Cellular energy (respiration)
Our bodies primarily use carbohydrates for energy but has devised complex ways to turn first fats then, if needed, proteins into energy. The numerous biochemical pathways responsible for energy delivery all ultimately involve the formation of adenosine triphosphate (ATP) from adenosine diphosphate ADP and reduced nicotinamide adenine dinucleotide (NADH) from NAD+. When the energy is needed they are metabolized (hydrolysed) releasing a spark of electron energy:
– ATP = ADP + energy
– NADH = NAD+ + energy
The energy used by human cells requires the metabolism of 100 – 150 moles of ATP daily, which is around 50 to 75 kg. A human will, therefore, typically use up his or her body weight of ATP over the course of the day.
The rest of this page explains how these little packets of energy are produced both in normal cells and cancer and how this knowledge could explain the pros and cons of nutritional interventions which try to harness energy producing pathways such as the ketogenic diet. The process of producing energy is called cellular respiration, summarised in the picture below and split into three main components:
- Glycolysis – producing 2 ATP and 2 NADH
- The critic acid (TCA) cycle or Kreb’s cycle – producing 2 ATP + 4NADH
- Oxidative phosphorylation (OXOPHOS) – producing 32 ATP
Glycolysis is the metabolic pathway that converts glucose, galactose, fructose and glycerol into pyruvate. The free energy released in glycolysis is used to form 2 ATP and 2 NADH molecules. The pyruvate generated as an end product of glycolysis then enters the next stage of cellular respiration the Critic acid, TCA or Krebs cycle. The monosaccharides sugars in the blood come from the breakdown of ingested carbohydrates such as bread, potatoes and pasta, milk ingested sugars directly or broken down from glycogen stores in the liver. When the blood sugar drops a hormone called glycagon stimulated the conversion of glycogen to glucose. On the other hand when sugar levels rise, after a meal, for example, insulin stimulates the conversion of glucose back to glycogen. Lactose, in milk is broken down to glucose and galactose by lactase which both enter the glycolysis pathway directly. Glycerol is released when triglycerides are broken down to free fatty acids (FFA) can enters the glycolysis pathway directly – this is one way triglycerides can be used for energy
Glycolysis is an oxygen independent metabolic pathway, meaning that it does not use molecular oxygen (i.e. atmospheric oxygen) for any of its reactions. However the products of glycolysis (pyruvate and NADH + H+ ) are metabolised using atmospheric oxygen. When molecular oxygen is used for the metabolism of the products of glycolysis the process is usually referred to as aerobic, whereas if no oxygen is used the process is said to be anaerobic, in which lactate (lactic acid) is produced. Lactic acid can be used as an energy source by some organs, particularly the heart but it is generally convert back to pyruvic acid when oxygen becomes available again.
Citric acid cycle
This is also called the Krebs cycle or the tricarboxylic acid cycle. When oxygen is present, acetyl-Coa is produced from the pyruvate molecules created from glycolysis. Once acetyl-Coa formed, aerobic or anaerobic respiration can occur. In the presence of oxygen, when acetyl-CoA is produced, the molecule then enters the Krebs cycle inside the mitochondrial matrix, and is oxidised to Co2 while at the same time producing NADH from NAD+ together with H2O and CO2, When oxygen is present, the mitochondria will undergo aerobic respiration which leads to the Krebs cycle. However, if oxygen is not present, fermentation of the pyruvate molecule will occur.
In humans oxidative phosphorylation also occurs in the mitochondria. The reason we need oxygen is so our cells can use this molecule during oxidative phosphorylation, the final stage of cellular respiration. Oxidative phosphorylation is made up of two closely connected components: the electron transport chain and chemiosmosis. In the electron transport chain, NADH moves from the cytosol into the mitochondria where it donates an electron to the electron transport chain. The electron transport chain consists of a group of proteins (and some lipids) that work together to pass electrons “down the line” to form an electrochemical gradient. Finally in the presence of oxygen, 32 ATP’s is formed, providing energy for many cellular functions.
Utilising fats, proteins and ketones to produce energy
So far we have talked mainly about how the monosaccharides glucose, fructose and galactose are used to form energy. They are the body’s preferred primary source but in times of fasting it can easily use fats instead. If starvation has set in, proteins can be used but, obvious, eating our own muscles is an emergency survival manoeuvre. This is commonly seen in severely ill patients who have had trouble eating or absorbing food for some time – a state called cachexia. Ketones can be used by cells outside the liver and some cells such as the heart can even use lactic acid. We will now expand on the biochemical pathways with allow us to produce energy from these sources and manipulation of which could have an impact on health.
Fats as cellular energy sources
Fats (lipids) are stored in adipose tissue. These stored fat molecules are synthesized in the body from the glycerol and fatty acids in a process known as lipogenesis. When the blood glucose drops the levels of insulin also drops and the levels of glycagon increases. This stimulates the release of triglycerides and Free Fatty Acids (FFA) from the adipose stores and mobilized in to the blood. As these flow, via the blood stream, through the liver the triglycerides are broken down to glycerol and fatty acids. As mentioned above glycerol is then converted into one of the intermediate products of glycolysis to produce pyruvic acid which then enters the Krebs cycle. Fatty acids are changed via a series of reactions called beta-oxidation into acetyl CoA molecules, which also enter the Kreb’s Cycle. The enzyme carnitine, is important in this process as it is also increased by glycagon and enhances the utilization of FFA by increasing their transport into the mitochondria of liver cells where the conversion to acetyl CoA occurs. Cells can happily transfer from sugar to fatty acid use throughout the day depending on the proximity to meals and amount of sugar in the blood stream. Obviously, if an individual never lets their blood glucose levels drop by snacking constantly, fatty acids are used less, fat stores are not ultilised and obesity sets in. The corollary of this is after fasting in which fatty acid conversion to acetyl CoA (in the liver) is enhanced and a third water soluble energy source call ketones is formed which is particularly useful for the brain which cannot directly use fatty acids for energy. This is highlighted in more detail below.
Proteins as cellular energy sources
When you eat proteins in food, your body has to break them down into amino acids before they can be used by your cells. Most of the time, amino acids are recycled and used to make new proteins, rather than oxidized for fuel. However, if there are more amino acids than the body needs, or if cells are starving, some amino acids will broken down for energy via cellular respiration. In order to enter cellular respiration, amino acids must first have their amino group removed in a process called deamination. This step makes ammonia as a toxic waste product, and in humans enzymes, in the liver, then convert it to urea and uric acid by adding carbon dioxide which is the then filtered and excreted by the kidneys.
Once the amino acids have been deaminated, products called alpha-keto acids are formed which enter the cellular respiration pathways at different stages depending on the type of amino acid they originated from (there are 20) and what type of deaminated product is formed. Some are ketogenic amino acids which can be degraded directly into acetyl CoA and ketone bodies which are used in the Krebs cycle where they are ultimately degraded to carbon dioxide. This is in contrast to the glucogenic amino which can enter the glycolysis pathway to form pyruvic acid.
Some intact amino acids are import for the maintenance of the Krebs cycle so are important for energy production. In particular, the non-essential amino acid glutamine has been generating academic interest recently. Glutamine serves as an inter-organ shuttle of carbon and nitrogen. It therefore helps cells import nitrogen which need it and clear it from cells which do not. It is a major source of nitrogen for other non-essential amino acids and nuclear (nucleotides). Glutamine is also needed to produce both acetyl-CoA and oxaloacetate (OAA) which condensate produce citrate in the first part of the Krebs cycle activity. In starvation, less puruvate enters the cycle via glycolysis but the cell is able to upregulate the glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enhancing krebs cycle function. Early laboratory work removing glutamine from cancer cell nutrients has resulted in reduced growth but this would be impractical in humans as glutamine is ubiquitous in meat, fish, pulses and vegetables.
Ketones as energy sources
As you have just read, ketones are produced when the body burns fats or proteins to produce energy molecules. They are also produced when there is not enough insulin to help your body use sugar for energy such as uncontrolled type 1-diabetes. Fatty acids are changed via a series of reactions called beta-oxidation into acetyl CoA molecules which enters the Kreb cycle to produce energy molecules. If fatty acids are used primarily acetyl CoA also produces ketone bodies. Three most reported are; acetone which is volatile and excreted in the breath; B-hydroxybutyrate which is converted to acetoacetate and acetoacetate itself. To understand why this mechanism an survival advantage, it is important to note that liver cells lack the enzyme (Succinyl CoA transferase) which allows ketones to utilize ketones as energy so instead ketones are released into the blood stream in order to feed other tissues such as the brain, muscles and heart. In these tissues they are converted back to acetyl CoA which then enters the TCA (Krebs) cycle to produce energy:
The difference between normal and cancer cell energy ulitisation
Normal cells fluctuate between using sugars or fatty acids depending of the blood sugar levels, degree of oxygenation and rate of proliferation required. Usually cells slow glycolysis in the presence of oxygen and low blood sugars and favor oxidative phosphorylation (OXPHOS). Likewise when blood sugars drop they switch to fatty acids metabolism which by-passes glycolysis. In normal conditions, the cell metabolism consumes energy, of which 70% is supplied by OXPHOS. In hypoxia, however, glycolysis becomes enhanced to compensate for the weakened function of OXPHOS. Interesting cells which required rapid proliferation such as healing scars also favour glycolysis because, although it only produces 2 ATP molecules, it is a much faster pathway so energy is provided instantly. Therefore, glycolysis and OXPHOS cooperate to maintain the cellular energetic balance. Cancer cells appear lose this regulation and favor glycolysis despite falling blood sugars. This aerobic glycolysis was first observed by Otto Warburg in the 1920’s and it was first through to be a achilles heal for the cancer cells and a target for drugs and nutritional strategies such as the ketogenic diet. This view is challenged by recent investigations, which found that the function of mitochondrial OXPHOS in many cancers is intact and cancer cells can switch from one to another with ease depending on the level of oxygen and other cellular conditions – this plasticity is explained further in the description of the ketogenic diet.