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Do mitochondria digest fats?

Do mitochondria digest fats?


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I am a student and I'm currently using the IB biology Oxford textbook. A few weeks ago I had a test on biochemistry. I studied on my textbook and it stated the following: "Mitochondrion: (… ) fat is digested here if it is being used as an energy resource in the cell" (page 22) "The energy store from them (Triglycerides) can be released by aerobic cell respiration" (page 78). My teacher told me that I was wrong to write these statements in my test. Is there something wrong? Is the term 'fat' too generic? Do different kinds of fats undergo either aerobic or anaerobic respiration? I am currently confused as I do not know who is right and who is wrong… Can someone answer my questions?

Thank you


You are not far off the mark I would say. Strictly speaking it's not correct to say that mitochondria oxidize fat. By "fat" we usually mean triacylglycerides, and these must first be hydrolyzed into free fatty acids (by enzymes known as lipases) that can be oxidized in the mitochondria. But many researchers and textbook authors are not always careful with this distinction.

Most fatty acids are indeed oxidized ("digested" sounds strange to me) in the mitochondria into acetyl-CoA units, in a process known as beta-oxidation. The acetyl-CoA units produced are then further oxidized into CO$_2$ by the TCA cycle. These processes generate NADH and FADH$_2$ which is converted into ATP by the respiratory chain.

There are exceptions though. Very long-chain or branched fatty acids are instead oxidized in peroxisomes, which contain enzymes specialized for this purpose.

There is no such thing as "anaerobic respiration": in animals, respiration always uses oxygen as the terminal electron acceptor. Mitochondrial beta-oxidation is coupled to the respiratory chain, and therefore requires oxygen. Peroxisomal oxidation is not directly coupled to respiration, but the process still requires oxygen, which in this case is reduced directly by the fatty acid oxidases. So there is no truly anaerobic form of fatty acid oxidation.


Mitochondrial Health: Ancient Wisdom in Your Body’s Cells

What Are Mitochondria | Dysfunctions | Tests | Diet | Supplements | Lifestyle
Known as the batteries that power almost every cell in our body, there’s much more to the mitochondria than energy production. The more we research the mitochondria, the more we learn how deeply they are involved in our health, well-being and our risk of chronic disease.

In this article we’ll cover the importance of the mitochondria to our health, how to know if your mitochondria aren’t working properly, and natural ways to optimize mitochondrial function.


Metabolic changes in fat tissue in obesity associated with adverse health effects

Researchers at the Obesity Research Unit of the University of Helsinki have found that obesity clearly reduces mitochondrial gene expression in fat tissue, or adipose tissue. Mitochondria are important cellular powerplants which process all of our energy intake. If the pathways associated with breaking down nutrients are lazy, the changes can often have health-related consequences.

A total of 49 pairs of identical twins discordant for body weight participated in the study conducted at the University of Helsinki: their body composition and metabolism were studied in detail, and biopsies from adipose and muscle tissue were collected. Multiple techniques for analysing the genome-wide gene expression, the proteome and the metabolome were used in the study.

The study was recently published in the journal Cell Reports Medicine.

According to the findings, the pathways responsible for mitochondrial metabolism in adipose tissue were greatly reduced by obesity. Since mitochondria are key to cellular energy production, their reduced function can maintain obesity. For the first time, the study also compared the effects of obesity specifically on the mitochondria in muscle tissue in these identical twin pairs: muscle mitochondria too were found to be out of tune, but the change was less distinct than in adipose tissue.

The study provided strong evidence of a connection between the low performance of adipose tissue mitochondria and a proinflammatory state. Furthermore, the findings indicate that metabolic changes in adipose tissue are associated with increased accumulation of fat in the liver, prediabetic disorders of glucose and insulin metabolism as well as cholesterol.

"If mitochondria, the cellular powerplants, are compared to the engine of a car, you could say that the power output decreases as weight increases. A low-powered mitochondrial engine may also generate toxic exhaust fumes, which can cause a proinflammatory state in adipose tissue and, consequently, the onset of diseases associated with obesity," says Professor Kirsi Pietiläinen from the Obesity Research Unit, University of Helsinki.

"What was surprising was that the mitochondrial pathways in muscle had no association with these adverse health effects," Pietiläinen adds.

Obesity also affected amino acid metabolism

In the study, changes in mitochondrial function were also seen in amino acid metabolism. The metabolism of branched-chain amino acids, which are essential to humans, was weakened in the mitochondria of both adipose tissue and muscle tissue.

"This finding was of particular significance because the reduced breakdown of these amino acids and the resulting heightened concentration in blood have also been directly linked with prediabetic changes and the accumulation of liver fat in prior twin studies," says Pietiläinen.

Obesity, with its numerous associated diseases, is a common phenomenon that is continuously increasing in prevalence. While lifestyle influence the onset of obesity, genes also have a significant role.

"Identical twins have the same genes, and their weight is usually fairly similar. In fact, studying twins is the best way to investigate the interplay between genes and lifestyle. In spite of their identical genome, the genes and even mitochondria of twins can function on different activity levels. We utilised this characteristic in our study when looking into the effects of weight on tissue function," Pietiläinen says.


6 mitochondrial ways to a strong heart

Here are six mitochondrial fixes that will ramp up your cardiovascular system STAT:

Minimize your exposure to 3 environmental toxins

Most chronic inflammation is the result of unwanted substances in the body, such as environmental toxins like pesticides, mold, and food toxins called mycotoxins. [6] Science strongly supports the fact that environmental toxicity lowers mitochondrial function [7] [8] , which in turns lowers vascular function. [9] To keep your mitochrondria in tip-top shape, eliminate these three toxins:

Pesticides like glyphosate, the active ingredient used in weedkillers like Roundup, affect mitochondrial ability to generate ATP. [10] While it’s nearly impossible to avoid glyphosate completely – unless you live off-the-grid on your own land – there are steps you can take to both minimize your exposure and get pesticides and herbicides out of your body.

  • Eat organic food that originates from sustainable farming practices. This reduces your exposure to water- and soil-based chemicals. The Bulletproof Diet is based on organic food for this very reason.
  • Detoxify from chemicals that are already in your body by breaking a sweat. Both exercise and time in a sauna help your body to excrete chemicals naturally. [11] Read on for more ways to detoxify from glyphosate.

Environmental mold

Mold, particularly as a result of water-damaged buildings, is a definitive culprit in compromised mitochondrial function [12] , Follow these steps to minimize your mold exposure immediately.

  • If you suspect mold in your home, have it professionally inspected. An ERMI (Environmental Relative Moldiness Index) Air Test evaluates the risk for indoor mold growth and associated health effects in your home or office.
  • Remove and remediate any existing mold from your home. If an ERMI reveals you do live in a mold-ridden environment, get out immediately. Stay with family or friends until a remediation specialist has given you the green light to go home again.
  • Prevent new mold from forming in your bathroom and other damp areas with Homebiotic, a probiotic spray that prevents mold growth.

Toxins in food called mycotoxins also inhibit mitochondrial function. [13] Mycotoxins, produced by mold, arise from the manipulation of food – through growing, cooking, and fermentation processes. To keep mycotoxins out of your body, avoid foods that most often contain them (more on that below) and take supplements to detox from mold exposure.

  • Avoid gluten, yeast, wheat, corn, grain (other than white rice), barley, peanuts, cottonseed, grain-fed meat and dairy, mushrooms, and commonly available chocolate. Even unfiltered tap water, unfiltered alcoholic beverages (beer and wine), and commonly available coffee can contain high mycotoxin levels.
  • Consume more organic vegetables and wild-caught fish, which bind to mycotoxins, thereby helping to remove them from your body.

Avoid overeating, especially sugary carbs

Overeating can cause you to get LPSs (lipopolysaccharides) which cause mitochondrial inflammation [14] , and have been linked to everything from Parkinson’s Disease to autism. [15] LPS is a compound made of fats and sugar that’s normally protective. However, when LPSs release into the bloodstream, they become a dangerous toxin that drives up inflammation. The solution? Eat plenty of fibrous veggies rather than binging on sugary carbs.

Bind and release your toxins

  • Take supplements that bind to toxins and flush them out of your system. Those include calcium d-glucarate, chlorella, and charcoal. Activated charcoal can absorb chemicals, drugs, pesticides, mercury, and even lead before they inflame your body. [16] Take 1-2 charcoal pills after you suspect exposure. Read Activated Charcoal: A Strange Way to Detox for more tips on how to use activated charcoal to bind unwanted materials from your body and release them rapidly.
  • Get all the details on the best supplements to eliminate toxins here.

Increase bile flow throughout your body

Bile is a fluid that helps you to digest fat properly, as well as to break down toxins. It’s secreted by the liver, though stored in the gallbladder. With insufficient bile, your body will have trouble binding and excreting the toxins that accumulate in it. [17] It’s somewhat of a catch-22 because toxins impair your body’s ability to produce bile, yet bile is a necessity to help you excrete toxins. What to do?

  • Consume saturated fats, like grass-fed meat and butter, to stimulate bile production. [18]
  • Avoid foods containing mold alfatoxins like peanuts, corn, milk, cheese, nuts, and soybeans that impair liver function, thus lowering bile production. [19]
  • Supplement with ox bile and lipase. Most people have been on a low-fat diet at one time or another, which has the effect of down-regulating the natural bile production in your gallbladder. When you switch to a high-fat diet, take the enyzme lipase to help you to digest fat better. Aim for a high-quality lipase supplement that is free of toxic mold species like Aspergillus. You can also combine lipase with ox bile, which further assists to break down fats and promote fat-soluble vitamin absorption.

Supplement to support maximal mitochondrial health

Supplementation can go a long way toward improved mitochondrial health. In particular, Bulletproof offers two supplements that help you sustain high energy at the cellular level:

    helps your mitochondria to create more energy (ATP) and keeps them running at peak performance. This formula pairs active PQQ with CoQ10, a well-known enhancer of mitochondrial function, to increase its overall effects. mimics the effect of calorie restriction, which assists your body to create new mitochondria. KetoPrime also helps to boost the overall output of your mitochondria, thereby giving you clean-burning energy sans jittery stimulants.

Contents

Fatty acids are stored as triglycerides in the fat depots of adipose tissue. Between meals they are released as follows:

    , the removal of the fatty acid chains from the glycerol to which they are bound in their storage form as triglycerides (or fats), is carried out by lipases. These lipases are activated by high epinephrine and glucagon levels in the blood (or norepinephrine secreted by sympathetic nerves in adipose tissue), caused by declining blood glucose levels after meals, which simultaneously lowers the insulin level in the blood. [1]
  • Once freed from glycerol, the free fatty acids enter the blood, which transports them, attached to plasma albumin, throughout the body. [4]
  • Long chain free fatty acids enter the metabolizing cells (i.e. most living cells in the body except red blood cells and neurons in the central nervous system) through specific transport proteins, such as the SLC27 family fatty acid transport protein. [5][6] Red blood cells do not contain mitochondria and are therefore incapable of metabolizing fatty acids the tissues of the central nervous system cannot use fatty acids, despite containing mitochondria, because long chain fatty acids (as opposed to medium chain fatty acids [7][8] ) cannot cross the blood brain barrier[9] into the interstitial fluids that bathe these cells.
  • Once inside the cell long-chain-fatty-acid—CoA ligase catalyzes the reaction between a fatty acid molecule with ATP (which is broken down to AMP and inorganic pyrophosphate) to give a fatty acyl-adenylate, which then reacts with free coenzyme A to give a fatty acyl-CoA molecule.
  • In order for the acyl-CoA to enter the mitochondrion the carnitine shuttle is used: [10][11][12]
  1. Acyl-CoA is transferred to the hydroxyl group of carnitine by carnitine palmitoyltransferase I, located on the cytosolic faces of the outer and inner mitochondrial membranes.
  2. Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase, as a carnitine is shuttled outside.
  3. Acyl-carnitine is converted back to acyl-CoA by carnitine palmitoyltransferase II, located on the interior face of the inner mitochondrial membrane. The liberated carnitine is shuttled back to the cytosol, as an acyl-CoA is shuttled into the mitochondrial matrix.
    , in the mitochondrial matrix, then cuts the long carbon chains of the fatty acids (in the form of acyl-CoA molecules) into a series of two-carbon (acetate) units, which, combined with co-enzyme A, form molecules of acetyl CoA, which condense with oxaloacetate to form citrate at the "beginning" of the citric acid cycle. [2] It is convenient to think of this reaction as marking the "starting point" of the cycle, as this is when fuel - acetyl-CoA - is added to the cycle, which will be dissipated as CO2 and H2O with the release of a substantial quantity of energy captured in the form of ATP, during the course of each turn of the cycle.
  1. Dehydrogenation by acyl-CoA dehydrogenase, yielding 1 FADH2
  2. Hydration by enoyl-CoA hydratase
  3. Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase, yielding 1 NADH + H +
  4. Cleavage by thiolase, yielding 1 acetyl-CoA and a fatty acid that has now been shortened by 2 carbons (forming a new, shortened acyl-CoA)
  • The acetyl-CoA produced by beta oxidation enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. This results in the complete combustion of the acetyl-CoA to CO2 and water. The energy released in this process is captured in the form of 1 GTP and 11 ATP molecules per acetyl-CoA molecule oxidized. [2][10] This is the fate of acetyl-CoA wherever beta oxidation of fatty acids occurs, except under certain circumstances in the liver.

In the liver oxaloacetate can be wholly or partially diverted into the gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled type 1 diabetes mellitus. Under these circumstances oxaloacetate is hydrogenated to malate which is then removed from the mitochondria of the liver cells to be converted into glucose in the cytoplasm of the liver cells, from where it is released into the blood. [10] In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-CoA when significant gluconeogenesis has been stimulated by low (or absent) insulin and high glucagon concentrations in the blood. Under these circumstances acetyl-CoA is diverted to the formation of acetoacetate and beta-hydroxybutyrate. [10] Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, are frequently, but confusingly, known as ketone bodies (as they are not "bodies" at all, but water-soluble chemical substances). The ketones are released by the liver into the blood. All cells with mitochondria can take ketones up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that this can occur in the liver. Unlike free fatty acids, ketones can cross the blood-brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive. [10] The occurrence of high levels of ketones in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise and uncontrolled type 1 diabetes mellitus is known as ketosis, and, in its extreme form, in out-of-control type 1 diabetes mellitus, as ketoacidosis.

The glycerol released by lipase action is phosphorylated by glycerol kinase in the liver (the only tissue in which this reaction can occur), and the resulting glycerol 3-phosphate is oxidized to dihydroxyacetone phosphate. The glycolytic enzyme triose phosphate isomerase converts this compound to glyceraldehyde 3-phosphate, which is oxidized via glycolysis, or converted to glucose via gluconeogenesis.

Fatty acids as an energy source Edit

Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both reduced and anhydrous. The energy yield from a gram of fatty acids is approximately 9 kcal (37 kJ), compared to 4 kcal (17 kJ) for carbohydrates. Since the hydrocarbon portion of fatty acids is hydrophobic, these molecules can be stored in a relatively anhydrous (water-free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of glycogen can bind approximately 2 g of water, which translates to 1.33 kcal/g (4 kcal/3 g). This means that fatty acids can hold more than six times the amount of energy per unit of storage mass. Put another way, if the human body relied on carbohydrates to store energy, then a person would need to carry 31 kg (67.5 lb) of hydrated glycogen to have the energy equivalent to 4.6 kg (10 lb) of fat. [10]

Hibernating animals provide a good example for utilizing fat reserves as fuel. For example, bears hibernate for about 7 months, and, during this entire period, the energy is derived from degradation of fat stores. Migrating birds similarly build up large fat reserves before embarking on their intercontinental journeys. [15]

Thus the young adult human’s fat stores average between about 10–20 kg, but varies greatly depending on age, gender, and individual disposition. [16] By contrast the human body stores only about 400 g of glycogen, of which 300 g is locked inside the skeletal muscles and is unavailable to the body as a whole. The 100 g or so of glycogen stored in the liver is depleted within one day of starvation. [10] Thereafter the glucose that is released into the blood by the liver for general use by the body tissues, has to be synthesized from the glucogenic amino acids and a few other gluconeogenic substrates, which do not include fatty acids. [1] Please note however that lipolysis releases glycerol which can enter the pathway of gluconeogenesis.

Carbohydrate synthesis from glycerol and fatty acids Edit

Fatty acids are broken down to acetyl-CoA by means of beta oxidation inside the mitochondria, whereas fatty acids are synthesized from acetyl-CoA outside the mitochondria, in the cytosol. The two pathways are distinct, not only in where they occur, but also in the reactions that occur, and the substrates that are used. The two pathways are mutually inhibitory, preventing the acetyl-CoA produced by beta-oxidation from entering the synthetic pathway via the acetyl-CoA carboxylase reaction. [1] It can also not be converted to pyruvate as the pyruvate dehydrogenase complex reaction is irreversible. [10] Instead the acetyl-CoA produced by the beta-oxidation of fatty acids condenses with oxaloacetate, to enter the citric acid cycle. During each turn of the cycle, two carbon atoms leave the cycle as CO2 in the decarboxylation reactions catalyzed by isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. Thus each turn of the citric acid cycle oxidizes an acetyl-CoA unit while regenerating the oxaloacetate molecule with which the acetyl-CoA had originally combined to form citric acid. The decarboxylation reactions occur before malate is formed in the cycle. [1] Only plants possess the enzymes to convert acetyl-CoA into oxaloacetate from which malate can be formed to ultimately be converted to glucose. [1]

However acetyl-CoA can be converted to acetoacetate, which can decarboxylate to acetone (either spontaneously, or by acetoacetate decarboxylase). It can then be further metabolized to isopropanol which is excreted in breath/urine, or by CYP2E1 into hydroxyacetone (acetol). Acetol can be converted to propylene glycol. This converts to formate and acetate (the latter converting to glucose), or pyruvate (by two alternative enzymes), or propionaldehyde, or to L-lactaldehyde then L-lactate (the common lactate isomer). [17] [18] [19] Another pathway turns acetol to methylglyoxal, then to pyruvate, or to D-lactaldehyde (via S-D-lactoyl-glutathione or otherwise) then D-lactate. [18] [20] [21] D-lactate metabolism (to glucose) is slow or impaired in humans, so most of the D-lactate is excreted in the urine thus D-lactate derived from acetone can contribute significantly to the metabolic acidosis associated with ketosis or isopropanol intoxication. [18] L-Lactate can complete the net conversion of fatty acids into glucose. The first experiment to show conversion of acetone to glucose was carried out in 1951. This, and further experiments used carbon isotopic labelling. [19] Up to 11% of the glucose can be derived from acetone during starvation in humans. [19]

The glycerol released into the blood during the lipolysis of triglycerides in adipose tissue can only be taken up by the liver. Here it is converted into glycerol 3-phosphate by the action of glycerol kinase which hydrolyzes one molecule of ATP per glycerol molecule which is phosphorylated. Glycerol 3-phosphate is then oxidized to dihydroxyacetone phosphate, which is, in turn, converted into glyceraldehyde 3-phosphate by the enzyme triose phosphate isomerase. From here the three carbon atoms of the original glycerol can be oxidized via glycolysis, or converted to glucose via gluconeogenesis. [10]


Protein Digestion and Absorption

For all food groups, the digestion process kicks off in your mouth, where you chew and swallow food, allowing it to make its way to your stomach, per the Cleveland Clinic.

Protein takes longer to break down than carbohydrates, according to University Hospitals, and fats take the longest amount of time.

Once food proteins hit your stomach's acidic environment, pepsin (a digestive enzyme) breaks it down into small pieces called peptides, per the Medicine Library. These peptides travel to your small intestine, where different digestive enzymes — secreted from your pancreas — break them down into even smaller molecules.

The digestion process has made the protein small enough to be absorbed through the cells lining the small intestines into capillaries, per the National Cancer Institutes — that is, these molecules can now move through your body via your bloodstream.


Contents

Most of the structures that make up animals, plants and microbes are made from four basic classes of molecule: amino acids, carbohydrates , nucleic acid and lipids (often called fats). As these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion. These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life. [8]

Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms
Amino acids Amino acids Proteins (made of polypeptides) Fibrous proteins and globular proteins
Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose
Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins Edit

Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds. Many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape. [9] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle. [10] Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle (tricarboxylic acid cycle), [11] especially when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress. [12]

Lipids Edit

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. [10] Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as alcohol, benzene or chloroform. [13] The fats are a large group of compounds that contain fatty acids and glycerol a glycerol molecule attached to three fatty acid esters is called a triacylglyceride. [14] Several variations on this basic structure exist, including backbones such as sphingosine in the sphingomyelin, and hydrophilic groups such as phosphate as in phospholipids. Steroids such as sterol are another major class of lipids. [15]

Carbohydrates Edit

Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals). [10] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways. [16]

Nucleotides Edit

The two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group which is attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, and its interpretation through the processes of transcription and protein biosynthesis. [10] This information is protected by DNA repair mechanisms and propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome. [17] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic-group-transfer reactions. [18]

Coenzymes Edit

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups of atoms and their bonds within molecules. [19] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. [18] These group-transfer intermediates are called coenzymes. Each class of group-transfer reactions is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously made, consumed and then recycled. [20]

One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day. [20] ATP acts as a bridge between catabolism and anabolism. Catabolism breaks down molecules, and anabolism puts them together. Catabolic reactions generate ATP, and anabolic reactions consume it. It also serves as a carrier of phosphate groups in phosphorylation reactions. [21]

A vitamin is an organic compound needed in small quantities that cannot be made in cells. In human nutrition, most vitamins function as coenzymes after modification for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells. [22] Nicotinamide adenine dinucleotide (NAD + ), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD + into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates. [23] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD + /NADH form is more important in catabolic reactions, while NADP + /NADPH is used in anabolic reactions. [24]

Mineral and cofactors Edit

Inorganic elements play critical roles in metabolism some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of a human's body weight is made up of the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur. Organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen most of the oxygen and hydrogen is present as water. [25]

The abundant inorganic elements act as electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate and the organic ion bicarbonate. The maintenance of precise ion gradients across cell membranes maintains osmotic pressure and pH. [26] Ions are also critical for nerve and muscle function, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cell's fluid, the cytosol. [27] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules. [28]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant of those. [29] Metal cofactors are bound tightly to specific sites in proteins although enzyme cofactors can be modified during catalysis, they always return to their original state by the end of the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage proteins such as ferritin or metallothionein when not in use. [30] [31]

Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules. [32] The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table below. Organic molecules are used as a source of energy by organotrophs, while lithotrophs use inorganic substrates, and phototrophs capture sunlight as chemical energy. [33] However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate. In animals, these reactions involve complex organic molecules that are broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms, such as plants and cyanobacteria, these electron-transfer reactions do not release energy but are used as a way of storing energy absorbed from sunlight. [34]

Classification of organisms based on their metabolism [35]
Energy source sunlight photo- -troph
Preformed molecules chemo-
Electron donor organic compound organo-
inorganic compound litho-
Carbon source organic compound hetero-
inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three main stages. In the first stage, large organic molecules, such as proteins, polysaccharides or lipids, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD + ) into NADH. [32]

Digestion Edit

Macromolecules cannot be directly processed by cells. Macromolecules must be broken into smaller units before they can be used in cell metabolism. Different classes of enzymes were being used to digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides [36]

Microbes simply secrete digestive enzymes into their surroundings, [37] [38] while animals only secrete these enzymes from specialized cells in their guts, including the stomach and pancreas, and salivary glands. [39] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins. [40] [41]

Energy from organic compounds Edit

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides. [42] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated. [43] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA through aerobic (with oxygen) glycolysis and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD + as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. [44] An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.

Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures. Steroids are also broken down by some bacteria in a process similar to beta oxidation, and this breakdown process involves the release of significant amounts of acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by the cell for energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis. [45]

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy. [46] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate. [47] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below). [48]

Oxidative phosphorylation Edit

In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the protagon acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane. [49] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane. [50]

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient. [51] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate – turning it into ATP. [20]

Energy from inorganic compounds Edit

Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen, [52] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate), [2] ferrous iron (FeII) [53] or ammonia [54] as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite. [55] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility. [56] [57]

Energy from light Edit

The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds. [58] [59]

In many organisms, the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves the storage of energy as a proton concentration gradient. This proton motive force then drives ATP synthesis [60] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres. Reaction centers are classed into two types depending on the nature of photosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two. [61]

In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast. [34] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP +. [62] fThese cooenzyme can be used in the Calvin cycle, which is discussed below, or recycled for further ATP generation.

Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. First, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids. [63]

Anabolism in organisms can be different according to the source of constructed molecules in their cells. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions. [63]

Carbon fixation Edit

Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle. [64] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions. [65]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle, [66] or the carboxylation of acetyl-CoA. [67] [68] Prokaryotic chemoautotrophs also fix CO2 through the Calvin–Benson cycle, but use energy from inorganic compounds to drive the reaction. [69]

Carbohydrates and glycans Edit

In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis. [43] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately, and prevents both pathways from running simultaneously in a futile cycle. [70] [71]

Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate plants do, but animals do not, have the necessary enzymatic machinery. [72] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids. [73] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose. [72] [74] Other than fat, glucose is stored in most tissues, as an energy resource available within the tissue through glycogenesis which was usually being used to maintained glucose level in blood. [75]

Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-Glc) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures. [76] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases. [77] [78]

Fatty acids, isoprenoids and sterol Edit

Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups: in animals and fungi, all these fatty acid synthase reactions are carried out by a single multifunctional type I protein, [79] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway. [80] [81]

Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products. [82] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate. [83] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA, [84] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. [83] [85] One important reaction that uses these activated isoprene donors is sterol biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol. [86] Lanosterol can then be converted into other sterol such as cholesterol and ergosterol. [86] [87]

Proteins Edit

Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can only synthesize eleven nonessential amino acids, so nine essential amino acids must be obtained from food. [10] Some simple parasites, such as the bacteria Mycoplasma pneumoniae, lack all amino acid synthesis and take their amino acids directly from their hosts. [88] All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Nonessensial amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid. [89]

Amino acids are made into proteins by being joined together in a chain of peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase. [90] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA. [91]

Nucleotide synthesis and salvage Edit

Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy. [92] Consequently, most organisms have efficient systems to salvage preformed nucleotides. [92] [93] Purines are synthesized as nucleosides (bases attached to ribose). [94] Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate. [95]

All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics. [96] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases, [97] UDP-glucuronosyltransferases, [98] and glutathione S-transferases. [99] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills. [100] Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds. [101]

A related problem for aerobic organisms is oxidative stress. [102] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide. [103] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases. [104] [105]

Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) cannot decrease. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments. [106] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder. [107]

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis. [108] [109] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. [110] Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway). [111] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway. [112]

There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products for example, a decrease in the amount of product can increase the flux through the pathway to compensate. [111] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway. [113] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of water soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface. [114] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins. [115]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin. [116] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen. [117] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes. [118]

The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal common ancestor. [4] [119] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism. [120] [121] The retention of these ancient pathways during later evolution may be the result of these reactions having been an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps. [5] [6] The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, while previous metabolic pathways were a part of the ancient RNA world. [122]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway. [123] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions created from pre-existing steps in the pathway. [124] An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database) [125] These recruitment processes result in an evolutionary enzymatic mosaic. [126] A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules. [127]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host. [128] Similar reduced metabolic capabilities are seen in endosymbiotic organisms. [129]

Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively labelled intermediates and products. [130] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell. [131]

An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 26.500 genes. [132] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior. [133] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies. [134] Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research. [135] These models are now used in network analysis, to classify human diseases into groups that share common proteins or metabolites. [136] [137]

Bacterial metabolic networks are a striking example of bow-tie [138] [139] [140] organization, an architecture able to input a wide range of nutrients and produce a large variety of products and complex macromolecules using a relatively few intermediate common currencies.

A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid. [141] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes. [142]

The term metabolism is derived from French "métabolisme" or Ancient Greek μεταβολή – "Metabole" for "a change" which derived from μεταβάλλ –"Metaballein" means "To change" [143]

Greek philosophy Edit

Aristotle's The Parts of Animals sets out enough details of his views on metabolism for an open flow model to be made. He believed that at each stage of the process, materials from food were transformed, with heat being released as the classical element of fire, and residual materials being excreted as urine, bile, or faeces. [144]

Islamic medicine Edit

Ibn al-Nafis described metabolism in his 1260 AD work titled Al-Risalah al-Kamiliyyah fil Siera al-Nabawiyyah (The Treatise of Kamil on the Prophet's Biography) which included the following phrase "Both the body and its parts are in a continuous state of dissolution and nourishment, so they are inevitably undergoing permanent change." [145]

Application of the scientific method Edit

The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina. [146] He described how he weighed himself before and after eating, sleep, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue. [147] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells." [148] This discovery, along with the publication by Friedrich Wöhler in 1828 of a paper on the chemical synthesis of urea, [149] and is notable for being the first organic compound prepared from wholly inorganic precursors. This proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry. [150] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism. [151] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle. [152] [74] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.


Biology of the Endoplasmic Reticulum

Abstract

Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (mitochondria-associated membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals.

In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains.

In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. In fact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.


Digestion

Prior to absorbing most of the components in your food, you must break down large molecules into smaller ones that can be taken into the bloodstream. Some simple sugars, such as glucose, do not require digestion prior to absorption. Table sugar, starches, proteins and fats must be broken down first. Digestion of carbohydrates begins in the mouth protein digestion starts in the stomach. Fat digestion does not begin until it reaches the small intestine, explains Dr. Lauralee Sherwood in her book, "Human Physiology."


Bad dancers

Gökhan Hotamışlıgil, a metabolic-disease researcher at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts, likens the relationship between the ER and mitochondria to a sensual and dynamic flamenco performance. Just like dancers, the organelles “contact and separate, and then come into contact again, and flirt a little bit and go away”, he says. But in diseased liver cells, the two organelles stay entwined, and the rhythm is sluggish.

“It doesn’t look very elegant,” says Hotamışlıgil, who has shown 13 that excessive contact between the ER and mitochondria in mouse liver cells is linked to insulin resistance, diabetes and obesity. “You can’t slow-dance flamenco — and that’s how the mitochondria–ER relationship becomes under metabolic stress,” he adds.

Other disease links are coming into view as researchers catalogue more proteins stationed at contact sites. For example, mitofusin 2, one of the proposed tethers of ER–mitochondrial junctions involved in calcium transport, is encoded by a gene that’s frequently mutated in people with Charcot–Marie–Tooth disease, a rare degenerative nerve disorder. And VAPB, a gene responsible for some inherited cases of amyotrophic lateral sclerosis, holds the recipe for making a protein that helps to latch the ER to several organelles.

Another disease-relevant contact is found in people diagnosed with Alzheimer’s disease, whose brains tend to have plaques formed of amyloid-β protein. Cell biologists Estela Area Gómez and Eric Schon at Columbia University in New York City have shown that a particular derivative of the amyloid-β precursor protein accumulates on the surface of the ER in affected cells 14 . Known as C99, the derivative triggers connections with nearby mitochondria, which throws cholesterol transport out of kilter.

Working in mice and human cell lines, Area Gómez says her group has identified unique patterns of metabolites produced as a consequence of the excessive contacts wrought by C99. She is exploring whether a blood test for these metabolites could identify subcellular signs of Alzheimer’s disease in otherwise healthy individuals.

As the evidence mounts that contact sites affect cellular function in both health and disease, some researchers have begun to talk about the need for a grand new synthesis of cellular transport. “An organelle cannot function in isolation,” Schuldiner says. And Lippincott-Schwartz sees an exciting future in cell biology: “This field of organelle–organelle communication and coupling is going to reveal really fundamental processes.”

But there are still technical details to work out. Most research has focused on lipid or calcium shuttling between the ER and other organelles. The challenge now is to uncover the whole spectrum of signals transmitted across all contact sites.

“In some ways, the field has gotten ahead of itself,” says Will Prinz, a cell biologist at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. Prinz agrees that contact sites are a “big, important, almost revolutionary concept in cell biology”, but says there is much work to do. “Is this really a game-changer for how we think about cells?” Prinz asks. “I think the jury is still out.”

At the very least, says Voeltz, there’s enough evidence for cell-biology textbooks to get a makeover. She teaches an undergraduate course on organelle and membrane trafficking using a textbook, last revised in 2015, that depicts the cell just as it did 20 years ago. In fact, textbook depictions of the cell’s innards have changed little since 1896, when cytologist Edmund Beecher Wilson drew the cell with organelles neatly tucked into their own distinct cytoplasmic compartments.

From the ER to the Golgi to the vacuole to the endosome, each organelle is still shown in isolation, not as a dynamic dance of parts that continuously embrace and separate. “Nothing is drawn the way the cell actually looks,” says Voeltz. “It would be nice to update that image.”

Nature 567, 162-164 (2019)

Updates & Corrections

Clarification 27 March 2019: This story has been modified to make clear that the 2017 study from DeCamilli was co-led by Yale cell biologist Karin Reinisch.



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