Chapter Two: The Dark Side of the Force: Health Conditions Linked to Mitochondrial Dysfunction

A Review of Bioenergetics

ATP is composed of adenine (a purine base), D-ribose (a pentose, or five-carbon sugar), and three phosphate groups. Energy is released to the cell when an enzyme removes a phosphate from ATP and converts the chemical energy stored in the bond into mechanical energy. After the phosphate is removed, what remains is ADP. Through the use of the ATPase in the inner mitochondrial membrane, the phosphate is reattached to ADP to re-form ATP.

A MI occurs when an artery that supplies fuel and oxygen to the heart muscle cells becomes blocked. The heart muscle continues to use energy at its regular pace, but it has no oxygen.

While it’s not possible to determine accurately if ATP pools are compartmentalized or if they flow around freely, scientific evidence strongly suggests that there are localized areas of higher concentrations to perform specific tasks (such as contraction in heart muscles or movement of ions across membranes). However, no matter where ATP is found, once the ATP releases its energy and is converted to ADP, it must be recycled back to ATP, where it once again leaves the mitochondria to where it’s needed.

• A small amount of ADP remains in the cytosol, where it is converted to ATP (instead of entering the mitochondria for recycling). This ATP is generally associated with cellular membranes and provides the energy needed to control the movement of ions across membranes.

ATP formed within the mitochondria must be moved back to the cytosol of the cell so that its energy can be used. At the same time, ADP from the cytosol must be moved back into the mitochondria to be recycled back to ATP. However, the mitochondrial membrane is impermeable to both ATP and ADP, so these compounds are “traded” across the mitochondrial membrane through the use of another enzyme called ATP-ADP translocase. This enzyme keeps ATP flowing out of the mitochondria to where its energy can be put to good use, and keeps ADP flowing into the mitochondria.

Food and Oxygen: The Ingredients for Producing Energy

Glycolysis takes place in the cytosol portion of the cell. Because much of this process occurs near the cell membrane, scientists believe this pathway is used primarily to generate ATP for the movement of ions across the cell membrane. And while glycolysis is capable of producing large amounts of ATP quickly, it cannot supply nearly enough energy to keep the cell functioning for long periods of time. Only two molecules of ATP are produced if we start the process directly from readily available glucose. If we start from the stored glycogen, three molecules of ATP are created.

During normal carbohydrate metabolism, the six-carbon glucose is converted to two three-carbon molecules called pyruvate. Pyruvate can then enter the mitochondria and participate in the second pathway of energy production: the TCA, or Krebs, cycle.

As long as the cell is supplied with sufficient oxygen, pyruvate is converted and broken down further by the TCA cycle, where the resulting compounds can enter the ETC (electron transport chain). However, if the cell is deprived of oxygen, such as during overly strenuous physical activity or if there is significant blockage of an artery, then the TCA cycle doesn’t function efficiently and pyruvate is converted to lactic acid (also called lactate). Lactic acid causes the pH of the cell to drop, which in turn signals to the cell that more energy is needed. However, if lactic acid levels build up too high, this causes cellular stress; on the macro level, we feel this as burning and pain in the case of physical activity, or chest pain (angina) that can occur if there is decreased blood flow to the heart (called cardiac ischemia).

So, while glycolysis is essential and glucose is readily available for most of the general population, it’s not actually the most efficient 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 all of the energy our cells create.

• 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-chain 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.

The product of beta-oxidation enters the TCA cycle (just like pyruvate). The role of the TCA cycle is to remove electrons from fatty acids and pyruvate and package them into other electron-carrying molecules, such as NADH and FADH2, which then enter the ETC.

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. 

Without CoQ10 (transfers electrons from Complex I and II over to Complex III), and oxygen, we’d only produce two ATP molecules via glycolysis.

ATP Production and Turnover

If oxygen supply is cut off or reduced, or if there is some other mitochondrial dysfunction, oxidative phosphorylation slows or stops, causing the cell to use ATP faster than it can be replaced.

When this happens, ATP concentrations in the cell decrease, while the ADP concentration increases. In an effort to continue to produce ATP and normalize the ratio of ADP to ATP, the cell combines two ADP molecules to produce one ATP and one AMP (adenosine monophosphate) in a process called the adenylate kinase reaction.

However, while this reduces the amount of ADP building up in the cell, it increases the amount of AMP, especially when the supply of oxygen is limited. The problem here is that the cell needs to maintain a relatively constant ratio of AMP to ADP to ATP. So, in order to reduce the amount of AMP (relative to ADP and ATP), the cell must degrade and eliminate this excess AMP. This reduction occurs through two biochemical pathways, and the end products ultimately exit the cell. Although the removal of excess AMP restores the AMP:ADP:ATP ratio, the absolute amount of these compounds becomes much lower. The total amount of energy the cell can produce becomes lower because it has lost its important building blocks.

• These building blocks are called purines, and their loss from the cell can be devastating. The body will rebuild its stock of purines, but this is a slow process and can only start with the five-carbon sugar D-ribose.
• There are two biochemical pathways for D-ribose in restoring the purine pool. The first is called the de novo pathway, which is a very slow process. It’s been calculated that it’d take over one hundred days for the human heart to make all its ATP via this pathway. The body just can’t make D-ribose fast enough for this pathway to be of much use in diseased states.
• The second pathway is called purine salvage. This happens when the cell, instead of eliminating the end products of AMP degradation, retains them as building blocks to accelerate the manufacture of D-ribose. However, even with this pathway, the rate-limiting factor is again the availability of D-ribose.
• The easy solution is to administer D-ribose 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.

During ischemia, oxygen levels in the cell drop and the mitochondria can no longer produce energy via oxidative phosphorylation. As the cell compensates by combining two ADP molecules to create an ATP molecule, the AMP concentration increases and then the cell needs to break this down to eliminate it. If the energy pool is low to begin with, it’s depleted rapidly during ischemia. If the energy pool is large, it takes longer to deplete it from the cell. The size of the energy pool determines the extent of permanent damage to an organ experiencing ischemia.

Hypoxia can happen due to plaque buildup in the heart’s arteries, which restricts blood flow. When blood flow is restricted, ATP is not generated as quickly, and the cell depletes its energy pool at an accelerated rate. In these cases, the cells simply cannot supply enough energy to keep up with demand. When this happens to the cardiovascular system, we call it coronary artery disease (CAD), angina, or congestive heart failure (CHF).

The Role of Mitochondria in Cardiovascular Disease

Conditions such as angina, hypertension, congestive heart failure, ischemia, and diastolic dysfunction all have their roots in mitochondrial energy. Not only can these conditions arise from a cellular energy deficiency, but they can also leak the purine building blocks of ATP out of the cell. When purine building blocks leak from the cell, they are 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).

In some smooth muscle cells, the contraction is maintained at a low level in the absence of external stimuli. This is known as smooth muscle tone and its intensity can be varied. Regardless of the stimulus, a smooth muscle contraction is initiated by calcium ions entering the cytosol (from the sarcoplasmic reticulum—a membrane-bound structure in muscle cells that stores calcium) and binding to a calcium-binding messenger protein called calmodulin. This stimulates another protein called myosin (the protein that contracts and is dependent on ATP) to attach to actin in cross-bridge cycling. Initiation of relaxation, on the other hand, begins with the removal of calcium ions from the cytosol and stimulation of an enzyme that deactivates myosin (referred to as myosin phosphatase).

Whether it is a conscious decision to relax skeletal muscles or the involuntary relaxation of smooth muscles, the process requires a decreased concentration of calcium ions. All this calcium must move out of the cytosol and into the sarcoplasmic reticulum. However, this process requires the use of a pump because the calcium must move up the concentration gradient, which requires ATP as energy. 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 signaling a contraction).

• This pump also has two ATP-binding sites, and both sites must have ATP attached for it to work. The first ATP-binding site has a high affinity for ATP, and therefore, any ATP in the vicinity binds to this site readily. Once bound to this site, ATP releases its energy, and is turned into ADP. The second ATP-binding site does not attract ATP so easily. In fact, the only way for ATP to bind to the second site is to ensure a high concentration of ATP so that hopefully one will just “fall” into the binding site. Building up this concentration obviously requires significant amounts of ATP to be produced.
• In death, fuel and oxygen are no longer delivered to the muscles, and ATP production stops. Without enough ATP, the calcium ions cannot be pumped out of the cell, and the muscles can no longer “relax.”
• Magnesium ions are also necessary for the activity of the Ca-Mg-ATPase; they bind to the catalytic site of this enzyme to mediate the reaction. Without magnesium, this enzyme cannot function and relaxation of the smooth muscle cannot occur (which can lead to things like high blood pressure, heart problems, or restricted breathing).

The systolic contraction ejects most of the blood out of the ventricles, and the percent of blood that’s pumped out (relative to its starting point when “relaxed”) is called the ejection fraction (normal range is 50–70 percent). While it’s easy to see how contraction of the heart requires energy, this stage requires the least amount of energy in the cycle of a heartbeat.

The diastole phase generally lasts less than a third of a second but requires the most ATP. Energy is required to separate the bonds formed during the contraction phase, which allows the muscle to return to its relaxed state. Also, the removal of calcium ions from the cell requires energy.

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. The beginning stages of diastolic dysfunction are characterized by a thickening and stiffening of the ventricular walls (typically left). The combination of hypertrophy and stiffening causes blood pressure to rise, reduces the amount of blood that’s pumped out per contraction (lower ejection fraction), and makes it more difficult for the heart to relax and fill up properly (which propagates this progressive cycle). Diastolic dysfunction is an early sign of serious heart problems around the corner—namely, congestive heart failure. Preserving diastolic function in patients is a major goal for cardiologists, and the solution is to ensure an abundant pool of ATP energy.

The proper flow of ions in and out of a heart muscle cell is essential to maintain the normal electrochemical gradient across the cell membrane. This gradient is what’s responsible for maintaining regular heart rhythm. When this gradient is disrupted, the result is arrhythmia. All of these high energy demands must be met by a small pool of ATP.

The Role of Mitochondria in the Nervous System, Brain, and Cognitive Health

The brain consumes a disproportionate share of the body’s circulating blood flow (14 percent) and oxygen (20 percent), yet despite its extraordinary energy demand, the brain’s energy reserves are actually very small. The brain’s metabolism can sustain energy production for only about one minute before it needs to be replenished. Thus, nerve cells are particularly vulnerable to ischemia (reduced blood flow) and hypoxia (reduced oxygen levels).

When the steady flow of blood through a portion of brain tissue ceases— as from a clot or hemorrhage—metabolism rapidly fails in the brain cells. As the oxygen supply runs out, the cells shift to anaerobic metabolism for the short term, but after a few minutes without blood, neurons suffer irreversible injury.

During a stroke, however, blood supply is not cut off uniformly. Instead, impairment in circulation is more severe toward the core of the affected area, where the lack of flow might be almost complete. Cells in the core tend to die quickly through necrosis. Remember, as opposed to apoptosis, necrosis is messy. Cells break apart, spilling their contents into nearby tissue, which further aggravates the situation by causing inflammation.

Mitochondria might actually suffer greater injury when blood flow is reduced rather than when it stops altogether. Complete blockage of blood flow also cuts off the supply of oxygen, which in turn reduces oxidative stress and free-radical production. When blood flow is merely reduced, a small amount of oxygen continues to flow, generating further free radicals in addition to those resulting from stroke-impaired cellular respiration. These additional free radicals could also explain the secondary damage that occurs days later.

With their high sensitivity to reduced blood flow, brain mitochondria exhibit the first signs of injury even during a moderate reduction of cerebral blood flow. Injury to mitochondria during and after a stroke has many consequences, and includes impaired bioenergetics, free-radical damage, calcium dysregulation, increased excitotoxicity, and promotion of programmed cell death. Unfortunately, as typical for mitochondrial impairment, mitochondrial brain injury causes further mitochondrial damage in those brain cells lacking blood flow, generating a vicious cycle of cellular injury after a stroke.

When blood flow is restored to the affected area, there is even greater injury to the mitochondria, called ischemia-reperfusion injury (IRI, or simply, reperfusion injury). IRI is also frequently seen after cardiac surgery.

• With reduced blood flow in the brain, ATP is still being used as usual for regular cellular activity, but is not being produced, and so the cell combines two ADP molecules to form ATP. This results in an increasing concentration of AMP, which is then eliminated from the cell, reducing the overall energy pool of the cell. Further, the absence of oxygen and fuel creates a condition where the mitochondria go into a low-use state, much like hibernation.
• When blood flow is restored, we see a perfect storm of events: a rush of fuel and lots of oxygen to the brain, a lag period for the mitochondria to “wake up,” and a deficiency of the building blocks of ATP (which were eliminated from the cell as AMP). So, even after the mitochondria wake up and are running at full speed, there is still an ATP deficiency because the purine nucleotides have been lost (which means ADP/ATP recycling is reduced).
• The result is a very high rate of free-radical production, rather than restoration of normal function. This high rate of free-radical production pushes any cells already close to their threshold for irreversible damage or death past that line, resulting in the damage that’s typically seen with IRI.

Mitochondrial Involvement in Neurodegeneration

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 oxygen and free radicals, and the brain’s vulnerability to degenerative diseases increases.

Studies have shown that CoQ10 (which shuttles electrons from Complex I or II to Complex III) protects against excitotoxicity by raising energy levels in nerve cells. In neurodegeneration, the brain becomes chronically oversensitive to glutamate, which then becomes a slow-acting “excitatory toxin” on brain cells. For mitochondria, this means that they are constantly under the direction to produce more energy—more energy than the neurons actually need. With this higher rate of activity comes a higher rate of free-radical production and, over time, comes the accelerated demise of these mitochondria.

A study by Sun and colleagues published in the summer of 2013 showed that rapidly moving mitochondria emit bursts of energy, and this might regulate neuronal communication.

• The production of neurotransmitters, their packaging and release, and the reception or removal of these chemicals all require energy. Previous studies showed that mitochondria can move rapidly along axons, from one bouton to another. This study showed that these moving mitochondria might control the strength of the signals sent from boutons.
• The presence of stationary mitochondria at synapses improves the stability and strength of the nerve signals. This is the type of data we need to confirm mitochondrial involvement in the pathogenesis of neurodegenerative diseases and any neurological disease that requires efficient and appropriate transmission of nervous system signals (such as depression, ADHD, etc.).
• The researchers manipulated mitochondrial movement by changing levels of syntaphilin, a protein that helps anchor mitochondria to the cell’s cytoskeleton inside the axons. Removal of syntaphilin resulted in mitochondria that moved quicker, and the electrical recordings from these neurons showed that the signals they sent fluctuated greatly. On the flip side, elevating syntaphilin levels slowed mitochondrial movement and resulted in boutons that sent signals with the same strength. Previously, it had been shown that about one-third of all mitochondria in axons move about; the rest are stationary. Nerve cell communication is obviously tightly controlled by highly dynamic events occurring at numerous synapses.
• The researchers also found that blocking ATP production in mitochondria reduced the strength of the signals sent even if mitochondria were near the boutons.

At the cellular level, there is an extensive loss of neurons and there are high levels of insoluble fibrous deposits (known as senile plaques and neurofibrillary tangles). At the core of the plaques is a toxic protein called amyloid beta. Amyloid beta generates free radicals, damages mtDNA, impairs cellular bioenergetics, and alters the proper folding of proteins so that they form neurofibrillary tangles. However, there is evidence to suggest that the formation of amyloid beta is the brain’s way of defending against oxidative stress (a result of Alzheimer’s, not a cause).

• A recent study suggests that cellular energy production might be a better indicator of Alzheimer’s disease severity than senile plaques. In this particular study, degree of clinical disability did not correlate with the density of senile plaques, but did correlate with a mitochondrial abnormality involved in cellular energetics.
• Regardless of whether amyloid beta is a cause of or result of oxidative stress, another potent free radical called peroxynitrite (formed from nitric oxide) oxidizes lipids in the membranes of nerve cells. This generates the highly toxic by-product hydroxynonenal (HNE), which is found in excess quantities in multiple brain regions of Alzheimer’s patients. HNE kills brain cells not only directly but also indirectly by making them more susceptible to excitotoxicity (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).
• A multiple-factor theory was proposed by Wan-Tao Ying in 1997. According to this theory, Alzheimer’s disease develops from the interplay of four causes: imbalances in APP (amyloid precursor protein), calcium, free-radical damage, and bioenergetic deficit.
• We need to ensure we’re eating a nutrient-dense diet, and minimize empty calories that come from foods such as added sugar, white bread, and salty snacks. Excess calories have also been linked to countless other degenerative diseases. Caloric restriction has been linked to life extension and possibly a reduction in the risk of degenerative diseases. This adds weight to the free-radical and bioenergetic components of Ying’s multiple-factor theory.

Recent 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. This finding is significant because it draws focus to the importance of mitochondrial dysfunction and cellular energy in Parkinson’s disease.

• In Parkinson’s disease, cell death is primarily targeted to the neurons in the substantia nigra, which that coordinates movement. These neurons produce dopamine; the death of these cells depletes dopamine stores, and ultimately leads to muscle rigidity, tremors, and difficulty initiating movement.
• Research has shown that 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 deficiencies 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.
• Superoxide radicals are generated when electrons leak and react with oxygen. Deficits in Complex I increase leakage of electrons and increase superoxide production, and ultimately diminish 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. Iron in its reduced form (Fe2+) 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.
• The mitochondria of Parkinson’s patients also exhibit some inhibition of Complex III activity (the second most prominent site of superoxide generation). A relative deficit of alpha-ketoglutarate dehydrogenase complex (KGDHC, a key enzyme of the TCA cycle found in the mitochondrial matrix) has also been noticed. KGDHC produces NADH, the substrate for Complex I, 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.

Depression

People with optimal mitochondrial function can cope with the energy demands of stress-induced neuroplasticity, which means that these individuals are at relatively low risk for depression. In individuals with mitochondrial dysfunction, on the other hand, stress-induced depletion of the brain’s energy supply could ultimately compromise neuroplasticity, could render an individual vulnerable to clinical depression as the adaptation response falters. 

Attention-Deficit/Hyperactivity Disorder: Pay Attention to the Mitochondria

Astrocytes play an important role in providing energy by supplying lactate to rapidly firing neurons. Astrocytes can also provide lactate to oligodendrocytes, where lactate is used as a substrate for myelin synthesis, and thus enables rapid neurotransmission.

• According to the Energy-Deficiency Model, the genesis of the behavioral symptoms in ADHD is directly linked to impairments in the astrocyte-neuron lactate shuttle. This shuttle is based on the astrocytes’ uptake of glucose from the blood, its storage as glycogen, and its conversion to lactate.
• Neural activity triggers the uptake of glucose from the blood, into the astrocytes. It also triggers the astrocytes to break down stored glycogen into glucose. This glucose (from both the blood and stored glycogen) gets metabolized to lactate, which in turn gets shuttled over to the neurons. The neurons then take this lactate into the TCA cycle and then on to oxidative phosphorylation to produce ATP.
• Lactate is the essential energy source for rapidly firing neurons, and is a more efficient fuel source than glucose. It is metabolized to form ATP more rapidly (glycolysis has already occurred) and, unlike glucose, it does not require ATP for its metabolism (remember: it takes two ATP molecules to convert glucose to lactate). Due to their high energy demands, it is imperative for neurons to make use of the most efficient energy supplies when rapid neural processing is required, and the brain has evolved ways to do so.
• However, in ADHD, this lactate production by astrocytes is not sufficient to supply rapidly firing neurons with energy during brief periods of increased demand. The insufficient amount of lactate leads to a localized and transient deficiency in ATP production, impaired restoration of ionic gradients across neuronal membranes (which requires energy to restore ions against a concentration gradient), and slowed neuronal firing. 
• These periods of rapid firing are then followed by slow unsynchronized firing, which exerts less demand on energy resources. This allows replenishment of energy reserves and restoration of function. The brief periods of energy deficiency, followed by periods of normal supply, are suggested to account for the variability of behavioral response seen in patients diagnosed with ADHD when performing complex tasks that require speed and accuracy.

Glutamate, a major excitatory neurotransmitter, stimulates glycolysis (glucose utilization and lactate production) in astrocytes. However, while glutamate is excitatory to the neurons, long-term exposure quickly depletes energy stores. Many who are sensitive to MSG (and not just those with ADHD) report a racing heart and sweating (referred to as excitation) followed by extreme fatigue (energy depletion).

• Astrocytes normally maintain low extracellular levels of glutamate, and this is achieved with the help of the membrane potential. 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 overexcitation (which means the mitochondria are pushed to their limit in energy production, which subsequently results in excessive free-radical damage, and the chain of events that leads to apoptosis).
• ADHD patients are known to have reduced gray matter in their brain; cell death due to mitochondrial dysfunction eventually results in the atrophy of any affected organ.
• Methylphenidate (Ritalin), for example, has been shown to increase glucose utilization by astrocytes in brain regions. This drug helps ADHD patients who have decreased glucose utilization and impaired energy supply, and might also help others who have impaired myelination from a longer-term lactate deficiency.

Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, and Fibromyalgia

Pain is the main factor for fibromyalgia, specifically, pain and tenderness in certain areas of the body when pressure is applied to them. Most of the other symptoms (such as fatigue, cognitive dysfunction, headaches, and sleep disturbances) are common to all three.

Investigations by Dr. Sarah Myhill and colleagues who have studied various possible root causes of CFS have concluded that CFS is a result of mitochondrial dysfunction. In a state of constant undersupply of energy, some ADP is combined together to form ATP, but this combination also creates AMP. AMP is eventually eliminated from the cell, which means a critical building block of ATP is lost. In order to rapidly meet the energy demands of the cell in the presence of a reduced energy pool, the body will make very small amounts of ATP directly from glucose through glycolysis (or anaerobic metabolism), which is much faster in generating energy, but far less efficient than aerobic metabolism. Switching to this anaerobic state is exactly what many people with CFS do.

• This switch results in lactic acid (the product of anaerobic metabolism) quickly building up, resulting in aches and pains known as the “lactic acid burn.” The person switches to anaerobic metabolism to meet the high energy demands in the short term, but pays for it later with this lactic acid buildup.
• Second, using glucose in this way means very little, if any is available to make D-ribose. So, people with CFS are never fully able to recover and get ahead in the progress of rebuilding their energy pool and capacity.

Diagnosis and Treatment of Chronic Fatigue Syndrome and Myalgic Encephalitis

Type 2 Diabetes

Type 1 is an autoimmune disease, and as a result of this destruction, the lack of insulin can no longer keep blood sugar levels in check. Type 2, on the other hand, occurs when the body can’t effectively utilize the insulin that is produced and released.

• Research has shown that hyperglycemia induces mitochondrial superoxide production in the endothelial cells, which is an important mediator of diabetic complications such as cardiovascular diseases. Endothelial superoxide production also contributes to atherosclerosis, hypertension, heart failure, aging, and sepsis.
• Further, the high glucose levels seen in diabetes will “glycate” proteins, known as AGEs (advanced glycated end products). These proteins have altered functions, from simply no longer working, to harming the cell’s functioning. These glycated proteins can also bind to mitochondria and compromise their function.
• In addition, the skeletal muscles of people with type 2 diabetes have shown a reduced capacity of the ETC, and the mitochondria are smaller than normal. Mitochondrial damage also appears to be a major cause of lipid accumulation in these cells. PPARG coactivator 1 (PGC1) is a key factor located in the mitochondrial matrix for lipid oxidation, and the expression of PGC1 is reduced in type 2 diabetes patients. The accumulated lipids turn into cytotoxic compounds, damaging the mitochondria and leading to insulin resistance.

Defects in the capacity to metabolize fatty acids in skeletal muscles are 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 so fatty acids accumulate.

• Fatty acids are particularly prone to oxidative damage, resulting in the formation of lipid peroxides. These lipid peroxides are toxic to the cell and highly reactive, leading to free- radical damage of proteins and mtDNA. 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.
• To prevent the development of this positive feedback loop, a protective mechanism is normally present in healthy cells. Uncoupling protein 3 (UCP3), located on the mitochondrial membrane, plays a major role, essentially acting as an overflow valve, so that an excessive proton gradient doesn’t slow down the ETC. However, research shows dysfunctional UCP3 leads to free-radical damage in cells, which is associated with insulin resistance and type 2 diabetes.

The chain of events looks something like this: (1) mitochondrial damage in the target cells, such as muscles, results in lipid accumulation; (2) lipid accumulation results in insulin resistance; (3) due to insulin resistance, the beta cells in the pancreas must increase their metabolism to create more insulin (and then package it up, and secrete it— all of which takes energy); (4) while this metabolism increase helps control blood sugar to some degree in the short term, over time these beta cells accumulate damage to their mitochondria due to chronically high metabolism and energetic demand; and finally, (5) the beta cells start to die off, resulting in a drop in insulin and a spike in blood glucose, which is what is typically seen in long-standing uncontrolled type 2 diabetes.

Mitochondrial Diabetes

Typically presenting at middle age, mitochondrial diabetes is a form that originates from a mtDNA defect, so this diabetes is maternally transmitted and often associated with hearing loss (particularly for high tones). This type of diabetes is characterized by decreased insulin secretion but not insulin resistance, suggesting that the major problem is with the mitochondria of pancreatic beta cells. The underlying clinical pathology of mitochondrial diabetes might seem to resemble that of type 1 diabetes, but in this case, the immune system doesn’t destroy beta cells.

Instead, this type of diabetes results from mtDNA mutations. The most common mutation leading to mitochondrial diabetes is one that encodes for “transfer RNA.” The defect in transfer RNA leads to impaired synthesis of multiple mitochondrial proteins and, ultimately, mitochondrial dysfunction.

Medication-Induced Mitochondrial Damage and Disease

Testing for mitochondrial toxicity is still not required by the Food and Drug Administration of the United States, Health Canada, or any other regulatory body responsible for drug approval. Medications can damage the mitochondria both directly and indirectly; they can directly inhibit mtDNA transcription of ETC complexes (the thirteen key subunits), damage ETC components through other mechanisms, or inhibit enzymes required for any of the steps of glycolysis and beta-oxidation. Indirectly, medications could cause mitochondrial damage through the production of free radicals, by decreasing the quantity of endogenous antioxidants such as superoxide dismutase and glutathione, or by depleting the body of nutrients required for the creation or proper function of ETC complexes or mitochondrial enzymes.

Barbiturates (used as sedatives or antianxiety drugs) were the first medications noted to impede mitochondrial function by inhibiting Complex I. This same mechanism also explains how rotenone (an agricultural pesticide) causes mitochondrial damage (which, incidentally, happens to make this a useful chemical for inducing Parkinson’s disease in animals so we can study them). Other drugs can sequester coenzyme A (e.g., aspirin, valproic acid), inhibit biosynthesis of CoQ10 (e.g., statins), deplete antioxidant defenses (e.g., acetaminophen), inhibit mitochondrial beta-oxidation enzymes (e.g., tetracyclines, several anti-inflammatory drugs), or inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (e.g., amiodarone). Other substances impair mtDNA transcription or replication. In severe cases, impairment of energy production could contribute to liver failure, coma, and even death.

Many psychotropic medications also damage mitochondrial function. These drugs include antidepressants, antipsychotics, dementia medications, seizure medications, mood stabilizers such as lithium, and Parkinson’s disease medications.

Adverse effects of the antiretroviral drugs for treating AIDS result from inhibition of the enzyme responsible for mtDNA replication. Inhibiting this enzyme can lead to a decrease in mtDNA, the thirteen critical subunits of the ETC, and, ultimately, cellular energy production. Mitochondrial dysfunction induced by these drugs explains the many adverse reactions reported for them, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, pancreatitis, pancytopenia, and proximal renal tubule dysfunction.

Each year more than 450 deaths are caused by acute and chronic acetaminophen toxicity. Acetaminophen is metabolized in the liver, and when acetaminophen passes through the enzyme that starts its elimination, it is metabolized to a toxic intermediate that is subsequently neutralized by glutathione before finally being excreted in 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.

• Because glutathione depletion is a mechanism by which acetaminophen causes death of liver cells, it is not surprising that the antidote for acetaminophen poisoning is a common nutritional supplement called Nacetyl-cysteine (the precursor of glutathione).

Valproic acid depletes L-carnitine, which causes a decrease in beta-oxidation in the liver, thereby contributing to fatty liver. The antipsychotic medications inhibit ETC function. The antianxiety medication diazepam was shown to inhibit mitochondrial function in the brain, while alprazolam does so in the liver. Long-term administration of corticosteroids has been shown to result in mitochondrial dysfunction and oxidative damage to mtDNA (and nDNA as well). The artificial blue color often used in candies and men’s shaving gels inhibits oxidative phosphorylation.

Acquired Conditions That Implicate Mitochondrial Dysfunction:

• Type 2 diabetes
• Cancers
• Alzheimer’s disease
• Parkinson’s disease
• Bipolar disorder
• Schizophrenia
• Aging and senescence
• Anxiety disorders
• Nonalcoholic steatohepatitis
• Cardiovascular diseases
• Sarcopenia (loss of muscle mass and strength)
• Exercise intolerance
• Fatigue, including chronic fatigue syndrome, fibromyalgia, and myofascial pain

Mitochondrial Disease

When mitochondrial diseases are a result of defective nuclear genes, the inheritance patterns do follow Mendel’s laws. However, there are two sets of genomes involved in making mitochondria work, mtDNA (inherited only from the mother) and nDNA (inherited from both parents), so inheritance patterns can range greatly from autosomal recessive to autosomal dominant to maternal inheritance.

Making matters more complicated, there are countless interactions between the mtDNA and the nDNA in a cell. The result is that the same mtDNA mutations can produce different symptoms between siblings in the same family (they will have different nDNA, even though they might all share the same mtDNA), while different mutations can produce the same symptoms.

However, the variation in mtDNA in the mother’s eggs is surprisingly high, and this fact throws a wrench in any predictions of inheritance. To illustrate the bizarre nature of this group of diseases, the onset of symptoms can vary by decades, and even between siblings with the identical genetic mitochondrial mutation. Moreover, occasionally the disease might even disappear in an individual who had (or should have) inherited them.

All cells (except red blood cells) contain mitochondria, so mitochondrial diseases tend to affect multiple body systems (either at the same time, or progressively at different times). Of course, some organs and tissues require more energy than others. When an organ’s energy requirements can no longer be fully met, the symptoms of mitochondrial disease manifest. They primarily affect the brain, nerves, muscles, heart, kidneys, and endocrine system—all organs with high demand for cellular energy.

An individual’s bioenergetic baseline might be established by understanding the level of inherited defects in mtDNA. As additional mtDNA defects develop over the course of a lifetime, their bioenergetic capacity might decline until an organ’s threshold is crossed, where the organ begins to malfunction or become susceptible to degeneration.

Another genetic complication is that each mitochondrion contains up to ten copies of mtDNA, and each cell and tissue contains many mitochondria, which means there could be countless different defects in the countless different copies of mtDNA in each cell, tissue, or organ. For a particular tissue or organ to become dysfunctional, a critical number of its mtDNAs must be defective. This is called the threshold effect. Each organ or tissue is more susceptible to some mutations than others and has its own particular mutational threshold, energy requirement, and sensitivity to free-radical damage.

The degree of heteroplasmy within a person might also differ from organ system to organ system and even cell to cell, leading to a vast array of possible disease presentations and symptoms. In a developing embryo, as cells divide, different mitochondria with different mutations will eventually populate different tissues with different metabolic requirements. If the defective mitochondria happen to get distributed to cells that eventually develop into metabolically active tissues, such as the heart or brain, these individuals will likely have a poor quality of life, if any. On the flip side, if the defective mitochondria end up in less metabolically active cells, such as skin cells (that are also constantly shed), then the individual might never know they have the genetic imprint for a mitochondrial disease.

When Mitochondrial Disease Is the Primary Disease

When mitochondrial disease exists right from birth, it is said to be the primary disease. In mild cases, young people might learn to cope and adapt to the amount of energy they have and don’t realize they even have mitochondrial disease. Mildly affected adults might say that they had a very normal and healthy life as a child, although they were never really good at sports or activities that required endurance.

Some common symptoms of more noticeable mitochondrial disease include developmental delay or regression in development, seizures, migraine headaches, muscle weakness (might be only occasional), poor muscle tone (hypotonia), poor balance (ataxia), painful muscle cramps, inability to keep up with peers in physical activities (low endurance), chronic fatigue, stomach problems (vomiting, constipation, pain), temperature problems from too little or too much sweating, breathing problems, eyes that are not straight (strabismus), decreased eye movement (ophthalmoplegia), loss of vision or blindness, droopy eyelids (ptosis), loss of hearing or deafness, heart/liver/kidney disease at a young age, and shaky parts of the body (tremors).

A recent study of dilated cardiomyopathy found that about one in four patients had mtDNA mutations in the heart tissue. Other patients might have a genetic CoQ10 deficiency and suffer dysfunctions in the brain, nerves, and muscles, often including fatigue on exertion, and seizures. Such patients appear to respond to CoQ10 supplementation, but observations are limited because diagnosis of this disorder is in its infancy. Primary CoQ10 deficiency is one of the mitochondrial diseases caused by mutations in nDNA.

Treating Mitochondrial Disease

Recent research has shown that several nutritional supplements can help relieve symptoms and improve function. Case reports and pilot studies have found that some patients with mitochondrial diseases respond to long-term CoQ10 therapy, and promising results have been reported in mitochondrial encephalomyopathy, lactic acidosis, and strokelike syndrome (MELAS); Kearns-Sayre syndrome; and maternally inherited diabetes with deafness.

Typically, CoQ10 is prescribed in combination with other nutrients: creatine monohydrate, vitamin C, vitamin E, alpha-lipoic acid, thiamine (vitamin B1), riboflavin (B2), niacin (B3), L-carnitine, or L-arginine. Others include D-ribose, PQQ, magnesium, and medium-chain fatty acids. Regular exercise and physical activity provide immense benefits for the body, mind, and spirit for everyone. However, for those with mitochondrial disease, physical activity becomes extremely important as a way to build more mitochondria in the cells (mitochondrial biogenesis), which generates more energy for the cells, resulting in increased tolerance to physical activity.

Examples of Inherited Disorders Caused by mtDNA Mutations:

• Mitochondrial encephalomyopathy, lactic acidosis, and strokelike syndrome (MELAS)
• Myoclonic epilepsy associated with ragged-red fibers (MERRF)
• Neuropathy, ataxia, and retinitis pigmentosa
• Maternally inherited Leigh syndrome
• Leber hereditary optic neuropathy (LHON)
• Chronic progressive external ophthalmoplegia
• Maternally inherited diabetes and deafness
• Nonsyndromic maternally inherited deafness
• Kearns-Sayre syndrome (KSS)
• Pearson syndrome

Examples of Mitochondrial Disorders Caused by nDNA Mutations:

• Autosomal recessive external ophthalmoplegia (paralysis of muscles that control eye movements)
• Hypertrophic cardiomyopathy (large, damaged heart)
• Myoneurogastrointestinal encephalomyopathy
• Leigh syndrome
• Mitochondrial depletion syndrome
• Dominant optic atrophy

Age-Related Hearing Loss

Age-related hearing loss (known as presbyacusia or presbycusis) affects approximately one-third of all people aged sixty-five and older, and is due to the changes that occur in the aging body. Circulatory disorders, for example, which limit the flow of blood throughout the body, as well as to the brain and auditory system, are common in later years. There are many reasons why circulation slows down as the body grows older, among them heart disease, hardening of the arteries, diabetes, and sedentary lifestyles.

“Cognitive load” is a possible explanation from newer research that shows that hearing loss is linked to cognitive decline. It’s possible that as hearing becomes worse, a person’s perceived intelligence decreases because, during a conversation, the brain spends more resources just trying to hear what’s being said, rather than processing the contents of what’s been spoken.

Exposure to noise is known to induce excess generation of free radicals in the cochlea, and genetic investigation has identified several genes that mutate, including those related to antioxidant defense and atherosclerosis. Genetic variation in the antioxidant defense system might also help explain the large variations in the onset and extent of age-related hearing loss among elderly subjects.

• Clinical work of a leading otolaryngologist show that it is possible to slow the progression of—and sometimes even reverse—hearing loss using an integrative approach that includes optimal nutritional and lifestyle choices. In his book, Save Your Hearing Now, Michael Seidman revealed that age-related hearing loss is linked to free-radical damage and mitochondrial dysfunction.
• A calorie-restricted diet is proven to reduce free-radical production and reduce mitochondrial damage. Compared to rats that were allowed to eat freely, the calorie-restricted rats and another group treated with antioxidants (including melatonin and vitamins E and C) had decreased progression of age-related hearing loss. Another study showed that elderly rats given either acetyl-L- carnitine or alpha-lipoic acid saw an improvement in hearing, compared to the placebo group.

Mitochondria, Aging Skin, and Wrinkles

The skin protects against pathogens; provides insulation, temperature regulation, and sensation; and helps synthesize vitamin D. The epidermis provides a waterproof barrier against the external environment, and largely contains keratin and melanin.

Below the epidermis is the dermis. In addition to providing essential support to the epidermis, the dermis contains nerves, glands, and essential proteins called collagen and elastin. Collagen is the skin’s main structural protein, while elastin provides elasticity to the skin. This layer also contains essential fats and glycosaminoglycans, which are large, sugarlike molecules that bind and hold water—all helping to keep moisture in the skin.

Fibroblasts are cells essential to youthful, healthy skin; they produce collagen and elastin. 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 aging, which might be why so many antiaging creams and concoctions now contain CoQ10, an essential component of the ETC.

Years of cumulative free-radical damage (from sources such as ultraviolet radiation) can induce mitochondrial dysfunction. This dysfunction eventually leads to dramatic changes in the skin’s health and appearance. The epidermis becomes less capable of tissue repair and renewal. Collagen becomes sparser and less soluble. Elastin fibers are slowly degraded and damaged, and areas of sun-damaged skin accrue abnormally structured elastin. Glycosaminoglycans can no longer properly interact with water, while lipid content decreases with age. The end result of these age-related changes is that skin becomes prone to wrinkling, dryness, sagging, decreased flexibility, dullness, and poor healing responses.

Infertility and Mitochondria

Each oocyte contains about one hundred thousand mitochondria—a huge number despite the lack of demand (most ooctyes are dormant for the majority of their existence, presumably to protect mitochondria from damage for as long as possible). In contrast, a sperm cell only has a few hundred mitochondria.

• To be motile, sperm need to have very high metabolisms. Unfortunately, this results in significant free-radical damage in their very short life spans, and sperm have been known to quickly accumulate mutations in their mtDNA. By eliminating this potential source of defective DNA, the oocyte prevents such mutations from being passed on and affecting the offspring.
• 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. This ensures only maternal inheritance of mtDNA. However, in a situation where autophagy is impaired, paternal mitochondria and their genome remain even in the first stages of embryonic development.
• For Complex I to be built properly, there needs to be clear communication between the mtDNA and nDNA. However, it’s the mtDNA that’s in charge because it codes for the critical subunits of the complexes, which get embedded into the inner mitochondrial membrane. Once there, it acts as a beacon that attracts the other subunits encoded by nDNA. If the mtDNA and nDNA are a good “fit,” the complexes get built properly and in sufficient quantities. This allows the production of sufficient energy that’s “clean” (meaning, there’s minimal free-radical leakage), and the mitochondria survive. As long as there are enough of these types of mitochondria in a cell, the cell survives.
• If they are not a good fit and energy production is suboptimal, the mitochondria die. If there are enough of these types of mitochondria in a cell, the cell dies. For this reason, ensuring only one set of mtDNA survives in the fertilized egg makes this whole process smooth. Oocytes from women of advanced reproductive age show accumulations of mtDNA mutations that impair function. Vast amounts of energy are needed for the rapid cell division in the embryo, so mtDNA mutations aren’t compatible with the prospects of normal and healthy fertility, and any fertilization of these eggs will quickly be terminated (i.e., result in a miscarriage).

Infertile women in their 30-40s, who were otherwise healthy, could be candidates for a procedure called nuclear genome transfer. This is where an oocyte from a healthy and fertile female donor has its nucleus removed (leaving all other components, including the healthy mitochondria), and then the nucleus from the fertilized egg of the infertile woman is transferred into the healthy donor egg.

• Although recent evidence suggests that mitochondrial disease can still creep back in, even if a mother’s defective mitochondria are virtually eliminated, one benefit that arose from this experiment in human reproduction was that it essentially confirmed the role of age-related mitochondrial dysfunction as a key contributor to infertility.

After the sperm fertilizes the oocyte, the resulting “zygote” goes through tremendous growth through cell division. This requires incredible amounts of energy. However, while the cells divide, the mitochondria do not. Instead, the initial number of mitochondria (about one hundred thousand) gets partitioned with each division, so that by a couple weeks after conception, each cell only has about two hundred mitochondria. Whereas defective mitochondria could hide and coast by in a sea of healthy mitochondria, when their numbers are reduced to about two hundred per cell, each mitochondrion had better be pulling its own weight. When exposed, these dysfunctional mitochondria will be eliminated, which is 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. 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.

• If the embryo is female, she will start to produce her own oocytes at an alarming rate. In fact, at five months’ gestation, she’s already produced about seven million oocytes. From this crest, the body starts its purging.
• During the development of the fetus, the body is comparing its mtDNA to the new nDNA to ensure that any incompatible oocyte is eliminated. By puberty, when she is biologically mature enough to bear her own children, she’s down to about three hundred thousand oocytes. By this point, only the cream of the crop (in terms of healthy oocytes) remains.

After our early 20s our body starts to produce less CoQ10. 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 our eventual demise, we’ll experience various symptoms, and for women, one of them is infertility. If there is a relative deficiency of CoQ10, the eggs cannot produce enough energy, and as a result, when they are fertilized by sperm, the zygote (embryo) is aborted. In cases where there might be sufficient cellular energy production to stay above the threshold for miscarriage, the embryo will continue to develop and mature. Yet, in some cases that evade miscarriage, there is still insufficient cellular energy to properly separate the chromosomes during cell division. An example of this is Trisomy 21 (Down syndrome), where there are three copies of chromosome 21. This example demonstrates why older women have a higher risk of bearing children with birth defects.

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.

Eye-Related Diseases

Free-radical damage seems to be the most important factor in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world, and the leading cause of blindness.

• Several studies have found an increase in mtDNA damage and a concurrent decrease in the efficacy of DNA repair—and both these factors are correlated with the occurrence and the stage of AMD.
• Considering that mtDNA repair is executed by proteins encoded by nDNA, certain mutations in the nucleus might affect the ability to repair mtDNA. It’s been suggested that this poor DNA repair, combined with the enhanced sensitivity of retinal cells to environmental stress factors (e.g., ultraviolet light, light in the blue spectrum, air pollution), contributes to the development of AMD.
• With age, the high energy demand and constant assault from ultraviolet and blue light produce debris and significant free-radical damage. In humans, this can result in a decline of up to 30% in the numbers of light-receptive cells in the eye by the time we are seventy and can lead to progressively poorer vision.

Glaucoma often progresses without symptoms until it succeeds in damaging the optic nerve. Mitochondrial-associated free-radical damage affects the eyes’ drainage system, where tissue integrity is essential to maintaining normal pressure and fluid flow out of the eye.

• Studies that suggest a common link between glaucoma and Alzheimer’s disease. Alzheimer’s disease has known deficits in mitochondrial function, and targeting bioenergetics in this cognitive disorder has shown 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.

Stem Cells Require Healthy Mitochondria

Stem-cell populations do not necessarily decline with advancing age, but instead they lose their restorative potential. This functional stem-cell decline is accompanied by eventual organ malfunction and increased incidence of disease, which bears some resemblance to oocytes and female infertility (where the number of oocytes doesn’t fall off with advancing age, but instead they lose their reproductive potential due to declining cellular energy production).

Inhibition of mitochondrial fission disrupted various processes and caused loss of stem-cell properties in the daughter cells. From this study, it appears there might be built-in mechanisms for stemlike cells to asymmetrically sort aged and young mitochondria, allowing at least one daughter cell to maintain a large pool of healthy mitochondria and, as a result, to keep its stemness going as long as possible.

Mitochondrial dysfunction thus underlies a degenerative cycle that robs aging humans of the renewal benefits of their own stem cells. The integration of mitochondria into stem-cell research has led scientists to propose that improvements in mitochondrial health (along with other cellular modulations) could yield advanced therapeutic strategies designed to rejuvenate tissues of the aged.

Cancers: Understanding the Causes Brings Us One Step Closer to Cures

Typically, a cell must accumulate eight to ten mutations in specific genes before it can transform into a malignant cell—a single mutation is rarely enough. Upon transformation to a malignant cell, its own interests are put before those of its community, the body. There are also several checkpoints in the cells, which is why it takes an average of eight to ten particular mutations before a cell becomes malignant. Some people might inherit some of these mutations from their parents, leaving them with a lower threshold of “new” mutations that must accumulate before the onset of cancer—they have a genetic predisposition to cancer.

Apoptosis is critical to immune function, and helps enable the immune system to distinguish between “self” and “nonself” (where cells that could react against our own body tissues commit apoptosis). Immune system cells can also exert many of their own effects by inducing apoptosis on damaged or infected cells. This kind of active screening by immune cells removes damaged cells before they get a chance to get a foothold and proliferate.

If the supply of ATP fails to meet the cell’s demand, the cell cannot commit apoptosis, and the defective cell is given a chance to run wild. Deficient ATP production can happen for many reasons, but two of them are due to gene mutations in either the mtDNA or nDNA that (1) no longer produce functional proteins involved in energy production, or (2) result in defects in any of the many proteins involved in the apoptosis cascade. Thus, mitochondrial function is in absolute control over apoptosis and prevention of cancers and, in addition, illustrates how nDNA mutations are in play because it encodes many mitochondrial proteins.

This association between mitochondrial dysfunction and cancers was made as early as 1930, when German scientist Otto Warburg first hypothesized that the increased rates of aerobic glycolysis, which he observed in a variety of tumor cell types, might be due to an impaired respiratory capacity in these cells.

• This increase in aerobic glycolysis changes the bioenergetics of the cell, and the shift has been confirmed by studies showing reduced activity of the TCA cycle and oxidative phosphorylation, increased gluconeogenesis, increased lactic acid production, and reduced fatty acid oxidation.

Tripping Over the Truth, by Travis Christofferson.

Cancer cells have been found to have 220 more mutated mtDNA than mutated nDNA. Mutant mtDNA is readily detectable in urine, blood, and saliva samples from patients with various cancers, and has been used as a marker in hepatocellular carcinoma and breast cancer. Recently, rapid sequencing protocols have been developed to detect mtDNA variants in tumor and blood samples taken from patients.

• Over one thousand different proteins are found in mitochondria, and advances in proteomic technologies have made the quantitative analysis of mitochondrial protein expression possible.

One chemotherapeutic approach utilizes delocalized lipophilic cations (DLCs) that selectively accumulate in cancer cells in response to the increased mitochondrial membrane potential. Several of these compounds have exhibited at least some degree of efficacy in killing cancer cells in the laboratory and in biological systems.

• Certain DLCs have been employed in photochemotherapy (PCT), an investigational cancer treatment involving light activation of a photoreactive drug (also known as a photosensitizer) that is selectively taken up or retained by cancer cells. There has been considerable interest in PCT as a form of treatment for cancers of the skin, lung, breast, bladder, brain, or any other tissue accessible to light transmitted either through the body surface or internally via fiber-optic endoscopes.
• Cationic (or positively charged) photosensitizers are particularly promising as potential PCT agents. Like other DLCs, these compounds are concentrated into the mitochondria of cancerous cells in response to the negative charge inside the matrix. In response to localized photoradiation, the photosensitizer can be converted to a more reactive and highly toxic species, thus enhancing the selective toxicity to carcinoma cells and providing a means of highly specific tumor cell killing without injury to normal cells.

An alternative strategy employs the mitochondrial protein-import machinery to deliver macromolecules to mitochondria. Certain short peptides with functional domains act as a sort of homing device that, when internalized into the target cells, readily penetrates the mitochondrial membrane, and becomes toxic by disrupting the proton gradient. Researchers are also attempting to develop drug and DNA delivery systems attracted to mitochondria. Recent data demonstrates that a liposome can be rendered mitochondria-specific via the attachment of known residues to its surface.

Aging as a Disease

There can be mutations in the protein subunits of the complexes (either in the nDNA or mtDNA), supercomplex disassociation, defective autophagy, defective fission or fusion, defective transcription, defective protein transport or channels, defective protein assembly or folding, defective permeability transition pores, defective caspase or apoptotic enzymes, mutations in any of the enzymes of the TCA cycle or beta-oxidation, mutations in UCP, defects in the peroxisomes or endoplasmic reticulum (or communication errors between these organelles and the mitochondria), inefficient mitochondrial movement, etc.