Key Mechanism Behind Some Forms of Deafness Identified

Summary: Researchers have identified a new protein, CIB2, that is key to helping the auditory system to turn soundwaves into meaningful brain signals. Mutations of this gene leave people unable to convert the soundwaves into signals that the brain can interpret, and are deaf.

Source: University of Maryland.

Study identifies a new protein that is essential to the process of turning sound waves into meaningful brain signals.

Although the basic outlines of human hearing have been known for years – sensory cells in the inner ear turn sound waves into the electrical signals that the brain understands as sound – the molecular details have remained elusive.

Now, new research from the University of Maryland School of Medicine (UM SOM), has identified a crucial protein in this translation process.

The findings were published today in the latest issue of Nature Communications. The study is the first to illuminate in detail how a particular protein, which is known as CIB2, allows hearing to work.

“We are very excited by these results,” said the senior author of the study, Zubair Ahmed, professor in the Department of Otorhinolaryngology-Head and Neck Surgery at UM SOM. “This tells us something new about the fundamental biology of how hearing works on a molecular level.”

CIB2, which is short for calcium and integrin-binding protein 2, is essential for the structure of stereocilia, the structures at the top of the sensory hair cells in the inner ear. Stereocilia are extremely small, less than a half a micrometer in diameter, which is about the wavelength of a visible light. Each ear contains 18,000 hair cells that do not divide or regenerate.

Dr. Ahmed and his colleague Saima Riazuddin, professor in the Department of Otorhinolaryngology-Head and Neck Surgery at UM SOM, along with their collaborators, discovered five years ago that CIB2 was involved in hearing. Since then, they have studied this protein in flies, mice, zebrafish and humans. The new study is the first to explain the mechanism behind CIB2 in hearing.

In this study, they genetically engineered mice without CIB2, as well as mice in which a human CIB2 gene mutation had been inserted. The researchers found that the human mutation affects the ability of the CIB2 protein to interact with two other proteins, TMC1 and TMC2, which are crucial in the process of converting sound to electrical signals. This process is known as mechanotransduction.

People with this mutation cannot turn soundwaves into signals that the brain can interpret, and so are deaf. When the researchers inserted the human CIB2 mutation into the mouse, they found that the mice were deaf.

“This is a big step in determining the identity of key components of the molecular machinery that converts sound waves into electrical signals in the inner ear,” said the study’s co-senior author, Gregory Frolenkov, of the Department of Physiology at the University of Kentucky.

Dr. Ahmed and his colleagues are now looking for other molecules beyond CIB2 that play a key role in the process. In addition, they are exploring potential therapies for CIB2-related hearing problems. In mice, they are using the gene editing tool CRISPR to modify dysfunctional CIB2 genes. They suspect that if this modification occurs in the first few weeks after birth, these mice, which are born deaf, will be able to hear. The scientists are also experimenting with gene therapy, using a harmless virus to deliver a normal copy of the normal CIB2 gene to baby mice that have the mutated version. Dr. Ahmed says the early results of these experiments are intriguing.

Nearly 40 million Americans suffer from some level of hearing loss. This includes around 74,000 children with profound, early-onset deafness. At least 50 percent of these deafness cases are due to genetic causes.

It is not clear how common CIB2 mutations are in the US population, or how large a role these mutations play in deafness in humans worldwide. In his research on a group of families in Pakistan that have a higher risk of deafness, Dr. Ahmed has found that about 8 to 9 percent seem to have mutations in CIB2. Overall, he says, the gene could play a role in tens of thousands of cases of deafness, and perhaps many more than that. He is also studying CIB2 among the general population. It may be that some versions of the gene also play a role in deafness caused by environmental conditions, creating a predisposition to hearing loss.


Arnaud Giese, a Post-Doc Fellow at UM SOM, and Yi-Quan Tang, from Cambridge University in England, are the first co-authors of this study. Other significant contributors include Dr. Riazuddin, William Schafer, from Cambridge University, Steve S.D. Brown, from the MRC Harwell Institute, UK, and Robert Fettiplace, from the University of Wisconsin.

Source: David Kohn – University of Maryland
Image Source: image is credited to BruceBlaus, licences CC BY 3.0.
Original Research: Full open access research for “CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells” by Arnaud P. J. Giese, Yi-Quan Tang, Ghanshyam P. Sinha, Michael R. Bowl, Adam C. Goldring, Andrew Parker, Mary J. Freeman, Steve D. M. Brown, Saima Riazuddin, Robert Fettiplace, William R. Schafer, Gregory I. Frolenkov & Zubair M. Ahmed in Nature Communications. Published online June 29 2017 doi:10.1038/s41467-017-00061-1

University of Maryland “Key Mechanism Behind Some Forms of Deafness Identified.” NeuroscienceNews. NeuroscienceNews, 28 June 2017.


CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells

Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.

“CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells” by Arnaud P. J. Giese, Yi-Quan Tang, Ghanshyam P. Sinha, Michael R. Bowl, Adam C. Goldring, Andrew Parker, Mary J. Freeman, Steve D. M. Brown, Saima Riazuddin, Robert Fettiplace, William R. Schafer, Gregory I. Frolenkov & Zubair M. Ahmed in Nature Communications. Published online June 29 2017 doi:10.1038/s41467-017-00061-1

Hemochromatosis patients should be on a low-iron diet

HEMAHemochromatosis is a common genetic condition and yet there are still a number of misperceptions surrounding the diagnosis and management of this condition. Hemochromatosis affects both men and women. Typical patients do not have alcoholism or viral hepatitis, and often have normal liver enzymes. Clinical expression is highly variable. Genetic testing is widely available and particularly useful in family studies. Hemochromatosis can be readily diagnosed and treated. The purpose of the present review is to address the medical myths and misconceptions of hemochromatosis.

Keywords: Genetic testing, Hemochromatosis, Iron

The medical landscape is vast with an expanding array of information about old and new diseases. Thus, it becomes an insurmountable task for any physician to be up-to-date on all of the recent developments in modern medicine. For most physicians, it is acceptable to inform patients that they may not have all of the current information about their medical condition. This may lead to further study in textbooks or increasingly on the Internet, or they may seek a referral to a specialist with expertise in this area. In the present review, some of the common myths and misconceptions of hemochromatosis are explored.


Hemochromatosis is rare

A large population study (1) has demonstrated that one in 227 Caucasians in North America is homozygous for the C282Y mutation of the hemochromatosis gene. This is the typical genetic pattern seen in over 90% of typical patients; however, there are many C282Y homozygotes who are asymptomatic. Approximately, 20% of male homozygotes and 50% of female homozygotes will have normal serum ferritin levels. If the disease is defined based on symptoms, the prevalence would be much lower, and because the symptoms may be non-specific, it is more difficult to assess the prevalence of symptomatic hemochromatosis. This differs significantly between referred patients and participants in population screening studies. There has also been considerable debate about whether the genotype should be used to define hemochromatosis or whether it should be based on the presence of iron overload, independent of genotype (2). The bottom line is that this condition is extremely common within the Caucasian population and physicians should have a low index of suspicion when ordering screening tests, such as the transferrin saturation test and the serum ferritin test, for iron overload.

Women are not affected by hemochromatosis

As an autosomal recessive condition, hemochromatosis affects men and women equally in regard to the inheritance of the hemochromatosis gene. It has been considered that the effects of menses and pregnancy will significantly offset the lifelong accumulation of iron with tissue injury. A study (3) of 176 female hemochromatosis patients, matched to 176 male patients with respect to birth year, demonstrated similar hepatic iron concentrations in both sexes. However, male patients had a higher prevalence of cirrhosis compared with female patients (26% versus 14%). Cirrhosis in a female hemochromatosis patient has rarely been discovered in a population screening study. It is also important to assess women so that genetic counselling can be provided to their children and siblings.

Most hemochromatosis patients are alcoholics

The misconception that most hemochromatosis patients are alcoholics stems from the fact that most alcoholics have elevations in serum ferritin levels and some patients with alcoholic liver disease have increased iron deposition in the liver (alcoholic siderosis). This latter condition was widely reported from the Boston area in the 1960s (4) and likely ‘contaminated’ the hemochromatosis literature with patients who did not actually have genetic hemochromatosis. Studies (5,6) on the prevalence of alcoholism based on hemochromatosis pedigrees have shown no increased evidence of alcoholism. The genetic test for hemochromatosis remains a powerful diagnostic tool to help separate alcoholic liver disease from hemochromatosis.

Many hemochromatosis patients have chronic viral hepatitis

The prevalence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) is not consistently higher in hemochromatosis patients. A screening study (7) that identified 302 C282Y homozygotes found one case of concomitant HCV and none with HBV. Much like alcoholic liver disease, both chronic HBV and HCV have been associated with elevations in serum ferritin levels and less commonly associated with increases in hepatic iron concentrations with advanced liver disease (8). Genetic testing is useful in this setting to differentiate hemochromatosis from iron abnormalities secondary to chronic viral hepatitis.

Diabetes is a cardinal feature of hemochromatosis

Although hemochromatosis was once called ‘bronze diabetes’, recent population screening studies (1,9) have not demonstrated an increased prevalence of diabetes in C282Y homozygotes compared with a control population. The pathogenesis of diabetes in hemochromatosis is likely multifactorial and can include defects in insulin secretion and insulin resistance (10,11).

Most hemochromatosis patients have elevated liver enzymes

Although liver disease is the most consistent feature of the disease, hemochromatosis is not an inflammatory liver disease and, therefore, many patients will have normal liver enzymes (12). In a review (13) of 351 C282Y homozygotes from our hemochromatosis clinic at the London Health Sciences Centre in London, Ontario, 277 of 351 (79%) patients had an aspartate aminotransferase level of less than 40 U/L and 238 of 351 (68%) patients had an alanine aminotransferase level of less than 40 U/L. It remains prudent to screen patients with unexplained enzyme elevations with transferrin saturation and serum ferritin tests.

Most patients with an elevated serum ferritin level have hemochromatosis

A population screening study (1) has demonstrated that elevation in serum ferritin levels is seen in approximately 10% of primary care patients. When these patients are investigated in a referral clinic, only 33% to 42% have genetic hemochromatosis. More common causes of increased serum ferritin levels include obesity, fatty liver and daily alcohol consumption (14).

An elevated hemoglobin is common in hemochromatosis

Some physicians have told patients that they do not have hemochromatosis because their hemoglobin levels are normal. Perhaps this is based on the concept that if iron deficiency reduces hemoglobin, iron excess could increase hemoglobin. A review of 634 C282Y homozygotes at our clinic at the London Health Sciences Centre (London, Ontario) showed a mean hemoglobin level of 145±13 g/L, which suggests that polycythemia is not a reliable marker for iron overload.

Hemochromatosis is not a cause of significant liver disease

It has been well established that with timely diagnosis and institution of iron depletion therapy, patients with hemochromatosis can be expected to have a prognosis equal to that of controls. However, among patients with severe iron accumulation, the risk of progression to cirrhosis is significant. As in other causes of cirrhosis, morbidity and mortality rates are increased due to the many associated complications of end-stage liver disease including the development of hepatocellular carcinoma. However, in the case of cirrhosis due to hemochromatosis, the incidence of hepatocellular carcinoma is significantly higher than that of many other causes of liver disease. Iron overload in hemochromatosis has also been shown to potentiate alcoholic liver disease and may have a similar effect on the course of HCV and nonalcoholic fatty liver disease (1517). Given that 1.8% of the population in the United States are HCV-positive and that up to 24% have nonalcoholic fatty liver disease, the coexistence of these disorders with hemochromatosis is likely to affect a reasonable proportion of our population.

Carriers of the hemochromatosis gene often have iron overload

It has been common for physicians to tell patients with mild elevations in serum ferritin levels that they may be carriers of the hemochromatosis gene. Mild elevations in serum ferritin levels in the general population are very common and occur in all ethnic groups, so they are unlikely to be explained on the basis of heterozygosity for the hemochromatosis gene. A large population study (1) has now demonstrated that C282Y heterozygotes have iron studies similar to those of the general population. There is an increased prevalence of mild iron overload in compound heterozygotes (C282Y/H63D), and some C282Y heterozygotes may also carry an unidentified second mutation.

Children of hemochromatosis patients are at the highest risk of disease

The misconception that children of hemochromatosis patients are at the highest risk of disease arises because of a misunderstanding by patients and physicians of the concept of autosomal recessive inheritance. Usually a typical C282Y homozygote has heterozygous parents and so there is a higher risk for siblings. The risk is slightly higher than 25% because there is a possibility that one of the parents is a homozygote. Children of homozygotes are at a much lower risk because the partner must also carry the C282Y mutation. Among Caucasian couples, the risk to children is approximately 5% (18). Genetic testing of children younger than 18 years of age is not recommended because of a number of potential concerns about informed consent and genetic discrimination.

Genetic testing for hemochromatosis is a research tool

Genetic testing for hemochromatosis has a number of unique characteristics. Unlike most genetic diseases, in hemochromatosis there is a single genetic mutation (C282Y) that explains most typical cases. The test is widely available and can be performed at a relatively low cost. There have been a number of studies (1921) that have assessed the psychosocial impact of genetic testing for hemochromatosis which have concluded that the test is well accepted by patients and has rarely been associated with insurance discrimination. For these reasons, the genetic test has become one of the most commonly requested tests and is a powerful diagnostic tool that is accessible to most physicians.

Hemochromatosis patients should be on a low-iron diet

Although dietary iron is the source of excess iron in hemochromatosis, a decrease in dietary iron has not been shown to decrease iron stores in hemochromatosis. All food groups contain iron and most humans will absorb only a small fraction of orally ingested iron. Iron absorption includes components from heme and nonheme iron sources (22), and the control or lack of control over these regulatory mechanisms is incompletely understood in hemochromatosis. It has been speculated that a defect in hepcidin, a circulating peptide produced by the liver, is a fundamental defect in hemochromatosis which results in an increase in intestinal iron absorption (23). Iron supplementation of food was introduced in the 1950s as a marketing tool, and the added iron has poor bioavailability. Generally, vegetarians have lower serum ferritin levels than meat-eating patients but this does not translate into a dietary recommendation (24). The description of bacterial infections from Yersinia (25) and other Vibrio species has led to recommendations to avoid raw shellfish which may be appropriate for all patients rather than just hemochromatosis patients. Hemochromatosis patients are advised to avoid iron supplementation and large doses of supplemental oral vitamin C which may adversely affect some patients with iron overload (26).

Hemochromatosis is a progressive disease

Because hemochromatosis patients presumably begin absorbing excess iron at birth, it seems intuitive that progressive iron overload over time would occur. However, it has not been possible to show a correlation between liver iron concentration and age in hemochromatosis (27). It has become apparent through various studies, in which genetic testing was performed after many years of observation such as in the Copenhagen Heart Study (28), that many C282Y homozygotes do not have a progressive rise in serum ferritin levels, even without phlebotomy treatment. This is the most likely explanation for the discordance between the high frequency of the hemochromatosis genotype and the relatively low representation of hemochromatosis in liver transplant registries (29) or in death certificate data (30). There have been patients who have refused phlebotomy therapy and have been observed over many years to not have any changes in their serum ferritin levels. Phlebotomy therapy has never been subjected to a randomized trial. The strongest supporting evidence for a beneficial effect of phlebotomy is the improvement of liver fibrosis that has been demonstrated on serial liver biopsies in hemochromatosis patients (31). Maintenance therapy is even less established following iron depletion, and many patients will not demonstrate any evidence of iron reaccumulation after many years of observation (32). Many patients enjoy the concept of continuous therapy for hemochromatosis and these patients can be encouraged to be voluntary blood donors several times per year (33). If they are ineligible, an annual ferritin determination is a reasonable alternative to guide maintenance therapy.


Hemochromatosis is a common and relatively simple genetic disease to diagnose and treat. It can be diagnosed and treated by family physicians using transferrin saturation, serum ferritin and C282Y genetic testing. Physicians who are not comfortable with interpretation of the genetic test and subsequent family counselling should refer to local specialists and try to avoid any perpetration of misinformation.

Connie’s comments: Calcium and magnesium supplements cancels iron absorption.

Metabolism is life sustaining and sum of all chemical reactions for growth and death of cells

Metabolism (from Greek: μεταβολή metabolē, “change”) is the set of life-sustaining chemical transformations within the cells of living organisms. The three main purposes of metabolism are the conversion of food/fuel to energy to run cellular processes, the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates, and the elimination of nitrogenous wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells, in which case the set of reactions within the cells is called intermediary metabolism or intermediate metabolism.

Metabolism is usually divided into two categories: catabolism, the breaking down of organic matter for example, the breaking down of glucose to pyruvate, by cellular respiration, and anabolism, the building up of components of cells such as proteins and nucleic acids. Usually, breaking down releases energy and building up consumes energy.

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, by a sequence of enzymes. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts that allow the reactions to proceed more rapidly. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell’s environment or to signals from other cells.

The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The speed of metabolism, the metabolic rate, influences how much food an organism will require, and also affects how it is able to obtain that food.

A striking feature of metabolism is the similarity of the basic metabolic pathways and components between even vastly different species.[2] For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants.[3] These striking similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and their retention because of their efficacy.[4][5]

Key biochemicals

Structure of a triacylglycerol lipid

This is a diagram depicting a large set of human metabolic pathways.

Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates 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.

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

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.[6] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle.[7] Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle (tricarboxylic acid cycle),[8] especially when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress.[9]


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.[7] Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform.[10] 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.[11] Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate as in phospholipids. Steroids such as cholesterol are another major class of lipids.[12]


The straight chain form consists of four C H O H groups linked in a row, capped at the ends by an aldehyde group C O H and a methanol group C H 2 O H.  To form the ring, the aldehyde group combines with the O H group of the next-to-last carbon at the other end, just before the methanol group.

Glucose can exist in both a straight-chain and ring form.

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).[7] 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.[13]


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.[7] 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.[14] 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.[15]


Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to the sulfur atom at the extreme left.

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.[16] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[15]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.[17]

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.[17] 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.

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.[18] 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.[19] 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.

Structure of hemoglobin. The protein subunits are in red and blue, and the iron-containing heme groups in green. From PDB: 1GZX​.

Minerals 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 mammal’s mass is made up of the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur.[20] Organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water.[20]

The abundant inorganic elements act as ionic 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.[21] 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.[22] 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.[23]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant of those.[24][25] These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin.[26] 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.[27][28]


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. 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. 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.[29] 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.[30]

Classification of organisms based on their metabolism
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.


Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and must be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes 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.

Microbes simply secrete digestive enzymes into their surroundings,[31][32] while animals only secrete these enzymes from specialized cells in their guts.[33] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins.[34][35]

A simplified outline of the catabolism of proteins, carbohydrates and fats

Energy from organic compounds

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides.[36] 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.[37] 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. 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.[38]

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.[39] 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.[40] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).[41]

Energy transformations

Oxidative phosphorylation

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.[42] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.[43]

Mechanism of ATP synthase. ATP is shown in red, ADP and phosphate in pink and the rotating stalk subunit in black.

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient.[44] 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.

Connie’s notes:

  • Chew our food well
  • Allow clean air and deep breathing to provide oxgygenation to our cells
  • With well tuned body, sufficient sunlight, sleep, stretching and exercise
  • Consuming whole foods and away from negative energies from light, X-rays and other chemicals/toxins both in the environment and that which affects our behaviour and nervous system
  • Those who are slow metabolizer, gets stomach upset/allergies, pain, fast heartbeat,nausea,vomitting,inflammation and head ache, from consuming processed foods, medications, drugs, dirty water, dirty air and other stressors must avoid these stressors or inflammatory substances.

Levels of DNA methylation reflect a person’s age

  • Certain DNA changes can better predict a person’s life expectancy than traditional risk factors such as age.
  • The findings could lead to novel insights into the molecular mechanisms of aging and new ways to evaluate methods for slowing the rate of aging.
Woman at three different stages of life.“Epigenetic age” might represent a person’s biological age more accurately than the number of years they’ve lived.KatarzynaBialasiewicz/iStock/Thinkstock

Our DNA changes as we age. Some of these changes are epigenetic—they modify DNA without altering the genetic sequence itself. Epigenetic changes affect how genes are turned on and off, or expressed, and thus help regulate how cells in different parts of the body use the same genetic code. Previous studies have shown that levels of one type of epigenetic modification, called DNA methylation, roughly reflect a person’s age.

Recent work suggests that epigenetic age might also be associated with health outcomes independent of chronological age. Dr. Steve Horvath from the University of California, Los Angeles, and his colleagues set out to investigate the relationship between epigenetic age and mortality.

The researchers analyzed DNA in blood samples from more than 13,000 people, including non-Hispanic whites, Hispanics, and African Americans. Many of the samples came from large NIH-funded studies, including the Framingham Heart Study and the Women’s Health Initiative. The researchers were funded in part by NIH’s National Institute on Aging (NIA). The team also included scientists from NIA and NIH’s National Heart, Lung, and Blood Institute (NHLBI). The study appeared on September 28, 2016, in Aging.

The researchers tested different models of epigenetic age. Different cell types—even similar ones like various blood cell types—have different epigenetic patterns. As people get older, the mix of immune cells in their blood shifts. When these age-related changes to blood cell composition were factored in, the researchers’ epigenetic age model predicted mortality from all causes better than previous measures of epigenetic age. The relationship between epigenetic age and mortality was significant within both sexes and across all the ethnic groups in the study.

“Our findings show that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics, and African-Americans in these cohorts, even after adjusting for traditional risk factors like age, gender, smoking, body-mass index, and disease history,” says NIA’s Dr. Brian Chen, the study’s first author.

These results support the notion that epigenetic age captures some aspect of biological aging over and above chronological age and other risk factors. “Our research reveals valuable clues into what causes human aging, marking a first step toward developing targeted methods to slow the process,” Horvath says.

The precise roles that epigenetic factors play in aging and death remain unknown and require further study. It’s important to note that many risk factors, including smoking, diabetes, and high blood pressure, have stronger effects on mortality than epigenetic age.

—by Harrison Wein, Ph.D.

Genomic profiling assay for hematologic malignancies and sarcomas

FoundationOneHeme is a comprehensive genomic profiling assay for hematologic malignancies and sarcomas. The test is designed to provide physicians with clinically actionable information to guide treatment decisions for patients based on the genomic profile of their disease. Test results provide information about clinically significant alterations, potential targeted therapies, available clinical trials, and quantitative markers that may support immunotherapy clinical trial enrollment.

FoundationOneHeme is validated to detect all classes of genomic alterations in more than 400 cancer-related genes. In addition to DNA sequencing, FoundationOneHeme employs RNA sequencing across more than 250 genes to capture a broad range of gene fusions, common drivers of hematologic malignancies, and sarcomas.

I believe that the use of genomic profiling facilitates precision medicine especially in the area of cancer treatment.  Your doctor orders this genomic profiling to be precise in delivery of your treatment.

Connie Dello Buono


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