496 lines
33 KiB
HTML
496 lines
33 KiB
HTML
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<head><title></title></head>
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<body>
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<h1></h1>
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<p></p>
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<p><strong>Mitonchondria and mortality:</strong></p>
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<p>Diet, exercise, and medicine, damaging or repairing respiratory metabolism</p>
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<p><strong><em>MAIN IDEAS AND CONTEXTS</em></strong></p>
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<strong><em>Lactic acid and carbon dioxide</em></strong>
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<em> have opposing effects.</em>
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<p>
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<strong><em>Intense exercise damages cells</em></strong>
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<em>
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in ways that cumulatively impair metabolism. There is clear evidence that glycolysis, producing lactic
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acid from glucose, has toxic effects, suppressing respiration and killing cells. Within five
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minutes, exercise lowers the activity of enzymes that oxidize glucose. Diabetes, Alzheimer's disease,
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and general aging involve increased lactic acid production and
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accumulated metabolic (mitochondrial) damage.</em>
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</p>
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<p>
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<strong><em>The products of glycolysis,</em></strong>
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<em> lactic acid and pyruvic acid, suppress oxidation of glucose.</em>
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</p>
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<p>
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<em> </em>
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<strong><em>Adaptation</em></strong>
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<em>
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to hypoxia or increased carbon dioxide limits the formation of lactic acid. Muscles are 50% more
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efficient in the adapted state; glucose, which forms more carbon dioxide than fat does when oxidized,,
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is metabolized more efficiently than fats, requiring less oxygen.</em>
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</p>
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<p>
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<strong><em>Lactic acidosis,</em></strong>
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<em>
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by suppressing oxidation of glucose, increases oxidation of fats, further suppressing glucose
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oxidation. </em>
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</p>
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<p>
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<strong><em>Estrogen</em></strong>
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<em> is harmful to mitochondria,</em>
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<strong><em> progesterone</em></strong>
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<em> is beneficial.</em>
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</p>
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<p>
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<strong><em>Progesterone's brain-protective</em></strong>
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<em> and restorative effects involve mitochondrial actions.</em>
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</p>
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<p>
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<strong><em>Thyroid hormone, palmitic acid, and light </em></strong>
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<em>activate a crucial respiratory enzyme, suppressing the formation of lactic acid. Palmitic acid occurs in
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coconut oit, and is formed naturally in animal tissues. Unsaturated oils have the opposite effect.</em>
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</p>
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<p>
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<strong><em>Heart failure, shock,</em></strong>
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<em>
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and other problems involving excess lactic acid can be treated "successfully" by poisoning glycolysis
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with dichloroacetic acid, reducing the production of lactic acid, increasing the oxidation of glucose,
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and increasing cellular ATP concentration. Thyroid, vitamin B1, biotin, etc., do the same.</em>
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</p>
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<p><strong><em>SOME DEFINITIONS</em></strong></p>
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<p>
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<strong><em>Glycolysis:</em></strong>
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<em>
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The conversion of glucose to lactic acid, providing some usable energy, but many times less than
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oxidation provides.</em>
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</p>
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<p>
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<strong><em>Lactic acid,</em></strong>
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<em>
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produced by splitting glucose to pyruvic acid followed by its reduction, is associated with calcium
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uptake and nitric oxide production, depletes energy, contributing to cell death. </em>
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</p>
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<p>
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<strong><em>Crabtree effect:</em></strong>
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<em>
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Inhibition of cellular respiration by an excess of glucose; excess of glucose promotes calcium uptake by
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cells.</em>
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</p>
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<p>
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<strong><em>Pasteur effect:</em></strong>
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<em> Inhibition of glycolysis (fermentation) by oxygen.</em>
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</p>
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<p>
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<strong><em>Randle effect:</em></strong>
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<em>
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The inhibition of the oxidation of glucose by an excess of fatty acids. This lowers metabolic
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efficiency. Estrogen promotes this effect.</em>
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</p>
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<p>
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<em> </em>
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<strong><em>Lactated Ringer's solution:</em></strong>
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<em>
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A salt solution that has\ been used to increase blood volume in treating shock; the lactate was
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apparently chosen as a buffer in place of bicarbonate, as a matter of convenience rather than
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physiology. This solution is toxic, partly because it contains the form of lactate produced by bacteria,
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but our own lactate, at higher concentrations, produces the same sorts of toxic effect, damaging
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mitochondria,</em>
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</p>
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<p>
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<strong><em>Estrogenic phytotoxins</em></strong>
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<em> damage mitochondria, kill brain cells; tofu is associated with dementia.</em>
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</p>
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<p><em><hr /></em></p>
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<p>
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Since reading Warburg's publications in the late 1960s and early 70s, and doing my own research on tissue
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respiration, I have been convinced that Warbug was on the right track in seeing mitochondrial respiration as
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the controlling influence in cell differentiation, and in seeing cancer as a reversion to a primitive form
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of life based on a "respiratory defect." Harry Rubin's studies of cells in culture have expanded Warburg's
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picture of the process of cancerization, showing that genetic changes occur only after the cells have been
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transformed into cancer.
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</p>
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<p>
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It is now well recognized that defective mitochondrial respiration is a central factor in diseases of
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muscles, brain, liver, kidneys, and other organs. The common view has been that the mitochondrial defects
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are produced by genetic defects, that are either inherited or acquired, and are irreversible.
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</p>
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<p>
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Mitochondria depend on some genes in the nuclear chromosomes, but they also contain some genes, and
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mutations in these specific mitochondrial genes have been associated with various diseases, and with aging.
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Although these aren't the genes that the cancer establishment has focussed on as "the cause" of cancer, for
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people interested in the achievements of Warburg and Rubin, it is important to know whether mutations in
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these mitochondrial genes are the <em>cause</em> of respiratory defects, or whether a respiratory defect
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causes the mutations. Recent research seems to show that physiological problems precede and cause the
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mutations.
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</p>
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<p>
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Warburg believed that mitochondria supported specialized cell functions by concentrating themselves in the
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places where energy is needed. This idea has some interesting implications. For example, when the amount of
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thyroid hormone is increased, or when the organism adapts to a high altitude, the number of mitochondria
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increases. But in energy deficient states such as diabetes, they don't. How are these crucial organelles
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called into existence by the hormone that increases respiration and energy, and also by the hypoxic
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conditions of high altitudes? In both of these conditions, the availability of oxygen is limiting the
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ability to produce energy. In both conditions, carbon dioxide concentration in tissue is higher, in
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one case, because thyroid stimulates its production, in the other, because
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the Haldane effect limits its loss from the lungs.
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</p>
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<p>
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Could carbon dioxide, a major product of mitochondria, help to call mitochondria into existence? My answer
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to this is "yes," and it will help to briefly explain how I see mitochondria. Although I have no hesitancy
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in accepting that organelles can be exchanged between species, and that it is conceivable that mitochondria
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might have been derived from symbiotic bacteria, I am reluctant to believe that something happens just
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because it <em>could</em> happen. For example, Francis Crick proposed that life on earth originated
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when genes arrived here on space dust from some other world. That's a theoretical possibility, but what's
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the point? It just avoids explaining how the highly organized material came into existence somewhere
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else, and it probably seriously interfered with the consideration of the ways life could arise here.
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Similarly, some people like to think that mitochondria and chloroplasts were originally bacteria, that came
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into symbiosis with another kind of living material, consisting of nucleus and cytoplasm. Like Crick's
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"space germs," it can be argued that it's possible, but the problem is that this explanation can stop people
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from thinking freshly about the nature of the various organelles, and how they came to exist. (How did cells
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originate? How did mitochondria originate? "Germs.")
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</p>
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<p>
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Since I have a view of how cells came to exist, under conditions that exist on earth, I should consider
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whether that view doesn't also reasonably account for their various components. Sidney Fox's proteinoid
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microspheres provide a good model for the spontaneous formation of primitive cells; variations of that idea
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can account for the formation of organelles (such as mitochondria and nuclei within cells, and chromosomes
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within nuclei). The value of this idea, of a self-stimulating process in mitochondrial generation, is that
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it suggests many ways to test the idea experimentally, and it suggests explanations for developmental and
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pathological processes that otherwise would have no coherent explanation.
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</p>
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<p>
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Proteinoid microspheres and coacervates form by acquiring molecules from solution, condensing them into a
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separate phase, with its own physical properties. At every phase boundary, there are numerous physical
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forces, especially electronic properties, that make each kind of interface different from other kinds.
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Small changes of pH, temperature, of salts and other solutes can alter the interfacial forces,
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causing particles to dissolve, or grow, or fragment, or to move. In the way that carbon dioxide alters the
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shapes and electrical affinities of hemoglobin and other proteins, I propose that it increases the stability
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of the mitochondrial coacervate, causing it to "recruit" additional proteins from its external environment,
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as well as from its own synthetic machinery, to enlarge both its structure and its functions.
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</p>
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<p>
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In the relative absence of carbon dioxide, or excess of alternative solutes and adsorbents, such as lactic
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acid, the stability of the mitochondrial phase would be decreased, and the mitochondria would be degraded in
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both structure and function. As the back side of the idea that carbon dioxide stabilizes and activates
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mitochondria, the idea that lactic acid is involved in the degrading of mitochondria can also be tested
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experimentally, and it is already supported by a considerable amount of circumstantial evidence.
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</p>
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<p>
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This combination of sensitivity to the environment, with a kind of positive feedback or inertia either
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upward or downward, corresponds to what we actually see in mitochondrial physiology and pathology.
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</p>
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<p>
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The Crabtree effect, which is the suppression of respiration by glycolysis, is often described as the simple
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opposite of the Pasteur effect, in which respiration limits glycolysis to the rate that allows its product
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to be consumed oxidatively. But the Pasteur effect is a normal sort of control system; when the Pasteur
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effect fails, as in cancer, there is glycolysis which is relatively independent of respiration, causing
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sugar to be consumed inefficiently. Embryonic tissues sometimes behave in this manner, leading to the
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suggestion that glycolysis is closely related to growth. Unlike the logical Pasteur effect, the
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Crabtree effect tends to lower cellular energy and adaptability. Looking at many situations in which
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increasing the glucose supply increases lactic acid production and suppresses respiration, leading to
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maladaptive decrease in cellular energy, I have begun thinking of lactic acid as a toxin. The use of
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Ringer's lactate solution in medicine has led many people to assume that lactate must be beneficial, or they
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wouldn't put it in the salt solution that is often used in emergiencies; however, I think its use here, as a
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buffer, is simply a convenience, because of the instability of some bicarbonate solutions.
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</p>
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<p>
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On the organismic level, it is clear that lactic acid is "the essence of hyperventilation," and that it
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produces edema and malfunction on a grand scale: The panic reaction, shock lung, vascular leakiness, brain
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swelling, and finally multiple organ failure, all can be traced to an excess of lactic acid, and the related
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features of hyperventilated physiology.
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</p>
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<p>
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Otto Warburg apparently thought of lactate as simply a sign of the respiratory defect that characterizes
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cancer. V. S. Shapot at least hinted at its possible role in turning on the catabolic reactions leading to
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cancer cachexia (wasting). I think a good case can be made for lactate as the <em>cause</em> of the
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respiratory defect in cancer, just as it is usually the immediate cause of the respiratory derangement of
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hyperventilation on the organismic level.
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</p>
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<p>
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The Crabtree effect is usually thought of as just something that happens in tumors, and some tissues that
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are very active glycolytically, and some bacteria, when they are given large amounts of glucose. But when we
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consider lactate, which is produced by normal tissues when they are deprived of oxygen or are disturbed by a
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stress reaction, the Crabtree effect becomes a very general thing. The "respiratory defect" that we can see
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on the organismic level during hyperventilation, is very similar to the "systemic Crabtree effect" that
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happens during stress, in which respiration is shut down while glycolysis is activated. Since oxidative
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metabolism is many times more efficient for producing energy than glycolysis is, it is maladaptive to shut
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it down during stress.
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</p>
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<p>
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Since the presence of lactate is so commonly considered to be a normal and adaptive response to stress, the
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shut-down of respiration in the presence of lactate is generally considered to be caused by something else,
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with lactate being seen as an effect rather than a cause. Nitric oxide and calcium excess have been
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identified as the main endogenous antirespiratory factors in stress, though free unsaturated fatty acids are
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clearly involved, too. However, glycolysis, and the products of glycolysis, lactate and pyruvate,
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have been found to have a causal role in the suppression of respiration; it is both a cause and a
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consequence of the respiratory shutdown, though nitric oxide, calcium, and fatty acids are closely involved,
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</p>
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<p>
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Since lactic acid is produced by the breakdown of glucose, a high level of lactate in the blood means that a
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large amount of sugar is being consumed; in response, the body mobilizes free fatty acids as an additional
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source of energy. An increase of free fatty acids suppresses the oxidation of glucose. (This is called the
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Randle effect, glucose-fatty acid cycle, substrate-competition cycle, etc.) Women, with higher estrogen and
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growth hormone, usually have more free fatty acids than men, and during exercise oxidize a higher proportion
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of fatty acids than men do. This fatty acid exposure "decreases glucose tolerance," and undoubtedly
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explains women's higher incidence of diabetes. While most fatty acids inhibit the
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oxidation of glucose without immediately inhibiting glycolysis, palmitic acid is unusual, in its inhibition
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of glycolysis and lactate production without inhibitng oxidation. I assume that this largely has to do with
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its important function in cardiolipin and cytochrome oxidase.
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</p>
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<p>
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Exercise, like aging, obesity, and diabetes, increases the levels of circulating free fatty acids and
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lactate. But ordinary activity of an integral sort, activates the systems in an organized way, increasing
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carbon dioxide and circulation and efficiency. Different types of exercise have been identified as
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destructive or reparative to the mitochondria; "concentric" muscular work is said to be restorative to the
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mitochondria. As I understand it, this means contraction with a load, and relaxation without a load. The
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heart's contraction follows this principle, and this could explain the observation that heart mitochondria
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don't change in the course of ordinary aging.
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</p>
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<p>
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When a person has an accident, or surgery, and goes into shock, the degree of lactic acidema is recognized
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as an indicator of the severity of the problem. Lactated Ringer's solution has been commonly used to
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treat these people, to restore their blood pressure. But when prompt treatment with lactated Ringer's
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solution has been compared with no early treatment at all, the patients who are not "rescuscitated" do
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better than those who got the early treatment. And when Ringer's lactate has been compared with various
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other solutions, synthetic starch solutions, synthetic hemoglobin polymer solution, or simply a concentrated
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solution of sodium chloride, those who received the lactate solution did least well. For example, of 8
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animals treated with another solution, 8 survived, while among 8 treated with Ringer's lactate, 6 died.
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</p>
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<p>
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Mitochondrial metabolism is now being seen as the basic problem in aging and several degenerative diseases.
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The tendency has been to see random genetic deterioration as the driving force behind mitochondrial
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aging. Genetic repair in mitochondria was assumed not to occur. However, recently two kinds of genetic
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repair have been demonstrated. One in which the DNA strand is repaired, and another, in which sound
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mitochondria are "recruited" to replace the defective, mutated, "old" mitochondria.
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</p>
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<p>
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In ordinary nuclear chromosomal genes, DNA repair is well known. The other kind of repair, in which
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unmutated cells replace the. genetically damaged cells, has been commonly observed in the skin of the face:
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During intense sun exposure, mutant cells accumulate; but after a period in which the skin hasn't been
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exposed to the damaging radiation, the skin is made up of healthy "young" cells.
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</p>
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<p>
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In the way that the skin can be seen to recover from genetic damage, that had been considered to be
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permanent and cumulative, simply by avoiding the damaging factor, mitochondrial aging is coming to be seen
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as both avoidable and repairable.
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</p>
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<p>
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The stressful conditions that physiologically harm mitochondria are now being seen as the probable cause for
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the mitochondrial genetic defects that accumulate with aging. Stressful exercise, which has been
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known to cause breakage of the nuclear chromosomes, is now seen to damage mitochondrial genes, too.
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Providing energy, while reducing stress, seems to be all it takes to reverse the accumulated mitochondrial
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genetic damage.
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</p>
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<p>
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Fewer mitochondrial problems will be considered to be inherited, as we develop an integral view of the ways
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in which mitochondrial physiology is disrupted. Palmitic acid, which is a major component of the cardiolipin
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which regulates the main respiratory enzyme, becomes displaced by polyunsaturated fats as aging progresses.
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Copper tends to be lost from this same enzyme system, and the state of the water is altered as the energetic
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processes change.
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</p>
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<p>
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While the flow of carbon dioxide moves from the mitochondrion to the cytoplasm and beyond, tending to remove
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calcium from the mitochondrion and cell, the flow of lactate and other organic ions into the mitochondrion
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can produce calcium accumulation in the mitochondrion, during conditions in which carbon dioxide
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synthesis, and consequently urea synthesis, are depressed, and other synthetic processes are
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changed.
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</p>
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<p>
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Glycolysis produces both pyruvate and lactate, and excessive pyruvate produces almost the same inhibitory
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effect as lactate; since the Crabtree effect involves nitric oxide and fatty acids as well as calcium, I
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think it is reasonable to look for the simplest sort of explanation, instead of trying to experimentally
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trace all the possible interactions of these substances; a simple physical competition between the products
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of glycolysis and carbon dioxide, for the binding sites, such as lysine, that would amount to a phase change
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in the mitochondrion. Glucose, and apparently glycolysis, are required for the production of nitric
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oxide, as for the accumulation of calcium, at least in some types of cell, and these coordinated changes,
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which lower energy production, could be produced by a reduction in carbon dioxide, in a physical
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change even more basic than the energy level represented by ATP. The use of Krebs cycle substances in the
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synthesis of amino acids, and other products, would decrease the formation of C02, creating a situation in
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which the system would have two possible states, one, the glycolytic stress state, and the other, the carbon
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dioxide producing energy-efficient state.
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</p>
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<p>
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Besides the frequently discussed interactions of excessively accumulated iron with the unsaturated fatty
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acids, producing lipid peroxides and other toxins, the accumulated calcium very probably forms some
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insoluble soaps with the free fatty acids which are released even from intracellular fats during stress.
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The growth of new mitochondria probably occasionally leaves behind such useless materials,
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combining soaps, iron, and porphyrins remaining from damaged respiratory enzymes.
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</p>
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<p>
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When the background of carbon dioxide is high, circulation and oxygenation tend to prevent the anaerobic
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glycolysis that produces toxic lactic acid, so that a given level of activity will be harmful or helpful,
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depending on the level of carbon dioxide being produced at rest.
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</p>
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<p>
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Preventively, avoiding foods containing lactic acid, such as yogurt and sauerkraut, would be helpful, since
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bacterial lactic acid is much more toxic than the type that we form under stress. Avoiding the
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stress-promoting antithyroid unsaturated oils is extremely important. Their role in diabetes, cancer, and
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other age-related and degenerative diseases (and I think this includes the estrogen-promoted autoimmune
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diseases) is well established. Avoiding phytoestrogens and other things that increase estrogen exposure,
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such as protein deficiency, is important, because estrogen causes increased levels of free fatty acids,
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increases the tendency to metabolize them at the expense of glucose metabolism, increases the tissue content
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of unsaturated fatty acids, and inhibits thyroid functions.
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</p>
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<p>
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Light promotes glucose oxidation, and is known to activate the key respiratory enzyme. Winter sickness
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(including lethargy and weight gain), and night stress, have to be included within the idea of the
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"respiratory defect," shifting to the antirespiratory production of lactic acid, and damaging the
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mitochondria.
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</p>
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<p>
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Therapeutically, even powerful toxins that block the glycolytic enzymes can improve functions in a variety
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of organic disturbances "associated with" (caused by) excessive production of lactic acid. Unfortunately,
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the toxin that has become standard treatment for lactic acidosis—dichloroacetic acid—is a carcinogen, and
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eventually produces liver damage and acidosis. But several nontoxic therapies can do the same things:<strong
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>
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Palmitate (formed from sugar under the influence of thyroid hormone, and found in coconut oil), vitamin
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Bl, biotin, lipoic acid, carbon dioxide, thyroid, naloxone, acetazolamide, for example.</strong>
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Progesterone, by blocking estrogen's disruptive effects on the mitochondria, ranks along with thyroid and a
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diet free of polyunsaturate fats, for importance in mitochondrial maintenance.
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</p>
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<p> </p>
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<p> </p>
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<p><strong><h3>REFERENCES</h3></strong></p>
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<p>
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Biochim Biophys Acta 1999 Feb 9;1410(2):171-82 <strong>Mitochondrial involvement
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in Alzheimer's
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</strong>disease.Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.
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</p>
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<p>
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Rev Pneumol Clin 1986;42(5):238-41.<strong>
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Acid-base balance and blood lactate and pyruvate levels in albino rats bred under normobaric hypoxia or
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normoxia, after muscular work in a hypoxic or hypoxic-hypercapnic environment.
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</strong>Quatrini U, Licciardi A.
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</p>
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<p>
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Muscle Nerve 1999 Feb;22(2):258-61.<strong>
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Acute exercise causes mitochondrial DNA deletion in rat skeletal muscle.</strong> Sakai Y, Iwamura Y,
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Hayashi J, Yamamoto N, Ohkoshi N, Nagata H.
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</p>
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<p>
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HumMol Genet 1999 Jun;8(6): 1047-52.<strong> Gene shifting:</strong>
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<strong>a novel therapy for mitochondrial myopathy.</strong> Taivassalo T, Fu K<em>,</em> Johns T, Arnold D,
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Karpati G, Shoubridge EA.
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</p>
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<p>
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Brain Dev 1989;11(3):195-7.<strong> Effect of sodium dichloroacetate on human pyruvate metabolism.</strong>
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