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From the September 2nd, 1996 issue of Smart Drug News [v5n3]. Copyright (c) 1996, 1997, 1998. All rights reserved.
Last issue, we summarized the rapidly developing field of what is now being called mitochondrial medicine [Luft, 1995]. We emphasized the critical importance of impaired mitochondrial function in the development of Parkinsons disease, but we only touched upon the potential relevance of mitochondria to fatigue syndromes, lack of stamina, psychological depression, cognitive dysfunction, muscular dystrophies, immune impairment, and senility syndromes.
As the biological techniques for measuring mitochondrial function have become increasingly refined since the 70s, more than a hundred diseases have been identified as having a mitochondrial basis [Luft, 1995]. Although these overt mitochondrial diseases affect only a small percentage of our population, we wonder to what degree subtle subclinical mitochondrial impairment may be involved in more common complaints. Are overt mitochondrial diseases just the tip of the iceberg of a much larger and as-yet-unidentified metabolic deficiency?
To understand the difficulty in noticing mitochondrial impairment, we might ask ourselves how much of a power drop would be necessary for the brown out effect in a lightbulb to be noticeable? If we are sitting quietly reading a book by incadescent light and somebody turns on a powerful appliance like an air conditioner, we often notice a brief dimming effect as the sudden electrical load drains energy from the system. But if this effect took place over minutes, would we notice? Probably not. Our pupils would gradually expand to let in more light as the illumination decreased, and it might get quite low before we noticed.
When I [SWF] walk into my living room, I have a hard time telling whether the three-way lamp is turned on to 50, 100 or 150 watts especially if I am coming inside after being in bright sunlight or evening darkness. Maybe I can tell the difference between 50 and 150 watts, but thats a relatively huge difference in absolute power use.
So the question remains: are subtle cellular energy deficits due to impaired mitochondrial function a common occurrence, or not? Could these deficits be a component of many of the more common diseases? We will begin to explore this issue with a look at basic energy production and how it is regulated.
The vast majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation [see previous issue for detailed explanation of this process]. Oxidative phosphorylation is a highly refined and efficient system for producing the prodigious amounts of energy that are required to maintain the structure and function of the body, and regulate body temperature in warm blooded animals. Oxidative phosphorylation takes place entirely in mitochondria (tiny cellular organelles that closely resemble bacteria in both size and structure).
The overall process is accomplished by two closely linked metabolic processes: the citric acid cycle, which is anaerobic (independent of oxygen), and the electron transport chain, which is aerobic (oxygen dependent) [see Figure 1 in SDN v5n2p2]. The overall consumption of oxygen and the generation of energy is called respiration. The rate of respiration as measured by the production of heat energy is called the basal metabolic rate (BMR). At the neuroendocrine level, BMR is regulated by thyroid hormone.
When thyroid hormone levels increase, thyroid receptors in the cell nucleus increase DNA transcription which increases the synthesis of specific mitochondrial proteins [see Figure 1 at right]. Increased synthesis of these mitochondrial proteins up-regulates mitochondrial energy production [Nelson et al., 1995; Kadenbach et al., 1995]. Decreases in thyroid hormone shut down synthesis of these proteins and down-regulate mitochondrial energy production.
The oxygen dependency of electron transport gives us a way to measure the overall activity of the respiratory system. By measuring the consumption of oxygen and the generation of body heat, we can quantify the basal metabolic rate. This is reliably accomplished by a whole-body calorimeter, a sealed transparent plastic box with thermometers and oxygen sensors built into the air circulatory system. Using whole-body calorimetry, it has been determined that there is an age-associated decrease in basal metabolic rate with increasing age [see Figure 2]. Basal metabolic rate has been proposed as a biomarker of aging [Hershey and Wang, 1980; Shock, 1981].
The symbiotic relationship between mitochondria and the cell is mutually beneficial. The cell provides fuel, nutrition and a protective environment for the mitochondria, and mitochondria provide energy (ATP and reducing power) for the cell. This symbiotic relationship is also one of dependence. Most cells can not survive or maintain their normal function without the energy produced by the mitochondria, and mitochondria cant survive outside of the protective environment of the cell.
In the distant past, the symbiosis between mitochondria and cells may not have been so close. It has been suggested that mitochondria were once independent bacteria-like organisms that were capable of independent existence. Whether they infected the cells they later came to inhabit, or the cells engulfed and absorbed the proto-mitochondria, is unknown. But we can surmise that the initial interdependency was probably mild and that it has grown over time.
One of the ways this interdependency has grown is through a transfer of mitochondrial inheritance. Of the 60-odd proteins now known to be required for the mitochondrial electron transport chain, all but 13 are now coded by nuclear DNA. These mitochondrial proteins are synthesized by the cell, transported into the mitochondria, and then trimmed and assembled into their final forms.
This arrangement not only increases mitochondrial dependence on the cell, but it also increases protection of those genes. Nuclear DNA is far more stable than mitochondrial DNA (mtDNA). Nuclear DNA has better protection from free radicals, it is associated with structural protective proteins called histones, and it has active and robust repair mechanisms. mtDNA is directly exposed to the high free radical flux within the mitochondrion, it has no protective histones, and it has minimal repair mechanisms. As a result of these differences, mtDNA mutates more than ten times more rapidly than nuclear DNA.
The fact that some mitochondrial proteins are produced by the cell and others by the mitochondrion provides a dualistic mechanism for both external (cellular) and internal (mitochondrial) control of mitochondrial function. While the specific mechanisms of mitochondrial regulation are still largely uncharacterized, the pace of research in this area is rapid. There will probably be some major breakthroughs before the end of the century.
Since mitochondrial energy production accounts for the vast majority of total energy production, mitochondrial function is a necessary and essential aspect of the regulation of basal metabolic rate. In other words, either decreased thyroid hormone or mitochondrial dysfunction can lower basal metabolic rate and induce the symptoms of hypothyroidism (cold hands and feet, sensitivity to cold weather, psychological depression, cognitive difficulties, dry skin, scaly scalp, brittle hair, menstrual problems, constipation, diminished stomach HCl production, etc.). Non-thyroid-related mitochondrial insufficiency could easily account for the high incidence of hypothyroid symptoms in individuals with otherwise-normal thyroid hormone levels. Perhaps a significant amount of subclinical hypothyroidism is really mitochondrial insufficiency.
Regardless of what it is called, decreased mitochondrial energy production reduces the capacity of the cell to function. Depending on the cell populations affected, this may decrease body temperature, lower immune function, impair growth, decrease DNA repair, impair hearing, weaken muscles, decrease steroid and neurotransmitter synthesis, and lower nervous system electrical potentials. These are all factors which are associated with both mitochondrial diseases and hypothyroidism.
The balance between energy consumption (calories consumed) and energy expenditure (calories burned) is a significant factor influencing body weight and composition. The adequacy of mitochondrial function is essential to maintaining a high basal metabolic rate and lean body mass.
Mitochondrial energy production depends on carbohydrate and fat fuels. Carbohydrates (i.e., sugars) are the primary fuel because of its quick availability. Fats (i.e., triglycerides) are the secondary (back-up) fuel because of its suitability for storage and its high caloric density. Gram for gram, fat contains more than twice the energy of carbohydrate.
Fat is mobilized when carbohydrate is insufficient to meet the needs of the body. Triglycerides are removed from storage and transported through the blood stream to the cells where they are broken down into fatty acids and glycerol. The fatty acids are then transported into the mitochondria by carnitine, where they are chopped into small pieces by a process called beta-oxidization. These pieces (acetate) are fed into the citric acid cycle to generate ATP, and NADH to fuel the electron transport chain.
The optimization of mitochondrial function to improve energy production may depend on utilizing both carbohydrate- and fat-burning pathways. We know that it does depend on critical nutrients that support mitochondrial function. In the last issue, we described the roles that 1) carnitine (and ALC) plays in fatty acid transport into mitochondria, 2) coenzyme Q plays in the electron transport chain, 3) lipoic acid plays in the citric acid cycle, 4) NADH and FADH2 play in coupling the citric acid cycle to the electron transport chain, and 5) B-complex vitamins play as co-enzymes in many of these processes. But there are also biochemical/nutritional requirements for the production of thyroid hormone that must be considered as well. Deficiencies of these nutrients can directly impair thyroid hormone production and thereby indirectly interfere with mitochondrial function.
The production of thyroid hormone takes place in the thyroid gland. This production involves the iodination of tyrosine, a dietary amino acid. Iodination is an energetically extreme process that seems to involve the use of strong oxidizing conditions and free radical intermediates. This process not only requires iodine, but also selenium.
Whether this special selenium requirement for the thyroid gland is for general antioxidant protection against an otherwise-dangerous reactive chemical species or for an essential co-enzyme for iodination has not yet been determined. But a liver enzyme responsible for deiodination of T4 into T3 has been determined to be a selenoenzyme [Arthur et al., 1991].
The extreme circumstances of the iodination process suggests that it may be fundamentally dependent on the mitochondrial (or microsomal?) activity within the thyroid gland. Factors impairing mitochondrial function at the systemic level may also impair mitochondrial function within the thyroid gland itself. This suggests the possibility of a positive feedback loop which might aggravate hypothyroidism caused by mitochondrial impairment.
For decades, evidence has been accumulating that hydrogen peroxide is necessary for the production of thyroid hormone. It seems highly likely that hydrogen peroxide is required to activate iodine for the iodination of tyrosine. Although antioxidants are clearly necessary to protect thyroid cells from the deleterious effects of the oxidative stress of this process, it is vital that they not interfere with the iodination process itself. At sufficiently high levels, some antioxidants may very well be capable of quenching key iodination free-radical intermediates and might thereby inhibit thyroid hormone production, lower basal metabolic rate, and impair weight loss and/or cause weight gain. We will be discussing this possibility in more detail in a future article.
Arthur JR, Nicol F and Beckett GJ. The roles of selenium in thyroid hormone metabolism. In: Trace Elements in Man and Animals VII, Edited by Berislav Momcilovic. Proceedings of the Seventh International Symposium on Trace Elements in Man and Animals, Institute for Medical Research, University of Zagreb, 1991.
Hershey D and Wang H, A New Age Scale for Humans, Lexington Books, Lexington, 1980.
Kadenbach B, Barth J, Akgun R, Freund R, Linder D and Possekel S. Regulation of mitochondrial energy generation in health and disease. Biochimica et Biophysica Acta 1271: 103-9, 1995.
Luft R. The development of mitochondrial medicine. Biochimica et Biophysica Acta 1271: 1-6, 1995.
Nelson BD, LuciaKova K, Li R, Betina S. The role of thyroid hormone and promoter diversity in the regulation of nuclear encoded mitochondrial proteins. Biochimica et Biophysica Acta 1271: 85-91, 1995.
Shock NW. Indices of Functional Age. In: Aging: A Challenge to Science and Society, Volume 1, Biology, Oxford University Press, New York, 1981.