3 Normal Energy Metabolic Production: the Goal of NAD Therapy

A lot of myths exist about energy for living and about what it actually is. By dissecting everything into its smaller components one will eventually end up with nothing. This is the wonder of life, that only God could have created everything from nothing.

3 Normal Energy Metabolic Production: the Goal of NAD Therapy

A lot of myths exist about energy for living and about what it actually is. By dissecting everything into its smaller components one will eventually end up with nothing. This is the wonder of life, that only God could have created everything from nothing. The metabolic energy required by our bodies is not mysterious vibration but is applicable chemical compounds changing from one form to another, and during the change, metabolic energy is released that can be used for all human activities. Just as a motor car cannot run on potatoes, our bodies cannot function on the vibrations of music or whatever. The nett result is: if the required chemical compounds are not present no appropriate metabolic energy can be released for utilisation by our bodies' cells, irrespective of other vibrations or resonances that could still be available. Prof Hans Krebs received the Nobel prize for medicine and physiology in 1953 for describing the cell's energy metabolic cycle and all the chemical compounds involved.

No behaviour is possible without the body, during the earthly part of one's life. All human activity (irrespective of whether it occurs on purpose, instinctively, knowingly or unknowingly), except dying, requires metabolic energy to take place, to be suppressed, maintained or controlled. If the body has enough metabolic energy in a usable form at its disposal, it can perform activities like eating, laughing, mourning, obedience, sleeping, praying, deciding, learning, playing, contemplation, conversion, attending church, concentration, cellular replacement, breathing, digestion, dreaming, sport, working, sex, temperature regulation and millions of other functions. The greater the amount of usable metabolic energy and available quantity thereof, the higher the quality of life and functioning. The brain, for example, uses ten times more metabolic energy than any other organ and has a very limited supply of metabolic energy, which has to be replenished continuously. The bodies of EMD sufferers do not on their own produce enough metabolic energy, to be able to perform all of these activities and this makes their bodies unstable.

"Energy metabolism is defined as the sum of complex and integrated chemical reactions by which the body derives energy from the environment and maintains the proper functioning of all biologic processes. The final common pathway for all these processes is the complete oxidation of carbohydrates and fats and partial oxidation of proteins to carbon dioxide and water. These processes occur primarily in the mitochondria and are coupled to the biochemical reactions of the tricarboxylic acid cycle (better known as the Krebs cycle)”.547

"At the cellular level, energy is used to make new proteins, to bring nutrients into a cell and expel cellular wastes, to repair damaged DNA, to synthesize neurotransmitters, etc. At the organ level, the heart uses energy to pump blood, the kidneys use energy to filter wastes while recycling precious nutrients, the brain uses energy to conduct electrical nerve impulses, the lungs use energy to take in oxygen and expel carbon dioxide and so on. At the level of the whole person, we use energy to walk, run, talk, chop wood, lift objects, work a computer keyboard, ad infinitum. The energy source for all these levels is the same - it is the bio-energy molecule ATP (adenosine triphosphate) the "universal energy currency of the cell"567.

Energy cannot be created or destroyed, it can only be converted from one form into another. This rule also applies to the generation of energy in the human body. The energy, that is stored in food, must be released or produced in the body, by means of particular chemical reactions referred to as metabolism. Dietary carbohydrate from which humans gain energy enters the body in complex forms. The major source of dietary carbohydrate for humans is starch from consumed plant material. This is supplemented with a small amount of glycogen from animal tissue, disaccharides such as sucrose from products containing refined sugar and lactose in milk544.

3.1 FROM FOOD TO METABOLIC ENERGY

"Food is of no use to our body until we have allowed the cells of our body to convert the food energy (organic energy) into chemical energy through respiration. Cell respiration is when organic material (the food we eat) is converted into chemical energy within the cells to provide the energy we use to perform our everyday activities. Chemical energy is stored within the bonds between carbon and hydrogen. Every time a bond is broken energy is released due to the exothermic reaction that takes place, that is, energy is given to the body. Glucose is a good energy store because of the six carbon-hydrogen bonds. However, the main source of energy is one that is produced within our body. It is the universal energy carrier, ATP, formally known as adenosine triphosphate"546.

Digestion is a complex process. The cells that line the digestive tract secrete into the lumen of the gut a variety of substances, such as hydrochloric acid and digestive enzymes, to break down food molecules into simpler nutrients. The cells absorb these nutrients from the gut lumen, process them, and then release them into the blood for utilization by other cells of the body. All of these activities are adjusted according to the composition of the food consumed and the levels of metabolites in the circulation.

The first step in the metabolism of digestible carbohydrate is the conversion of the higher polymers to simpler, soluble forms that can be transported across the intestinal wall and delivered to the tissues. The breakdown of sugars begins in the mouth. Saliva is slightly acidic and contains lingual amylase that begins the digestion of carbohydrates. Once the food has arrived in the stomach, acid hydrolysis contributes to its degradation; specific gastric proteases and lipases aid this process for proteins and fats, respectively. The mixture of gastric secretions, saliva, and food, known collectively as chyme, moves to the small intestine. The resultant glucose and other simple carbohydrates are transported across the intestinal wall to the hepatic portal vein and then to parenchymal liver cells and other tissues. There they are converted to fatty acids, amino acids, and glycogen, or else oxidized by the various catabolic pathways of cells544. Most of these pathways are in the mitochondria, whose outer membrane forms an aqueous channel through which proteins up to 10,000 daltons can pass and go into the intermembrane space.742 The average person's body contains enough glycogen to provide energy for 6-12 hours. In contrast to this, it contains enough fat to provide energy for up to 40 days149. An adult man produces enough heat every day during the metabolism of energy, to boil almost 40l of water209.

Energy is also required to enable these digestive and metabolic processes. Between 5% and 10% of the energy that is available in the body is required for metabolising food. Various factors play a role in the generation, storage and utilisation of energy, and include the body's surface-area, age, gender, thyroid hormones, dopamine, serotonin, adrenaline, body temperature and women's menstrual cycle143.

3.2 MAJOR PATHWAYS OF ENERGY METABOLISM

Glucose is oxidised by all tissues to synthesise ATP. The first pathway which begins the complete oxidation of glucose is called glycolysis. The normal pathways are briefly described320, 545:

3.2.1 Glycolysis

Glycolysis (the breakdown of glucose to pyruvate and lactate, occurs in the cell cytoplasm): Glucose + 2 ATP + 4 ADP + 2 NAD -> 2 Pyruvate + 2 ADP + 4 ATP + 2 NADH + energy. Oxidation of glucose is known as glycolysis. Glucose is oxidized to either lactate or pyruvate. Under aerobic conditions, the dominant product in most tissues is pyruvate and the pathway is known as aerobic glycolysis. When oxygen is depleted, as for instance during prolonged vigorous exercise, the dominant glycolytic product in many tissues is lactate and the process is known as anaerobic glycolysis. “These studies demonstrate that orderly glycolysis in the erythrocyte is regulated by the NAD-to-NADH ratio and also provide a method that makes possible the in vitro study of erythrocyte glycolysis.”235

The conversion of pyruvate to lactate, under anaerobic conditions, provides the cell with a mechanism for the oxidation of NADH (produced during the G3PDH reaction) to NAD which occurs during the LDH catalyzed reaction. This reduction is required since NAD is a necessary substrate for G3PDH, without which glycolysis will cease. Normally, during aerobic glycolysis the electrons of cytoplasmic NADH are transferred to mitochondrial carriers of the oxidative phosphorylation pathway generating a continuous pool of cytoplasmic NAD.546, 733

3.2.2 Gluconeogenesis

Gluconeogenesis is the biosynthesis of new glucose, (i.e. not glucose from glycogen). The production of glucose from other metabolites is necessary for use as a fuel source by the brain, testes, erythrocytes and kidney medulla since glucose is the sole energy source for these organs. Under fasting conditions, gluconeogenesis supplies almost all of the body's glucose tothe brain as energy from ketone bodies which are converted to acetyl-CoA. Synthesis of glucose from three and four carbon precursors is essentially a reversal of glycolysis. The three reactions of glycolysis that proceed with a large negative free energy change are bypassed during gluconeogenesis by using different enzymes. Lactate is a predominate source of carbon atoms for glucose synthesis by gluconeogenesis.730, 733

3.2.3 The Pyruvate Dehydrogenase Complex

The pyruvate dehydrogenase complex (which oxidizes pyruvate to enter the citric acid cycle, operates only under aerobic conditions): Pyruvate + NAD + Coenzyme A -> CO2 + acetyl-CoA + NADH + energy. Cofactors required for pyruvate dehydrogenase include five different coenzymes namely: thiamine pyrophosphate (TPP) from thiamin; flavine adenine dinucleotide (FAD) from riboflavin; Coenzyme-A (CoA), from pantothenate; nicotinamide adenine dinucleotide (NAD), from vitamin niacin and alpha-lipoic acid.544

3.2.4 The Citric Acid Cycle (Krebs Cycle)

The citric acid cycle (which completes the oxidation of carbohydrates and other substrates to carbon dioxide, occurs in mitochondria of cells): Acetyl-CoA + 3 NAD + FAD + ADP -> 2 CO2 + Coenzyme A + 3 NADH + FADH2 + ATP. Regulation of the TCA cycle, like that of glycolysis, occurs at both the level of entry of substrates into the cycle as well as at the key reactions of the cycle. Fuel enters the TCA cycle primarily as acetyl-CoA. The generation of acetyl-CoA from carbohydrates is, therefore, a major control point of the cycle. This is the reaction catalyzed by the PDH complex. The PDH complex is inhibited by acetyl-CoA and NADH and activated by non-acetylated CoA (CoASH) and NAD. Since three reactions of the TCA cycle as well as PDH utilize NAD as cofactor it is not difficult to understand why the cellular ratio of NAD/NADH has a major impact on the flux of carbon through the TCA cycle.737

3.2.5 Electron Transport and Oxidative Phosphorylation

Mitochondrial oxidative phosphorylation in vivo is dependent on the degree of reduction of the intramitochondrial reducing power ([NADH]/[NAD], cytoplasmic energy state ([ATP]/[ADP][Pi]) and intracellular oxygen pressure. Electron transport and oxidative phosphorylation (occurs in membranes of mitochondria in cells only under aerobic conditions). Nutritional implications and chemical structures are NAD and FAD. While the large quantity of NADH resulting from TCA cycle activity can be used for reductive biosynthesis, the reducing potential of mitochondrial NADH is most often used to supply the energy for ATP synthesis via oxidative phosphorylation. Oxidation of NADH with phosphorylation of ADP to form ATP are processes supported by the mitochondrial electron transport assembly and ATP synthase, which are integral protein complexes of the inner mitochondrial membrane. Oxidative phosphorylation traps this energy as the high-energy phosphate of ATP. In order for oxidative phosphorylation to proceed, two principal conditions must be met. First, the inner mitochondrial membrane must be physically intact so that protons can only reenter the mitochondrion by a process coupled to ATP synthesis. Second, a high concentration of protons must be developed on the outside of the inner membrane.731, 742 “A prolonged decrease in ATP levels underlies a number of neurodegenerative disorders. Defects in oxidative phosphorylation are associated with a number of neurodegenerative disorders.”748

“The precise relationship between mitochondrial DNA mutations, impairment of oxidative phosphorylation and clinical phenotypes is not well understood. The prevailing view is that defects in ATP generating capacity due to mitochondrial DNA defect leads to energy failure, cellular dysfunction and eventually cell death in the affected tissues.”765

3.2.6 The Pentose Phosphate Pathway

The pentose phosphate pathway (an alternate pathway for glucose oxidation). The pentose phosphate pathway is primarily an anabolic pathway to generate reducing equivalents, in the form of NADPH, for reductive biosynthesis reactions within cells, to provide the cell with ribose-5-phosphate (R5P) for the synthesis of the nucleotides and nucleic acids and to metabolize dietary pentose sugars derived from the digestion of nucleic acids as well as to rearrange the carbon skeletons of dietary carbohydrates into glycolytic/gluconeogenic intermediates.738

3.2.7 Beta-Oxidation of Fatty Acids

Beta-oxidation of fatty acids (occurs in mitochondria of cells, only under aerobic conditions): Chemical structures and nutritional implications are coenzyme A (CoA), from pantothenic acid; flavin adenine dinucleotide (FAD), from riboflavin (vitamin B2) and nicotinamide adenine dinucleotide (NAD), from niacin. Fatty acid oxidation is reduced as this process requires NAD as a cofactor. Glycogenolysis is the breakdown of glycogen to glucose.732

3.3 ENERGY FACTORIES: THE MITOCHONDRIA

The mitochondria are essentially the body's power plants. All mitochondria are inherited from our mothers via the ovum, with virtually no mitochondria coming from our fathers, because the sperm head that penetrates the ovum in fertilization does not contain any mitochondria548, 549. If a number of the mitochondria in the ovum are defective, problems may arise as they divide and the infant is formed. If the defective mitochondria are in the muscles, the muscles may be weak due to poor energy production. This is true for all the body's organs including the brain549. Depending on where a metabolic block is in an inborn error of metabolism, we can try to provide energy from foodstuff that does not need that particular defective metabolic pathway550. "Pyridine nucleotides (NAD etc) are mostly stored within mitochondria where they are involved in different functions ranging from energy metabolism to cellular signaling. Here we discuss the mechanisms of mitochondrial NAD(+) metabolism and release that may contribute to the crucial roles played by these organelles as triggers or amplifiers of physiological and pathological events".687

The mitochondria are small structures which are present in all cells. The quantity of mitochondria varies amongst the different types of cells. Liver cells, for example, contain many more mitochondria than sperm cells129. The energy that is generated, is apportioned for use in cellular activity, for storage as chemical compounds that are rich in energy (like ATP and NAD derivatives), and the remainder is released as heat39. The primary "objective" of the energy metabolism is the manufacturing of ATP (about 50kg per day in the average human being) thereby providing the power for all cellular activities370.

Ninety per cent of the body's energy is provided by the mitochondria's process of oxidative phosphorilisation. It is an extremely effective system for providing sufficient energy, to maintain the body's structure and functioning, and for regulating the body's temperature. The process consists of two metabolic processes that are closely linked to each other, i.e. the citric-acid cycle and the electron-transfer chain. In complex I of the electron-transfer chain, NAD to NADH is involved; in the citric-acid cycle three NAD to NADH compounds are involved82. The citric-acid cycle cannot function without the availability of NAD and NADP. Slight deviations in the activity of the mitochondria can lead to weakness, fatigue and cognitive problems51, 68.

Mitochondria have a crucial role both in energy production and the viability of the cell and recently mitochondria have been implicated in programmed cell death (apoptosis). Although much smaller than the nuclear genome, mtDNA is equally important. MtDNA defects and the resulting mitochondrial dysfunction are important contributors to human degenerative diseases, ageing and cancer356. Mitochondria play a pivotal role in cellular metabolism and in energy production in particular. Defects in structure or function of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis and other metabolic pathways, have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogeneity of mitochondrial diseases357, 361.

The Krebs or citric acid cycle is the final common pathway of food components, and is also the source of basic structural or anabolic molecules that feed and support organ maintenance and neurological function. This fundamental pathway of energy flow is critical for all organ systems. Conversions of the Krebs cycle intermediates are under the control of enzymes that often require vitamin-derived cofactors and minerals for their function. Mild inborn errors of energy metabolism which may be compatible with survival at least into young adulthood, but not with normal development of mental and neurological functions, have been associated with the abnormal spilling of the Krebs cycle's intermediates532.

3.4 ENERGY SYSTEMS USED DURING EXERCISE

The Cori cycle operates during exercise, when aerobic metabolism in muscle cannot keep up with energy needs. Glucose synthesized in liver and transported to muscle and blood. A highly exercising muscle generates a lot of NADH from glycolysis but without oxygen there is no way to regenerate NAD from the NADH (need NAD!). Lactic acidosis can and would result from insufficient oxygen (an increase in lactic acid and decrease in blood pH). So, the NADH is reoxidized by reduction of pyruvate to lactate by enzyme lactate dehydrogenase. Results in replenishment of NAD for glycolysis. Then the lactate formed in skeletal muscles during exercise is transported to the liver where it is used for gluconeogenesis. Lactate is transported through the bloodstream to the liver. Lactate is oxidized to pyruvate in the liver. Liver lactate dehydrogenase reconverts lactate to pyruvate since has high NAD/NADH ratio. Pyruvate is used to remake glucose by gluconeogenesis. Glucose is transported back to the muscles via the bloodstream.733

3.4.1 LESS THAN 10 SECONDS

The immediate energy system provides energy rapidly but for only a short period of time. It is used to fuel activities that last for about 10 or fewer seconds. For example weight lifting and picking up a bag of groceries. Components include existing cellular ATP stores and creatine phosphate (CP).733

3.4.2 10 SECONDS TO 2 MINUTES

The nonoxidative (anaerobic) energy system used at the start of an exercise session and for high intensity activities lasting for about 10 seconds to 2 minutes. Examples, 400 meter run or to dash up several flights of stairs. Creates ATP by breaking down glucose and glycogen. Does not require oxygen. Two key limiting factors (1) body's supply of glucose and glycogen is limited (2) nonoxidative system results in the production of lactic acid.733

3.4.3 LONGER THAN 2 MINUTES

The oxidative (aerobic) energy system requires oxygen to generate ATP. The aerobic production of energy does not produce any toxic waste products and so is the preferred system for prolonged exercise. Used during physical activity that lasts longer than 2 minutes (e.g. distance running, hiking ATP production takes place in cellular structures called mitochondria. Can use carbohydrates (glucose and glycogen) or fats to produces ATP. The actual fuel source depends on: intensity and duration of the activity as well as the fitness status of the individual.733

3.4.4 LONGER THAN 70-92 MINUTES

In general, carbohydrate use increases with increasing intensity and falls with increasing duration of an activity. Fats are used for lower ― intensity exercise. Glycogen stores are finite, and inevitably become depleted during long continuous exercise lasting in excess of 70-92 minutes (the more intensive the exercise, the quicker the glycogen is depleted). This applies not only to endurance events, such as marathon running but also to intermittent exercise sports such as soccer and rugby. When glycogen stores have been used up, the muscles attempt to cover their energy needs from fat metabolism. Unfortunately, because fat cannot supply energy at as rapid a rate as carbohydrate, the competitor is forced to slow down or reduce his/her rate of work to the level at which energy expenditure and energy synthesis are matched. This situation is made worse by the fact that when glycogen stores in the muscles are used up, blood glucose (hypoglycemia) reduces the supply of glucose to the brain, contributing to the feeling of exhaustion and causing a decrease in technique and the ability to make correct decisions.733

3.4.5 RECOVERY AFTER EXHAUSTIVE EXERCISE

Choice of diet has a dramatic effect on glycogen recovery following exhaustive exercise. A diet consisting mainly of protein and fat results in very little recovery of muscle glycogen even after 5 days! On the other hand a high carbohydrate diet provides faster restoration of muscle glycogen. Even though, however, complete recovery of glycogen stores takes about 2 days. During a prolonged exercise session, carbohydrates are the predominant fuel at the start of a workout, but fat utilizations (aerobic) increases over time. Carbohydrate metabolism is an energy system that does not depend on oxygen, but is only available for a short period of time as it rapidly causes fatigue. One of the reasons for this fatigue is the accumulation of lactic acid which quickly reduces the ability of the muscles to contract effectively. Lactic acid in the muscles can cause discomfort both during and after exercise, and total recovery will not occur until the excess lactic acid produced during exercise has been fully degraded. 733