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Mitochondria are inherited maternally, so if we trace our genetic lineage from child to mother, to maternal grandmother, and so on, Mitochondrial Eve would be the mother of all mothers.
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Free-radicals attack the DNA in each of our cells tens of thousands of times daily. Much of the resulting damage is fixed silently by the extensive repair machinery within the cells, but sometimes these attacks cause irreversible damage—permanent mutations in the DNA sequence. As the onslaught of free-radicals continue day-in and day-out, these mutations build up over a lifetime. Once the damage reaches a threshold, the cell dies, and slowly over time, tissues start to degenerate with each dying cell. This steady degeneration is what’s responsible for both ageing and many diseases.
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One of the most important aspects of the mitochondria over the last couple decades is its role in apoptosis (pronounced “A-po-TOE-sis” with the second “p” in its spelling being silent), which is programmed cell death or suicide. This is when individual cells commit suicide for the greater good of the body as a whole. Previously, apoptosis was thought to be governed by the genes in the nucleus. However, in an eye-opening turn of events starting around the mid-1990s, researchers discovered that apoptosis is actually governed by the mitochondria. The implications to medical field are profound, especially to cancer research. Why? Simply because failing to commit suicide when needed to is a root cause of cancer.
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Chromosomes are not just composed of DNA. They are coated with specialized proteins—among them are the histones, which not only shield the DNA from harm, but also act as gate-keepers to the genes. This is an important distinction to make with bacteria, whose DNA is not protected by histones, and therefore, said to be “naked.”
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In fact, virtually every aspect of a eukaryotic cell’s life—shape shifting, growing large, building a nucleus, hoarding reams of DNA, sex, multicellularity—all require large amounts of energy, and thus depends on the existence of mitochondria.
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In fact, in an interesting calculation outlined by Nick Lane in his book Power, Sex, Suicide, it seems we produce 10,000 times more energy (per gram) than the sun every second!
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Metabolically active cells, such as those in the heart, muscles, and brain, have thousands of mitochondria. The egg cell (oocyte) has a whopping 100,000 mitochondria. In contrast, sperm usually have fewer than 100. Red blood cells and skin cells have very few, if any at all. By weight, up to 10% of the human body is mitochondria. In numbers, there are about ten million billion.
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These rogue electrons then prematurely react with oxygen, resulting in the formation superoxide—a potentially dangerous “free-radical.” Free-radicals are a highly reactive molecules that contribute to “oxidative stress.”
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ETC is the main site for endogenous free-radical production
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Complex I Also known as NADH dehydrogenase, is a large molecule made of forty-six protein subunits. It removes two electrons from NADH and transfers them to a lipid-soluble carrier, ubiquinone (oxidized CoQ10, or simply “Q”). In a two-step process, this “reduces” the CoQ10 to ubiquinol (QH2), and pumps four protons (H+) across the membrane, creating a proton gradient. This is the primary site within the ETC where electrons leak to produce harmful superoxide radicals.
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Complex II This unique complex is also known as succinate dehydrogenase, and is directly involved in both the TCA cycle and ETC. It’s a small complex, consisting of only four protein subunits, and the only complex in the ETC that does not pump protons. Its purpose is to deliver additional electrons from succinate to CoQ10 (via FADH2). Other electron donors (like from fatty acids) also enter the ETC at Complex II via FADH2.
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This is where the Q-cycle occurs, which is a multi-step process whereby ubiquinol (reduced CoQ10) is converted to ubiquinone (oxidized CoQ10). In the process, a net of four protons are pumped to contribute to the proton gradient. This is the second most prevalent site in the ETC where electrons can fall out and react with oxygen to form superoxide free-radicals.
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This fat not only serves as a large store of energy, but when this fat is metabolized through oxidative phosphorylation, water is generated at Complex IV as just described (approximately 1 g—or 1 mL—of water for every 1 g of fat burned). This is partially why camels can go so long without drinking water (along with other adaptations).
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We know the primary cause of mitochondrial damage is the free-radicals generated by the mitochondria themselves. Current evidence suggests that the majority are generated by complexes I and III (Complex I seems to generate free-radicals if there is too much fuel relative to demand, and Complex III seems to generated
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During normal oxidative phosphorylation, 0.4 – 4.0% of all the oxygen consumed is converted in mitochondria to the superoxide radicals. Superoxide is transformed to hydrogen peroxide (H2O2) by superoxide dismutase. H2O2 is then converted to water by glutathione peroxidase (one of the body’s primary antioxidants) or peroxiredoxin III. However, when these enzymes cannot convert superoxide radical to H2O fast enough (or when superoxide generation greatly increases for one reason or another), oxidative damage occurs and accumulates in the mitochondria.
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superoxide has been shown to damage the iron-sulphur cluster that resides in the active site of an enzyme in the TCA cycle (aconitase). This exposes iron, which reacts with H2O2 to produce hydroxyl radicals. Further, nitric oxide (NO) is produced within the mitochondria by mitochondrial NO synthase, and also freely diffuses into the mitochondria from the cytosol. NO reacts with oxygen to produce another free-radical, peroxynitrite. Together, these two radicals as well as others can do great damage to mitochondria and other cellular components. However, all this depends on
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However, what about a well-fed sedentary person? Now the mitochondria have plenty of fuel, but the cells don’t use the ATP that’s been generated. ATP levels remain high with little turnover. With this low demand for ATP, the ETCs become backed up with excessive electrons. Since there is still plenty of oxygen and an abundance of highly-reactive electrons, there is a high rate of free-radical leakage. This burst of free-radicals will exceed the built-in antioxidant defence system, and oxidize the lipids in the mitochondrial membranes. This releases cytochrome c (which normally transfers electrons from Complex III to Complex IV) from the inner mitochondrial membrane and into the inter-membrane space. When this happens, electron flow down the ETC is completely stopped. Now the upstream sections of the ETC are fully and completely brimming with electrons, and these continue to leak and form more free-radicals. Once this stress crosses a threshold, pores in the outer mitochondrial membrane open up and initiate the first steps of cellular suicide.
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A central event in many forms of apoptosis is activation of the mitochondrial apoptosis channel (mAC) by certain stimuli. Opening of the mAC causes the mitochondrial outer-membrane to become highly permeable), and therefore, loses its electrical charge and proton gradient. This leads to a sudden burst in free-radicals that oxidize various lipids of the inner membrane. For example, when cardiolipin becomes oxidized, it can bind Complex IV, which is released from its position in the inner membrane, shutting down the ETC. This free-radical burst also releases cytochrome c (and other molecules) that join with other components in the cytoplasm to form the “apoptosome,” which in turn activate the enzymes of cellular death, the caspases. Remember, cytochrome c is responsible for shuttling electrons from Complex III to Complex IV.
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A number of independent studies have advocated that there is actually a negative correlation between endogenous antioxidant levels and maximum lifespan. Simply put, the higher the antioxidant concentration, the shorter the lifespan. Thankfully, the dietary supplement industry has recognized this and we no longer hear much about antioxidants the way we used to. Even up to a few years ago, ORAC (oxygen-radical absorption capacity)—a measure of a substance’s antioxidant power in a test tube—was flaunted by savvy marketers as the cure for everything. But
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called the “retrograde response” because it’s opposite to the normal chain of command (from the nucleus to the rest of the cell). The overall intention is to correct the metabolic deficiency. Retrograde signalling switches energy generation towards anaerobic respiration (energy production without using mitochondria and oxygen), and this stimulates the genesis of more mitochondria, called mitochondrial biogenesis, which also protects the cell against future metabolic stress. In the long run, this is the only option a cell really has to correct any bioenergetic deficiency.
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Caloric restriction differs because a person may significantly lower the calories they consume, but they ensure that the foods they do consume are nutrient-dense. The result is that very few free-radicals leak due to a lack of electrons. This also helps explain the opposite. Excessive caloric intake introduces an excessive amount of fuel into the body, and ultimately excessive electrons into the mitochondrial ETCs. As there is now an overabundance of electrons, these leak at a very high rate, which may be why obesity (when a person consumes far more calories than what’s expended) is linked to countless degenerative diseases.
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this explains why we don’t see mitochondrial mutations spiralling out of control—defective mitochondria, and the cells that contains them, are constantly eliminated. However, the number of functional cells in any particular organ will decrease, which is known as atrophy.
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Sometimes it is “uncoupled” from energy production and the gradient it is dissipated as heat. This is where the electron flow and proton pumping continue normally, but the protons don’t flow back through the ATPase, and ATP is not produced. Instead, the protons pass back through other pores in the membrane (descriptively called uncoupling proteins, or UCP), where the energy contained in the proton gradient is released as heat.
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and adaptability to cold environments, it protects mitochondria from damage by maintaining electron flow during times of low energy demand.
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In resting mammals, up to 25% of the proton gradient is dissipated as heat. Small mammals like rats, and even human infants, need to supplement their normal heat production with brown fat, which has lots of mitochondria and lots of UCPs. Since basically all the protons leak back through UCPs to generate heat, brown fat is essentially specialized, and dedicated, to heat production.
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all this accumulated fat, fat consumption (mainly seal blubber), and fat-burning to keep warm means polar bears rarely need to drink water—instead they meet their water demand from food and burning the accumulated fat, which ultimately results in water production (at Complex IV, similar to camels). Apparently, if you see a polar bear drinking, it means they are suffering from extreme exhaustion and starvation.
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On the other hand, those of African descent, whose mitochondria have evolved in the blistering heat of the equatorial sun, would not benefit from excessive heat production, and therefore, have relatively small amounts of brown fat. This means their mitochondria are “tight” and more of the proton gradient is used to generate ATP and energy, not heat. Unfortunately, this also means there is a larger amount of free-radical generation; we know African-Americans, for example, have a much higher risk of degenerative diseases than most other populations. This is why exercise and physical activity is critical in individuals whose maternal lineage can be traced back to equatorial cultures—they must ensure they are using up ATP constantly. This also explains why African-Americans can put on weight so much more quickly if they don’t exercise regularly. On the positive side, this tight coupling of the proton gradient to ATP production may also explain why those of African descent are exceptional athletes—per given amount of exertion or fuel, they are able to generate more power and energy (with less waste as heat).
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For example, in healthy hearts, it’s estimated that there is only one-millionth the ATP outside compared to inside a cardiac cell. However, in compromised heart cells, like during a heart attack, the concentration outside the cell can increase tenfold. The body does this to supply adenosine, which is a vasodilator (helps blood vessels relax and expand) that helps to increase blood flow and deliver oxygen to the oxygen-starved cells.
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So while glycolysis is essential, it’s not the preferred pathway of energy production, and glucose is not the ideal source of fuel—fatty acids are. Fatty acids are metabolized in a process called beta-oxidation, and the burning of fatty acids is responsible for 60-70% of the energy our cells create. This is where L-carnitine (discussed in more detail later) enters the picture. The inner mitochondrial membrane is impermeable to long-chain fatty acids, but the fatty acids must enter the mitochondrial matrix where beta-oxidation takes place. L-carnitine is the only molecule that can transport long fatty acids into the matrix, and without L-carnitine, the body’s ability to use long-chain fatty acids to create energy would not exist.
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The net result is that each molecule of glucose forms a total of thirty-eight ATP molecules (two from glycolysis, thirty-six from TCA/ETC), but each molecule of a sixteen-carbon fatty acid called palmitate produces 129 ATP molecules. You can clearly see why fatty acids are the preferred source of fuel.
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Without CoQ10 (a key nutrient that transfers electrons from Complex I & II over to Complex III) and oxygen, we’d only produce two ATP via glycolysis.
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When this happens, ATP concentrations in the cell decrease, while the ADP concentration increase. In an effort to 1) continue to produce ATP, and 2) normalize the ratio of ADP to ATP, the cell combines two ADP molecules to produce one ATP and one AMP (adenosine monophosphate).
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The easy solution is when D-ribose is administered as a supplement. In this situation, the body isn’t responsible for manufacturing its own D-ribose, and so this pathway—no longer limited by availability of D-ribose—can proceed at full-speed.
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but they can leak the purine building blocks of ATP out of the cell. Interestingly, when purine building blocks leak from the cell, it’s metabolized to uric acid, and high uric acid in patients is often reflective of dysfunctional ATP metabolism (an important point to understand for clinicians treating gout).
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All this calcium must be move back out of the cytosol and into the sarcoplasmic reticulum. However, this process requires the use of a pump since the calcium must now move up the concentration gradient—and going against the gradient requires energy. That energy, of course, comes from ATP. The enzyme embedded in the membrane of the sarcoplasmic reticulum called calcium-magnesium-ATPase (Ca-Mg-ATPase), when activated, binds two calcium ions, which are then transferred to the inner part of the sarcoplasmic reticulum and released (sequestered, ready for the next stimulus signalling a contraction).
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After this contraction/systolic phase, comes diastole, or the “relaxation” phase when the ventricles fill up with blood. This generally lasts less than a third of a second, but requires the most ATP.
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Without enough ATP, the calcium ions cannot be pumped out of the heart muscle cells, and the heart can no longer relax and fill up with blood efficiently. This is called diastolic dysfunction. The beginning stages of diastolic dysfunction are characterized by a thickening (hypertrophy, or enlarging of the heart muscle, usually specific to the left ventricle) and stiffening of the ventricular walls.
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A paper published as early as 1992 suggested that the transition from reversible to irreversible ischemia depends on the functional state of mitochondria. More specifically, the ability to restore oxidative phosphorylation determines functional recovery.
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When blood flow—and oxygen—is restored to the affected area, there is greater injury to the mitochondria. This is called ischemia-reperfusion injury (IRI, or simply as reperfusion injury), and it is also frequently seen after cardiac surgery.
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So even after the mitochondria wake up and are running at full-speed, there is an ATP deficiency since the purine nucleotides have been lost. This results in a very high rate of free-radical production, rather than restoration of normal function.
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The brain is relatively under-defended against oxidative free-radical damage.
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Most of the brain’s fatty acid content is contained in the cell membranes, their extensions (such as axons and dendrites), and their mitochondria. As we age, more of these lipids become oxidized from being exposed to the brain’s rich supply of oxygen and free-radicals.
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Subsequent research has confirmed this, as studies have shown that CoQ10 protects against excitotoxicity by raising energy levels in nerve cells.
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new study in the summer of 2013 showed that rapidly moving mitochondria emit bursts of energy, and this may tune neuronal communication.
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This new study showed that these moving mitochondria may control the strength of the signals sent from boutons. The researchers used advanced techniques to watch mitochondria move between boutons while they released neurotransmitters, and found that boutons only sent consistent signals when mitochondria were nearby—when the mitochondria were absent or moving away from boutons, the signal strength fluctuated. These results suggest that the presence of stationary mitochondria at synapses improves the stability and strength of the nerve signals.
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At the core of the plaques is a toxic protein called amyloid-beta—the hallmark of Alzheimer’s—that attacks cells on several fronts. Amyloid-beta generates free-radicals, damages mtDNA, impairs cellular bioenergetics, and alters the proper folding of proteins so that they form neurofibrillary tangles.
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Together with amyloid-beta, another potent free-radical called peroxynitrite (formed from nitric oxide) oxidizes lipids in the membranes of nerve cells. This generates the highly toxic byproduct hydroxynonenal (HNE), which is found in excess quantities in multiple brain regions of Alzheimer’s patients. HNE not only kills brain cells directly, but also indirectly by making them more susceptible to excitotoxicity. As a quick side-note, CoQ10 and vitamin E can protect cell membranes from lipid peroxidation, and CoQ10 has been found to reduce peroxynitrite damage and HNE formation in the bloodstream.
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Mayo Clinic Study on Aging (presented in 2012) suggest that consuming between 2100 to 6000 calories per day may double the risk for mild cognitive impairment (MCI, the precursor to Alzheimer’s) in adults aged seventy years and older (compared to those who consumed less than about 1500 calories daily).
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Newer research in animal models of Parkinson’s disease suggests that CoQ10 can protect brain cells from neurotoxicity and excitotoxicity, even in cases where other powerful antioxidants cannot.
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Research shows the substantia nigra is the part of the brain that has the greatest number of mutations in mtDNA, and human evidence reveals that the mitochondria of patients with Parkinson’s disease exhibit several deficiencies. One of the most well-characterized is diminished Complex I activity. In rat studies, Complex I inhibition has been observed to directly follow the administration of dopa or dopamine in a dose-dependent manner. Other rat studies, have shown a dose-dependent increase in hydroxyl free-radicals in the mitochondria when administered dopa. As previously discussed, superoxide radicals are generated when electrons leak and react with oxygen. Deficits in Complex I increase leakage of electrons and, in turn, increase superoxide production (Complex I being the primary site for superoxide radicals, as discussed earlier, and ultimately diminishes ATP production). As superoxide is neutralized, hydrogen peroxide is generated in the interim. As hydrogen peroxide is broken down, hydroxyl radicals can be produced instead of water. This is consistent with the observation that hydroxyl radical production is increased when Complex I is inhibited. The question is, why are hydroxyl radicals formed instead of water? The answer relates to iron in its reduced form (Fe2+), which catalyzes the breakdown of hydrogen peroxide into hydroxyl radicals. For this reason, the association between tissue iron stores and Parkinson’s disease (incidence and progression) should receive more attention.
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Now that the evidence is showing that L-dopa may actually aggravate some of the underlying causes of Parkinson’s disease, it may be time to reconsider the costs and benefits of L-dopa therapy. In fact, it’s well known that L-dopa therapy eventually loses its effect and the symptoms return with vigour. Is short-term relief of symptoms worth accelerating the progression and increasing the severity of the disease?
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and has been found to be significantly depleted in the lateral part of the substantia nigra regions of Parkinson’s patients. Interestingly, reductions in KGDHC levels have been noted in the cortex of Alzheimer’s patients as well.
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In a later study on mice, oral supplementation with CoQ10 attenuated chemically-induced neurotoxicity (which had been shown to cause a Parkinsonian syndrome in test animals). After
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According to one bioenergetic theory, the genesis of the behavioural symptoms in ADHD is directly linked to impairments in the astrocyte-neuron lactate shuttle. This shuttle is based on the astrocyte’s uptake of glucose from the blood, its storage as glycogen, and conversion to lactate.
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However, in ADHD, this lactate production by astrocytes is not sufficient to supply rapidly-firing neurons with energy during brief periods of increased demand.
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Glutamate stimulates glycolysis (glucose utilization and lactate production) in astrocytes. However,
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However, due to the impaired ability to maintain electrochemical gradient in ADHD, removal of glutamate from the extracellular fluid is hampered. Failure to maintain low levels of extracellular glutamate not only impairs glutamate’s neurotransmitter function, but also affects neuroplasticity, learning, and memory. Cell death can also result from this over-excitation (which means the mitochondria are pushed to their limit in energy production, and subsequently results in excessive free-radical damage, and the chain of events that lead to apoptosis). Similar to any other organ affected by mitochondrial dysfunction, where cell death eventually results in the atrophy of the affected organ, ADHD patients are known to have reduced grey matter in their brain.
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Switching to an anaerobic state is exactly what many CFS sufferers do.
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First, lactic acid (the product of anaerobic metabolism) quickly builds up—especially in the muscles—to cause pain, heaviness, aching and soreness (“lactic acid burn”).
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Second, using glucose in this way means very little, if any, is available to make D-ribose. This means new ATP cannot be made easily when you are really run down. Recovery takes days!
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While the glucose-to-lactic acid reaction produces two molecules of ATP for the body to use quickly, the reverse process requires the use of six ATP molecules (this takes place in the liver, in a process called the Cori cycle).
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Interestingly, the enzyme which does this (cyclic AMP) is activated/up-regulated by caffeine. So for those CFS sufferers who enjoy coffee as much as I do, a cup of organic coffee with a teaspoon of D-ribose would seem like a great therapy!
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CFS, the drop may be from 5 L/min lying down to 3.5 L/min standing. At this level the CHS sufferer has a cardiac output that causes borderline organ (heart) failure. Further, the level of impairment in cardiac output correlates very closely to the level of disability in CFS patients.
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When blood supply to the skin is reduced, it has two main effects. Since the skin is responsible for controlling body temperature, the first effect is that CFS patients become intolerant of heat. When our body gets too hot, the core body heat is
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Since the skin, via sweat, is also a major way our bodies remove toxins, the second problem is related to the build-up of toxins.
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Research has shown hyperglycemia induces mitochondrial superoxide production in the endothelial cells (the cells that line the blood vessels), which is an important mediator of diabetic complications such as cardiovascular disease. Endothelial superoxide production also contributes to atherosclerosis, hypertension, heart failure, ageing, and sepsis.
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These glycated proteins can also bind to mitochondria and compromise their function.
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the skeletal muscles of type 2 diabetics have shown a reduced capacity of the ETC, and the mitochondria are smaller than normal.
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Mitochondrial damage also appears to be a major cause of lipid accumulation in the cells. PPARG coactivator 1 (PGC1) is a key factor located in mitochondria matrix for lipid oxidation, and the expression of PGC1 is reduced in type 2 diabetes patients. These accumulated lipids then turn into cytotoxic compounds, damaging the mitochondria, and this is what leads to insulin resistance.
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Defects in the capacity to metabolize fatty acids in skeletal muscles is a common characteristic of type 2 diabetes. Under normal physiological conditions, lipids are metabolized through beta-oxidation in mitochondria. However, with mitochondrial damage, lipids cannot be metabolized normally, and this results in accumulation of fatty acids.
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Here, the positive feedback loop rears its ugly head again. Lipid accumulation is a cause of lipotoxicity and leads to mitochondrial dysfunction through oxidative damage. On the other hand, mitochondrial damage promotes the accumulation of lipids, which cannot be metabolized, and promotes further lipid accumulation.
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Essentially, UCP3 acts as an overflow valve, so that an excessive proton gradient doesn’t slow down the ETC, as we discussed earlier. However, research shows dysfunctional UCP3 leads to free-radical damage in cells, which is associated with insulin resistance and type 2 diabetes. This is an active area of diabetes research.
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Typically presenting at middle age, mitochondrial diabetes is an mtDNA defect, so this form of diabetes is maternally transmitted, and interestingly, often associated with hearing loss (particularly for high tones).
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testing for mitochondrial toxicity is still not required by the US FDA, Health Canada or any other regulatory body responsible for drug approval. Medications can damage the mitochondria both directly and indirectly (Table 1).
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Other drugs can sequester CoA (aspirin, valproic acid), inhibit biosynthesis of CoQ10 (statins), deplete the antioxidant defences (acetaminophen), inhibit mitochondrial beta-oxidation enzymes (tetracyclines, several anti-inflammatory drugs), or inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (amiodarone).
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These include antidepressants, antipsychotics, dementia medications, seizure medications, mood stabilizers such as lithium, and Parkinson’s disease medications.
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it is metabolized to a toxic intermediate that is subsequently neutralized by glutathione before finally being excreted in the urine. Therefore, the earliest effect of acetaminophen poisoning is a depletion of the liver’s glutathione, the accumulation of free-radicals, and decreased mitochondrial function. Since glutathione depletion is a mechanism by which acetaminophen causes death of liver cells, it is not surprising that the antidote for acetaminophen poisoning is N-acetyl-cysteine (the precursor to glutathione), which increases glutathione.
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Table 1: Medications documented to induce mitochondrial damage Drug Class Drugs Alcoholism medications disulfiram (Antabuse) Analgesic (for pain) and anti-inflammatory Aspirin, acetaminophen (Tylenol), diclofenac (Voltaren, Voltarol, Diclon, Dicloflex Difen, Cataflam), fenoprofen (Nalfon), indomethacin (Indocin, Indocid, Indochron E-Rm Indocin-SR), Naproxen (Aleve, Naprosyn) Anesthetics bupivacaine, lidocaine, propofol Angina medications perhexiline, amiodarone (Cordarone), Diethylaminoethoxyhexesterol (DEAEH) Antiarrhythmic amiodarone (Cordarone) Antibiotics tetracycline, antimycin A Antidepressants amitriptyline (Lentizol), amoxapine (Asendis), citalopram (Cipramil), fluoxetine (Prozac, Symbyax, Sarafem, Fontex, Foxetin, Ladose, Fluctin, Prodep, Fludac, Oxetin, Seronil, Lovan) Antipsychotics chlorpromazine, fluphenazine, haloperidol, risperidone, quetiapine, clozapine, olanzapine Anxiety medications alprazolam (Xanax), diazepam (valium, diastat) Barbiturates Amobarbital (Amytal), aprobarbital, butabarbital, butalbital (Fiorinal), hexobarbital (Sombulex), methylphenobarbital (Mebaral), pentobarbital (Nembutal), phenobarbital (Luminal), primidone, propofol, secobarbital (Seconal), Talbutal), thiobarbital Cholesterol medications Statins: atorvastatin (Lipitor, Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pitavastatin (Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor), simvastatin (Zocor, Lipex) Bile acids: cholestyramine (Questran), clofibrate (Atromid-S), ciprofibrate (Modali), colestipol (Colestid), colesevelam (Welchol) Cancer (chemotherapy) medications Mitomycin C, profiromycin, adriamycin (also called doxorubicin and hydroxydaunorubicin and included in the following chemotherapeutic regimens – ABVD, CHOP, and FAC) Dementia Tacrine (Cognex),Galantamine (Reminyl) Diabetes medications Metformin (Fortamet, Glucophage, Glucophage XR, Riomet), troglitazone, rosiglitazone, buformin HIV/AIDS medications Atripla, Combivir, Emtriva, Epivir (abacavir sulfate), Epzico, Hivid (ddC, zalcitabine), Retrovir (AZT, ZDV, zidovudine), Trizivir, Truvada, Videx (ddI, didanosine), Videx EC, Viread, Zerit (d4T, stavudine), Ziagen, Racivir Epilepsy/Seizure medications Valproic acid (Depacon, Depakene, Depakene syrup, Depakote, depakote ER, depakote sprinkle, divalproex sodium) Mood stabilizers Lithium Parkinson’s disease medications Tolcapone (Tasmar, Entacapone (COMTan, also in the combination drug Stalevo)
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A recent study of dilated cardiomyopathy found that about one in four patients (25%) had mtDNA mutations in the heart tissue.
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number of other studies have also confirmed the value of CoQ10 in mitochondrial disease. Typically, it’s prescribed in combination with other nutrients, in what’s often called the “Mitochondrial Cocktail,” and a doctor may recommend some or all of these supplements: creatine monohydrate, vitamin C, vitamin E, alpha-lipoic-acid, thiamine (vitamin B1), riboflavin (B2), niacin (B3), L-carnitine, and/or L-arginine. Others include D-ribose, PQQ, magnesium, and medium-chain fatty acids.
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understanding of how these nutrients function in relation to mitochondria indirectly confirms the organelle’s involvement in age-related hearing loss. Along with improved hearing in the supplemented rats, they found a much lower level of mitochondrial damage all throughout the body. The supplements actually reduced the amount of free-radical damage everywhere, creating an anti-ageing effect that not only improved hearing, but carried over to other cells throughout the body. A new study
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Emerging research now suggests that impaired mitochondrial energy production plays an important role in ageing of the skin. For example, in ageing adults, fibroblast cells demonstrate dramatic mitochondrial dysfunction. Fibroblasts are cells essential to youthful, healthy skin and produce collagen and elastin.
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With mitochondrial dysfunction, fibroblasts are less capable of producing the energy required to carry out their essential skin-related functions of manufacturing collagen and elastin. Scientists believe that this energy deficit in fibroblast cells contributes to the visible signs of skin ageing. This may be why so many beauty/anti-ageing creams and concoctions now contain CoQ10,
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Within minutes after fertilization, if and when sperm-derived mitochondria enter the oocyte, a localized reaction is triggered around the sperm’s mitochondria where the, “autophagosomes” engulf the paternal mitochondria, resulting in their degradation (called autophagy). This will ensure only maternal inheritance of mtDNA. However, in a situation where autophagy is impaired, paternal mitochondria and their genome remain even in the first larval stage.
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Now, getting back to fertilization, after the sperm fertilizes the oocyte, the resulting “zygote” goes through tremendous growth through cell division. As mentioned, this requires incredible amounts of energy. However, while the cells divide, the mitochondria do not. Instead, the initial number of mitochondria (100,000) gets partitioned with each division, so that a couple weeks after conception, each cell now only has about 200 mitochondria. Again, this is by design. Whereas defective mitochondria could be overlooked in a sea of healthy mitochondria, when their numbers are reduced to about 200 per cell, each mitochondrion must pull their own weight. Defective ones can no longer coast alongside their harder-working comrades. When exposed, these dysfunctional mitochondria will be eliminated. Probably not a big deal if this results in only one cell dying, but when enough mitochondria are defective in enough cells, the pregnancy is terminated. From this point, after all the defective mitochondria and cells have been eliminated (and if that hasn’t resulted in a miscarriage) the number of mitochondria per cell can multiply in normal fashion as the embryo grows.
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One of the things that happen is our body start to produce less and less CoQ10. Remember, CoQ10 is the compound that shuttles electrons from Complex I (or II) to Complex III in the ETC. As we produce less of this essential compound, we produce less and less cellular energy, starting the chain of events that will ultimately lead to our demise. However, before
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CoQ10 deficiency—either alone, or in combination with mtDNA mutations or a mismatch between mtDNA and nDNA—is thought to be responsible for a significant percentage of age-related infertility cases in women. Animal studies have shown promising results, and based on this, infertile women undergoing various fertility treatments are now being recommended CoQ10 supplementation—even in the absence of human studies. As I write this book, however, I’m aware of at least one human clinical trial underway in Toronto, Canada.
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Collectively, the scientific data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis. Further, the retina requires proportionally more energy (per cell) than any other tissue in the body and also where the density and number of mitochondria per cell is among the highest found in the body. This has real implications for AMD.
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Mitochondrial-associated free-radical damage affects the eyes’ drainage system, whose tissue integrity is essential to maintaining normal pressure and fluid flow out of the eye. Encouraging news reveals that several of glaucoma’s underlying causative factors may be prevented and even reversed through natural interventions, offering new hope to the millions at risk for this widespread, debilitating condition. The picture is even more encouraging with studies suggesting a common link between glaucoma and Alzheimer’s disease. Why? Because Alzheimer’s disease has known deficits in mitochondrial function (as discussed), and targeting bioenergetics in this cognitive disorder as shown unbelievable improvements in symptoms and disease progression. So if we can do that for Alzheimer’s disease, we should be able to do the same with glaucoma.
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Interestingly, researchers have discovered that stem cell populations do not necessarily decline with advancing age, but instead lose their restorative potential.
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In apoptosis, the chain of events is perfectly coordinated, and leaves no evidence that the cell ever existed. However, there is a price to pay for such a coordinated series of events. All steps along way require ATP—if the supply of ATP fails to meet the cell’s demand, the cell cannot commit apoptosis, and the defective cell is now given a chance to run wild.
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Salicylic acid (or its derivatives, like Aspirin) is a mitochondrial uncoupler, and this is likely the reason it’s been shown to reduce the risk of a number of degenerative diseases, and even cancer.
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A thought-provoking study published in June of 2014 demonstrated that metformin consistently benefited African-Americans more than their Caucasian counterparts. Based on our earlier discussion regarding “tight” mitochondria in those with equatorial origins, it’s predictable this uncoupler would have benefited these individuals to a significantly greater extent.
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Caloric restriction is currently the only proven method to extend lifespan in numerous mammals.
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without adequate supply of nutrients like L-carnitine to transport fatty acids into the mitochondria (and also remove toxic metabolites), cellular energy production will be inefficient—which
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Mitochondrial Component Nutrients Required TCA cycle Thiamin (B1) Riboflavin (B2) Niacin (B3) Pantothenic acid (B5) Iron Sulphur Magnesium Manganese Cysteine Alpha-lipoic acid Heme (required for elements in the TCA cycle and ETC) Zinc Riboflavin (B2) Pyridoxine (B6) Iron Copper Synthesis of L-carnitine Vitamin C (or take L-carnitine itself) Pyruvate dehydrogenase Thiamin (B1) Riboflavin (B2) Niacin (B3) Pantothenic acid (B5) Alpha-lipoic acid Electron transport chain Riboflavin (B2) Iron Sulphur Copper Coenzyme Q10
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D-ribose, a simple 5-carbon sugar, was the primary intermediate in an important metabolic pathway called the pentose phosphate pathway.
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Why? Let’s think back to the process here. Remember that if ATP cannot be generated fast enough, two ADPs will combine to produce ATP and AMP. This AMP will be broken down and eliminated from the cell, reducing the purine pool. It takes a significant time for the purine pool to recover naturally, but instead of resting and allowing the heart to recover, the athlete goes out the next day (or even later that same day) and does more exercise, which further depletes the purine pool.
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Due, in part, to reduced oxygen levels and resulting loss of mitochondria (no need for mitochondria if there is no oxygen), the heart shifts energy metabolism to the less efficient pathway of glycolysis. Not only does this result in lactic acid build-up, but with reduced energy efficiency, there is a progressive loss in contractility. The heart tries to compensate by enlarging its size, and this in turn worsens the ejection fraction and diastolic function, which in turn further deprives the heart of oxygenated blood. It’s a vicious cycle that will continue to get worse unless nutritional intervention takes place.
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Research has revealed that in fibromyalgia patients, the lining of the capillaries (the tiny blood vessels that supply blood and oxygen to the muscles) become thickened. When this happens, oxygen cannot cross the blood-tissue barrier, and without enough oxygen to adequately supply the tissues, localized ischemia develops and drains the energy pool in the affected muscles. Without oxygen, again, the cells shift energy production from oxidative phosphorylation to anaerobic glycolysis. This results in lactic acid production and build-up, which aggravates symptoms of severe pain, muscle stiffness, soreness, and overwhelming fatigue. Also, since muscle relaxation takes just as much, if not more energy than muscle contraction, the cell sustains a contraction and keeps the muscle tense.
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Many fibromyalgia patients who use D-ribose to support cellular bioenergetics report that are able to become involved in the normal activities of daily life again.
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When administered, a whopping 97% (approximately) is absorbed into the blood, and eventually moves into tissues without any difficulty. Once in the cells, D-ribose is used by the body to synthesize and salvage the energy pool, produce RNA and DNA, and use it to manufacture other critical molecules used by the cell. Of all the naturally-occurring sugars found in nature, D-ribose is the only sugar that functions in these essential metabolic processes.
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Without supplemental D-ribose, the heart is forced to create it from glucose (again, through the pentose phosphate pathway). However, the problem is that under ischemic conditions when oxygen is in short supply, the mitochondria cannot produce ATP through oxidative phosphorylation, and the cell must rely more heavily on anaerobic metabolism or glycolysis, which uses glucose. Glycolysis is great because it’s fast, but needs a constant supply of glucose to ensure quick energy turnover. The downside of this is that the cell does not want to sacrifice or donate any glucose to the pentose phosphate pathway to produce D-ribose,
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Any amount of D-ribose given to energy depleted cells will help. Doses as low as 500 mg could be beneficial, but likely not nearly enough to make a real improvement in health. Standard dosages range from 3 to 5 g/day.
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For healthy people and athletes, a dose taken before exercise helps the cell with the process of purine salvage as they are broken down. A dose after exercise helps speed the de novo process to aid recovery.
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It is safe even at large doses, and many clinical trials have studied amounts ranging from 10 to 15 g daily, with one study on McArdles’s disease using 60 g/day!
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That is why PQQ (pyrroloquinoline quinone) is so exciting. Early in 2010, researchers found it not only protected mitochondria from oxidative damage, it also stimulated the growth of new mitochondria!
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Further, varying PQQ levels in diets causes modulation in mitochondrial content, alters lipid metabolism, and reverses the negative effects of Complex I inhibitors.
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PQQ is capable of catalyzing continuous redox cycling (the ability to catalyze repeated oxidation and reduction reactions),
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PGC-1alpha is a transcriptional co-activator that regulates genes involved in energy metabolism. An interaction with this protein and its resulting association with multiple transcription factors can provide a direct link between an external physiological stimulus (like PQQ) and the regulation of mitochondrial biogenesis. Indeed, such interactions have recently been reported. PGC-1alpha is also a major factor that regulates muscle fibre type and appears to be involved in controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity. Moreover, PGC-1alpha is associated with a reduction in reactive oxygen species and protection against various mitochondrial toxins. In addition to interacting with PGC-1alpha, PQQ can also reduce cancer risk by mechanisms separate from mitochondrial biogenesis. For example, PQQ has been shown to affect the activity of ras (a gene that can potentially cause cancer).
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PQQ also has another beneficial effect on mitochondria. It appears that PQQ may be an essential cofactor in one of the many protein subunits that make up Complex I of the ETC. With the bulk of endogenous free-radicals being produced at Complex I, you can see why having an abundance of PQQ is important to mitochondrial health.
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PQQ may also have anti-inflammatory effects, be an effective neuroprotectant
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double-blind, randomized, placebo-controlled human clinical trial found that 20 mg of oral PQQ daily improved short-term memory, attention/concentration, information identification, and processing ability in healthy adults. Effects were greatly enhanced with the addition of CoQ10 supplementation.
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Coenzyme Q10 (CoQ10) is an antioxidant, a membrane stabilizer, and a vital cofactor in the mitochondrial ETC (shuttling electrons from Complexes I/II over to Complex III). While many may have already known that, most don’t know the other functions of this compound. It regulates gene expression and apoptosis; it’s an essential cofactor of uncoupling proteins and permeability transition pores; and has anti-inflammatory, redox modulatory, and neuroprotective effects.
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Research has shown that oil-based formulations (typically softgels) are much better absorbed, and water-dispersible liposomal or pre-emulsified formulations are even better. Ubiquinol (reduced CoQ10) seems to offer much better absorption than ubiquinone (oxidized CoQ10), and here again, water-dispersible (solubilized) ubiquinol is even better absorbed than the standard fat-soluble ubiquinol.
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this way, CoQ10 can even take free-radicals and put them (or more specifically, their electrons) to good use as it can bring those rogue electrons back into the ETC for energy production. But even more important is that this antioxidant activity will help prevent the associated damage typically caused by free-radicals, by protecting mtDNA, membranes, and other peptides, enzymes, etc.
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Long-lived mammalian species show a greater proportion of mitochondrial membrane-associated CoQ10 than short-lived species.
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without oxygen to be the final acceptor of electrons at Complex IV, the ETC backs up and starts to spill free-radicals, aggravating that vicious cycle you’re probably sick of hearing about by now.
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Second, it can prevent the oxidation of LDL (bad cholesterol), which, when oxidized, can lead to plaque build-up and hardening of the blood vessels (called atherosclerosis). As long as LDL is not oxidized, it’s actually not a bad thing (contrary to what many people think based on conventional medicine).
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Without enough energy, these muscles remain more tense than they should, increasing blood pressure. By supplying CoQ10 and improving the energy efficiency of the mitochondria, muscles have the ATP they need to relax, thereby normalizing blood pressure. I specifically say “normalize” as opposed to “lower” blood pressure, because clinical trials have shown that CoQ10 can lower high blood pressure, but will not lower normal (or low) blood pressures. Again, if you understand the biochemistry and physiology behind this effect, it’s clear that CoQ10 “normalizes” blood pressure.
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This same enzyme, however, is involved in making CoQ10 (and also vitamin D, all the sex hormones, etc.); many of the adverse side-effects associated with these drugs (like muscle pain and muscle damage) are theorized
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Beta-blockers are a group of drugs, typically prescribed for hypertension and arrhythmias, that have been shown to deplete CoQ10 levels—meaning CoQ10 supplementation is recommended
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Since the chemical structure of CoQ10 and vitamin K are very similar (they’re both “quinones”), there is the potential for CoQ10 to decrease the effectiveness of warfarin. Just note that CoQ10 will not have a negative impact on other classes of blood thinners—just warfarin—and will not “thicken” blood (knowledge of the biochemistry of clotting is required to understand this, but beyond the scope of this book). On the other hand, CoQ10 can have anti-platelet action, similar to another class of blood thinners called “antiplatelet agents.” It seems that CoQ10 can reduce the “stickiness” of platelets, and can help prevent clots from forming.
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It’s also important to remember that CoQ10 is an important antioxidant that prevents oxidation of LDL cholesterol (predominantly as ubiquinol when found in the blood). If CoQ10 is one of the primary antioxidants that keep LDL from oxidation, and statins deplete CoQ10 levels, again, you can see the paradox in prescribing this class of drugs.
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Should you choose to supplement with this critical nutrient, the ideal dose for cardiovascular benefits would be one that raises blood levels above a minimum of 2.5 mcg/mL, but ideally over 3.5 mcg/mL.
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individualized) is to work in typical dosage ranges. For example, cardiovascular conditions are typically dosed between 200 to 600 mg/day. Doses for neurological conditions range from 600 to 3000 mg/day (no, that’s not a typo, and even this high dose was perfectly safe). However, large daily doses should be divided up into multiple smaller doses throughout the day, and unless taking a solubilized formulation, should be taken with food.
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ubiquinol seems to be the ideal form supplementally. However, ubiquinol is a very unstable molecule and can easily oxidize, converting back to ubiquinone, and losing its benefits. That’s why choosing a stable product is the single-most critical factor when choosing ubiquinol supplements.
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The mitochondria’s preferred source of fuel is fatty acids. In fact, fatty acids are so dense in energy, that approximately 60-70% of the total amount of ATP our bodies produce originate from fatty acids. The mitochondrial metabolism of cytosolic
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Another important role for carnitine is clearing lactic acid build-up. Lactic acid, or lactate, is a by-product of anaerobic metabolism, which is the pathway of ATP production when there isn’t enough oxygen for oxidative phosphorylation, or when energy production needs to proceed superfast.
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In a study where one group was given L-carnitine, the rise in lactic acid in response to exercise was significantly lower than those in the control group. It also helps speed recovery by helping to restore the ratio of lactate to pyruvate (meaning less burning during exercise, and less pain afterwards).
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One reason most are deficient in this mineral is that water softeners, while great for making your faucets shiny, has reduced its hardness by removing minerals like magnesium.
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Further, high intake of calcium can reduce the absorption of dietary magnesium, and with the focus on calcium intake for bone health, we’ve seen a corresponding decrease in magnesium levels. Then there’s our rising caffeine intake, which increases the amount of magnesium we lose through urine, and rising use of antacids and proton pump inhibitors—drugs that can reduce the absorption of magnesium. This all contributes to the alarming statistic that 70-80% of the population is deficient in magnesium.
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magnesium is a critical cofactor in over 300 biochemical reactions in the body, including the production of ATP.
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For muscles to relax, they not only require ATP (which magnesium plays a role), but the enzymes involved in this relaxation process also require magnesium as a cofactor. Without magnesium, calcium cannot be removed from the muscle cell and the muscle remains in a contracted state. This is why magnesium has been labeled as “Nature’s calcium channel blocker” (calcium channel blockers are a class of drugs commonly used to treat hypertension).
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a magnesium deficiency means that they remain more tense than they should, called vasoconstriction.
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Similarly, a deficiency of magnesium doesn’t allow the heart to fully relax between contractions, and we discussed this diastolic dysfunction previously.
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Further, it has an important role in the production of glutathione, one of the “primary” antioxidants produced directly by the body. Where ALA surpasses other conventional antioxidants is that it is targeted to the mitochondria. Most other antioxidants can’t effectively concentrate at the level of the mitochondrion and so almost meaningless in their ability to support the most important generator of free-radicals.
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Another benefit of ALA is its ability to modulate the state of the energy carrier nicotinamide adenine dinucleotide (NAD). For example, when exposed to high levels of glucose, cells are not able to properly “discharge” NADH (the electron-carrying form) to NAD+ (its free form). The resulting imbalance of NAD+ to NADH creates an undesirable situation in the cell. First, the cell is denied access to the free NAD+ (it needs this for a number of essential functions, including the proper uptake and utilization of glucose and protein for fuel). Second, the excess NADH leads to free-radical damage through two distinct mechanisms. Excess NADH causes a breakdown of the cell’s iron stores, accelerating the production of free-radicals.
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However, even more concerning is that excess NADH, in the absence of sufficient numbers of electron transport chains, causes the mitochondria to become backed-up with excessive electrons. Remember, NADH enters the ETC at Complex I, and this is the primary location the excess electrons are fumbled, where they react with oxygen and generate superoxide radicals. ALA resolves this metabolic mess by helping to restore the balance of the two forms of NAD.
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As it turns out, the availability of NAD+ is critical to the anti-ageing effects of sirtuins (while excessive NADH inhibits them). Knowing that ALA can boost the cellular levels of free NAD+ while lowering NADH, it may facilitate sirtuins’ anti-ageing activity, providing a second pathway whereby ALA could influence the ageing process. Further, some exciting animal research has shown that supplementing the diet with ALA—especially when combined with acetyl-L-carnitine—can have profound anti-ageing benefits by restoring youthful activity levels, cognitive performance, and heart function.
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The body can only use one form, what we call the R(+) form. Many commercial ALA products are synthetic, and contain the inactive S(-) isomer in equal parts to the biologically active R(+) isomer. This means you’re only getting 50% biological activity from the product. Also, ALA is not stable at room temperature
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Since creatine is stored in the body as creatine phosphate, it can donate a phosphate molecule to ADP to regenerate ATP. This is a very speedy process that is the main source of cellular energy production at the start of high-intensity anaerobic activity (such as a 100-metre sprint or lifting heavy weights). A large pool of creatine phosphate means this fast pathway of ATP regeneration can be sustained longer. This is exactly why creatine has been so beneficial for athletes.
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A significant body of research has shown that administering supplemental creatine (usually as creatine monohydrate) can increase the total body pool of creatine phosphate. Although this leads to positive outcomes for energy generation and performance during explosive, anaerobic forms of exercise, the benefits of creatine in longer duration activities and sports (such as long-distance running, rowing, and swimming) are questionable at this time.
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TPP functions in carbohydrate metabolism to help convert pyruvate to acetyl-CoA for entry to the TCA cycle and subsequent steps to generate ATP. Because of this role, thiamin also functions in maintaining the nervous system, memory, and heart muscle health. A deficiency of thiamine causes a condition known as beriberi,
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The major role of FAD in the mitochondria is its role in shuttling energy (electrons) from the TCA cycle and beta-oxidation to Complex II of the ETC. Since
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a precursor to NAD, vitamin B3 is logically the single greatest nutrient for NAD biology. As the rate-limiting co-substrate for the sirtuin enzymes, NAD modulation is emerging as a valuable tool in regulating sirtuin function and, consequently, oxidative metabolism and protection against metabolic diseases. Recently, more biologically efficient forms of B3 have emerged. For example, nicotinamide riboside (NR) currently appears as the most efficient precursor to NAD and NADH. NR is found naturally in trace amounts in milk and other foods, and is a more potent version of niacin or niacinamide because it enters the biochemical pathway after the rate-limiting step in NAD synthesis.
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Therefore, as a precursor to CoA, vitamin B5 plays a critical role allowing energy production to occur through aerobic metabolism in the mitochondria, and not just anaerobic energy production in the cytosol.
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The two metabolically active forms are methylcobalamin and adenosylcobalamin (this latter form being the predominant form found in the mitochondria).
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B12 plays an important role in supplying essential methyl groups for protein and DNA synthesis, and has numerous functions. However, for the mitochondria, B12 is involved in several important metabolic processes, including, the generation of S-adenosyl methionine (SAMe), which is important for cell function and survival. In turn, SAMe has a number of functions itself, but also supports the formation of creatine, the precursor of creatine phosphate as discussed earlier. It’s also a part of various protein subunits that make up the complexes in the ETC.
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Heme, which is the major functional form of iron, is synthesized by the mitochondria.
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it’s also an essential component of various proteins within the complexes of the ETC
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Studies have shown that when heme metabolism is disrupted, the result is mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing. Biosynthesis of heme requires vitamins B2, B5, B6, biotin, alpha-lipoic acid, and the minerals zinc, iron, and copper.
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These are essential for the production of succinyl-CoA (the precursor for heme) by the TCA cycle. Therefore, the mitochondrial pool of succinyl-CoA may limit heme biosynthesis when nutrient deficiencies exist, especially iron.
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Scientists have also discovered another closely related compound called pterostilbene (pronounced “terro-STILL-been”), and this is likely the “next resveratrol” that will be highly sought after at your local health food store. Pterostilbene is mainly found in blueberries, but also grapes and the bark of the Indian Kino tree (used for centuries in Ayurvedic medicine—traditional medicine in India).
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Resveratrol and pterostilbene are closely related and classified as “stilbene” compounds. Due to the similarity in chemical structure, they have similar functions, but not identical. What’s interesting, however, is that that these two compounds work in a synergistic fashion. Pterostilbene produces its beneficial effects on gene expression in ways that enhance those produced by resveratrol.
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One of the major benefits of resveratrol and pterostilbene include the ability to mimic many of the beneficial effects of calorie restriction (discussed next in detail) by favourably regulating genes involved in the development of cancer, atherosclerosis, diabetes, and the system-wide inflammation that underlies a variety of age-related disorders. Research has found that resveratrol activates genes near the start of the molecular cascade precipitated by caloric restriction, while pterostilbene directly activates genes downstream from that of resveratrol’s action. This synergistic and complementary action helps prevent cancer and diabetes, supports healthy blood lipids, and produces longevity-promoting effects across the cycle of gene expression.
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Since fatty acids are so dense in energy, and with the heart being one of the most energy-intensive organs, under normal physiologic conditions, it preferentially uses fatty acids as its fuel source. However, under ketotic conditions, the heart can effectively utilize ketone bodies for energy.
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After three days of low blood glucose, the brain gets 25% of its energy from ketone bodies. After about four days, this jumps to 70%!
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Since ketones are efficiently used by brain mitochondria for ATP generation and may also help protect vulnerable neurons from free-radical damage, ketogenic diets are being evaluated for their ability to benefit patients with Parkinson’s and Alzheimer’s diseases, and various other neurodegenerative disorders (with some cases reporting remarkable success).
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Regarding life extension, even smaller levels of caloric restriction (only 10 – 20% of unrestricted calorie intake) produces longer-lived animals and disease-prevention effects.
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it would indicate that calorie-restriction may extend lifespan by up to 60%, making a human lifespan of 130-150 years a real possibility without fancy technology or supplements/medications. The
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Second, simply restricting the intake of fat, protein, and/or carbohydrates without overall calorie reduction does not increase the maximum lifespan of rodents.
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Third, calorie restriction has shown to be effective in disease prevention and longevity in diverse species.
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Fourth, these calorie-restricted animals stay “biologically younger” longer.
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Fifth, caloric restriction does not need to be started in early age to reap its benefits. Initiating this in middle-aged animals also slowed
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New studies are showing that beta-hydroxybutyric acid can block a class of enzymes, called histone deacetylases, which would otherwise promote free-radical damage.
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that therapeutic massage can increase the biomarkers of mitochondrial biogenesis.
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It’s been shown that white adipose tissue (WAT) can undergo a process known as “browning” where it takes on characteristics of BAT. This happens with physiological or biochemical stimulation (such as chronic cold exposure, hormonal stimuli, or pharmacological treatment). These
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Methods on how to achieve this include repeated and/or chronic exposure to cold temperatures (such as being out in the cold more during winter months, turning down the thermostat in your home in the winter, or a number of other methods, such as traditionally done in hydrotherapy). A great study published in the summer of 2014 found that sleeping with the set at 19 ºC (vs. 24 ºC) induced BAT in an adult population, and consequently improved insulin sensitivity and glucose metabolism. That’s an easy way to save on your winter heating bills and simultaneously do something great for your health! Going from hot sauna to cold shower repeatedly could increase BAT over time.
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Similarly, just finishing your shower with a cold rinse could do the same. However,
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This is further compounded if inadequate time is given for recovery (and some scenarios specific to loss of the energy pool was discussed in the D-Ribose section). The beneficial effects of regular, non-exhaustive physical activity have been known for a long time.
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Not only does exercise increase the energy demand, which results in mitochondrial fission and biogenesis (through signalling from the relative abundance of AMP vs. ATP, and various other mechanisms like increased expression of PGC-1 alpha and PPAR-gamma), but the free-radicals that are produced send a signal to the cell indicating it needs to produce more complexes for the ETC. As we discussed near the beginning of this book, sometimes free-radicals play a key role in cell signalling.
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After repeated bouts of moderate intensity exercise, the number of mitochondria per cell has increased, and each mitochondrion now has a higher number of ETC.
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This means, at rest, those who are physically fit and active produce far less free-radicals in the mitochondria than sedentary individuals. During physical activity, physically fit and active people will also produce more energy (translated as improved physical performance) while producing much less free-radicals. It’s a real-life cellular example of needing to take a step back (oxidation) to take two steps forward (improved mitochondrial function and capacity).
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This means at rest, they have a vast amount of spare capacity, and because of this, they product far, far less free-radicals during the majority of their lifetime.
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The other benefit is that all this physical activity also uses up the ATP. If we don’t use up the ATP, we end up with a backlog of energy, and the elections in ETC will overflow and create free-radicals. However, unlike the situation where free-radicals are produced in the presence of abundant ATP (that’s not used)—which has no benefit in stimulating mitochondrial biogenesis—free-radicals produced in combination with insufficient ATP does trigger mitochondrial biogenesis.
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It’s been known for decades now that aerobic exercise can increase the number of mitochondria in your muscle cells by up to 50% in as little as six weeks.
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aerobic exercise can modify the gene responsible for producing brain-derived neurotrophic factor (BDNF).
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My two favourite supplements for mitochondrial health would be a combination of CoQ10 and PQQ as the pillars of therapy. Adding alpha-lipoic acid, a good B-complex (providing the vitamins in their most metabolically active forms), and magnesium would be next on the list. I’d then round out any therapy on an individual basis by adding D-ribose, L-carnitine (I prefer acetyl-L-carnitine), and perhaps creatine.
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For example, a really interesting botanical I’m looking into now, Gynostemma pentaphylum, seems to have powerful benefits to mitochondria by activating AMPK. It’s been shown to enhance mitochondrial biogenesis, reduce body fat and blood sugar, and modulate inflammation.
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