from less neurodegenerative diseases. Lipoic acid and acetyl L-carnitine have also showed good results in some studies.

How to get enough CoQ10 to the brain is being researched. Ubiquinol is believed to be better absorbed and delivered. Other helpful supplements include PQQ, which is believed to help the cells make new mitochondria, and a substance called shilajit which works along with CoQ10 to make its antioxidant effect last longer.

Since research continues in all these areas, there will probably be other supplements, vitamins, or possibly even drugs found that can improve mitochondrial function and prevent or slow down neurodegenerative diseases and aging.

Both carnitine and coenzyme Q 10 levels can be easily measured in a routine blood test and repleted accordingly.

References

1. Anderson M. Lipoic Acid Reverses Mitochondrial Decay. Life Extension Magazine. August 2011. Accessed 1/10/2014.

2. Bronwell L. Carnitine Restores Cellular Function. Life Extension Magazine. March 2013. Accessed 1/15/2014.

3. Downey M. Three-Step Strategy to Reverse Mitochondrial Aging. Life Extension Magazine. August 2013. Accessed 1/10/2014.

4. Dumont M., Beal M. F. Neuroprotective strategies involving ROS in Alzheimer's disease Free Radic Biol Med. 2011 September 1; 51(5): 1014?1026.

5. Gaweda-Walerych K., Zekanowski C. Integrated pathways of parkin control over mitochondrial maintenance ? relevance to Parkinson's disease pathogenesis. Acta Neurobiol Exp 2013, 73: 199?224.

6. Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA. 2002 Feb 19;99(4):1870-5.

7. Moreira P.I., Zhu X., Wang X., et al. Mitochondria: A Therapeutic Target in Neurodegeneration. Biophys Acta. 2010 January ; 1802(1): 212?220.

8. NAMDC (North American Mitochondrial Disease Consortium) Accessed 1/10/2014.

9. Peizhong M., P. Reddy P.H. Aging and Amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's Disease: Implications for early intervention and therapeutics. Biochim Biophys Acta. 2011 November ; 1812(11): 1359?1370.

10. Perier C., Vila M. Mitochondrial Biology and Parkinson's Disease. Cold Spring Harb Perspect Med 2012.

11. United Mitochondrial Disease Foundation. Accessed 1/10/2014.

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"Zina Kroner. DO is a board-certified internist who completed her residency at North Shore University Hospital in NY, during which time she served as assistant Chief Resident, and has since opened Advanced Medicine of New York on the upper East side. While in active practice, she authored a peer-reviewed medical article on the association between Alzheimer's disease and insulin, a textbook entitled Vitamins and Minerals and chapter authored an Integrative Medical Approach to Diabetes in the Biography of Diabetes. Dr. Kroner engages in proactive (rather that reactive) medical and nutritional management, encouraging discussion of cause and effect, patient education, and application of up-to-date prevention strategies."

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