If so, we can expect an increase in the number of people suffering from mitochondrial diseases caused by those mutations. In order to prevent this process, it is necessary to investigate the way mtDNA mutations are selected and which can or cannot be related to disturbances in OXPHOS Stewart and Chinnery, Modern life puts a real burden on the normal functioning of mitochondria in multiple organs.

Factors such as sitting time Nogueira Silva Lima et al. LGI and mitochondrial dysfunction are two cross-connected mechanisms. Although mitochondrial dysfunction can induce low-grade inflammation Zampino et al. OXPHOS defects involve energetic cost, hypermetabolism, and increased aging velocity in most, if not all, organs Diaz-Vegas et al.

Mitochondria-induced inflammation can be highly detrimental to overall health. Therefore, several control mechanisms exist to prevent mitochondria-driven inflammation and mitochondria from becoming damage-associated molecular patterns DAMPs and even prevent autoreactivity and possible autoimmune diseases Marchi et al.

The Baltimore Longitudinal Study of Aging, investigating a total number of individuals with an average age of 67 years, showed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically showing markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate compared with participants with better oxidative capacity, independent of age and sex Zampino et al.

The possibility of mitochondrial damage should be considered part of the fact that organisms live. Therefore, it seems logical that many mechanisms are in place to prevent mitochondrial damage and the subsequent possibility of systemic inflammation.

Marchi et al. described the different protective pathways of mitochondria-induced inflammation, including mitophagy, autophagy, and cell apoptosis Zampino et al. Although mitochondria-induced inflammation has been evidenced in multiple chronic diseases, interventions are scarce, and only one medicine, venetoclax, has been approved till now Roca-Portoles et al.

This review proposes that the use of physiological stress triggers, such as intermittent fasting, intermittent cold, and intermittent hypoxia, should be able to provide primary and secondary prevention of mitochondrial-induced systemic inflammation the scope of this review.

Aerobic glycolysis in non-immune cells is responsible for the production of biomass. On the one hand, site aerobic glycolysis can protect against oxidative stress and serve as an anabolic pathway of cell repair, growth, and cell division Brand, ; Yuan et al.

On the other hand, long-term aerobic glycolysis, called the Warburg effect, leads to cell swelling, metabolic disturbances, lack of ATP, and, depending on the type of cell, cell death through apoptosis or necrosis and possibly cancer Schwartz et al.

Modern life is responsible for the metabolic switch from OXPHOS to aerobic glycolysis through LGI, energy abundance caused by a high-calorie diet, lack of physical activity and sitting time, leading to chronic hyperglycemia and a surplus of fatty acids Segovia et al.

We speculate that aerobic glycolysis in non-dividing and dividing cells should be considered the central pathway of most, if not all, chronic diseases, including most types of cancer and its hallmarks Kaur et al. Long-term aerobic glycolysis can uncouple enzymes of normal OXPHOS, causing a chronic Warburg effect and accumulation of intracellular fatty acids, nucleotides, amino acids, and, through the activation of the polyol-mechanism, sorbitol and sorbitol-attracted water Singh et al.

Chronic accumulation of biomass through aerobic glycolysis and the polyol pathway is responsible for retinopathy, nephropathy, and neuropathy next to all aforementioned diseases Balestri et al. In line with the reviewed data, people suffering from metabolic syndrome Mets are susceptible to the development of many, if not all, CNCDs.

MetS is characterized by numerous metabolic dysregulations, including insulin resistance, leptin resistance, dysregulated hypothalamus—hypophysis—suprarenal gland axis function, atherogenic dyslipidemia, vascular calcification, central obesity, mitochondrial dysfunction, and altered blood pressure.

All these disrupted mechanisms lead to immune dysregulation and LGI, which are part of the hallmarks responsible for the development of CNCDs Uzunlulu et al.

Many of the pathophysiological mechanisms that characterize MetS are related to mitochondrial dysfunction caused by excessive ROS production when suffering from metabolic disturbances. In case of oxidative pressure that exceeds anti-oxidative capacity, mitochondria and other organelles can be severely damaged.

Several mechanisms and risk factors can lead to oxidative overload Tian et al. Spilling some of these high-energy electrons off the TCA chain leads to excessive ROS production.

The excessive amounts of glucose and free fatty acids in adipocytes activate NADPH oxidase, an enzyme that produces H2O2 Annie-Mathew et al. Insulin-resistance induces an increase in the production of oxidative stress, reduced OXPHOS, and energy production Wu et al.

A sedentary lifestyle reduces mitochondrial density, whereas mitochondrial biogenesis only functions in response to high-energy requirements Magalhães et al.

The absence of a healthy dietary pattern diversity in vegetables and spices, mushrooms, good healthy proteins and fats, fruits , which we often find in people suffering from MetS, leads to deficiency in a variety of polyphenols and micronutrients Phillips et al.

Polyphenols are a group of substances with evidenced hormetic effects in healthy food. They are phytochemical compounds that improve metabolism, cell signaling, and mitochondrial health; the phenolic compound works as a hormetic trigger.

The same mechanism characterizes the impact of the use of acute physiological stress strategies, such as intermittent fasting, therapeutic cold, therapeutic heat, and intermittent hypoxia. We speculate that the absence of hormetic triggers in modern life will decrease the transcription of NRF1 and NRF2, subsequently TFAM and mitochondrial transcription factor B2 TFB2M , and ultimately leading to a decrease in mitochondrial mass Kokura et al.

The absence of hormetic triggers can also alter the activity of PGC-1α, which could result in metabolic dysfunction of tissues, leading to the development of various metabolic diseases Vandenbeek et al.

The mechanistic target of rapamycin mTOR is seen as a central hub of nutrient signaling, cell growth, and division.

It facilitates the metabolic switch between the use of OXPHOS and aerobic glycolysis Liu and Sabatini, a. It is also seen as a regulator of mitochondrial functions and is influenceable by acute stressors; therefore, it is of special interest in this review. mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy.

It is made up of two complexes called mTORC1 and mTORC2. On cellular metabolic demand, mTORC1 and mTORC2 initiate biosynthetic cascades to support cell proliferation and anabolic state Blagosklonny, ,. FIGURE 3. mTOR pathway: mTORC1 promotes protein synthesis by phosphorylating eukaryotic initiation factor 4E-binding proteins 4E-BPs and p70 S6 kinase 1 S6K1 , increasing the production of ATP, nucleotides, and lipids.

In the absence of sterols, SREBPs translocate to the nucleus to regulate genes for de novo cholesterol and other lipid synthesis.

mTORC1 regulates the transcription factor hypoxia-inducible factor 1α HIF1α , which increases the expression of glycolytic enzymes and favors glycolysis over OXPHOS. mTORC1 activates mitochondrial transcripts through 4E-BP1 and stimulates mitochondrial biogenesis by driving PGC1α.

mTORC1 can simultaneously activate SREBPs, transcription factor ATF4, HIF1, Yin Yang 1 YY1 , PPARy, and PGC1a to drive mitochondrial regulation, ATP regulation, macromolecules synthesis, and cellular growth, blocking lysosomal biogenesis through transcription factor EB TFEB.

mTOR2 plays a role in cytoskeletal rearrangement, actin regulation, chemotaxis, migration, and cell survival. Akt is a central early effector in the phosphatidylinositol 3-kinase-protein kinase B PI3K pathway, where it mediates the cellular response to insulin and promotes proliferation.

In addition, Akt can mediate between mTORC1 and mTORC2 complexes by inactivating tuberous sclerosis complex 2 TSC2 , a strong inhibitor of mTORC1 activity. mTORC1 promotes protein synthesis by phosphorylating eukaryotic initiation factor 4E-binding proteins 4E-BPs and p70 S6 kinase 1 S6K1 , increasing the production of ATP, nucleotides, and lipids.

In the absence of sterols, SREBPs translocate to the nucleus and regulate genes for de novo cholesterol and other lipid synthesis. It further regulates methylenetetrahydrofolate dehydrogenase 2 MTHFD2 , the mitochondrial tetrahydrofolate cycle enzyme, carbamoyl-phosphate synthetase 2 CPS2 , aspartate transcarboxylase ATCase , dihydroorotase CAD, the rate-limiting enzyme in pyrimidine biosynthesis , among others.

mTORC1 activates mitochondrial transcripts through 4E-BP1 and stimulates mitochondrial biogenesis by driving PGC1α Summer et al. mTORC1 can simultaneously activate SREBPs, transcription factor ATF4, HIF1, Yin Yang 1 YY1 , PPARy, and PGC1a to drive mitochondrial regulation, ATP regulation, macromolecule synthesis, and cellular growth, blocking lysosomal biogenesis through transcription factor EB TFEB Liu and Sabatini, b ; Zhu et al.

mTORC2 also collaborates with PDK1 to activate other AGC family kinases and the Akt oncogene. Akt is a central early effector in the phosphatidylinositol 3-kinase-protein kinase B PI3K pathway, where it mediates the cellular insulin response and promotes proliferation. In addition, Akt can mediate between mTORC1 and mTORC2 complexes by inactivating tuberous sclerosis complex 2 TSC2 , a strong inhibitor of mTORC1 activity, and phosphorylating mSin1, an obligate component of mTORC2.

As the FOXO proteins are regulated by SGK1 and Akt, SGK can be the mTORC2 effector, whereas Akt appears to be a more subtle modulator Liu and Sabatini, a ; Choi et al.

Macrophages exposed to an inflammatory stimulus switch their metabolism from OXPHOS to aerobic glycolysis, increasing glucose metabolism enzymes, activating transcription factors, such as mTOR and HIF1α, to support ATP production independently of the availability of oxygen and facilitating the synthesis of nucleotides, fatty acids, and proteins to support cellular function Peruzzotti-Jametti et al.

In the cells of the immune system, maintained glycolysis tends to switch immune cells to a pro-inflammatory phenotype. Upregulated glycolysis is observed in many immune cells, such as T cells, NK cells, B lymphocytes, and dendritic cells.

Upregulated glycolysis could lead to immune activation with altered antibody production, lower self-tolerance, and increased cytokine release, resulting in transcriptional and post-transcriptional upregulated pro-inflammatory mediators affecting immune efficiency.

This also leads to increased post-prandial inflammation responses, an important risk factor for LGI and its consequences Teng et al. Hypertrophic adipose tissue is associated with immune cell recruitment, increased basal fatty acid release, pro-inflammatory cytokine release, hypoxia, necrotic-like abnormalities, fibrosis, decreased adiponectin, impaired insulin sensitivity, and insulin-dependent glucose uptake related to a defect in GLUT4 trafficking Choe et al.

The differentially hyperplasic adipose tissue shows increased adiponectin, decreased basal fatty acid release, and improved insulin sensitivity. It also releases pro-inflammatory cytokine and induces hypoxia and fibrosis but with fewer immune cells and a higher proportion of small adipocytes, leading to a healthier adipose tissue phenotype Choe et al.

The adipocytes that determine a pro-inflammatory immune system are white adipocytes with low mitochondrial density. Beige and brown adipocytes characterized by high healthy mitochondrial density are metabolically efficient and maintain an anti-inflammatory and antitumoral phenotype Corrêa et al.

In particular, white hypertrophic adipose tissue acts as an endocrine regulator that uses many adipokines such as hormones leptin and adiponectin ; some peptides such as resistin, angiotensinogen, and apelin, among others; immune factors; and inflammatory cytokines such as interleukin-1, interleukin-4, interleukin-6, interleukin-8, interleukin, interleukin, monocyte chemoattractant protein-1, nerve growth factor, neuropeptide Y, retinol-binding protein-4, transforming growth factor-β, tumor necrosis factor- TNF- alpha, vascular endothelial growth factor VEGF , visfatin, omentin, and chemerin.

All of these oversee controlling orexigenic hunger or anorexigenic satiety stimuli Coelho et al. Risk factors of Mets and switchers to glycolysis are excess sugar and unhealthy fats consumption, obesogens, sedentarism, consumption of processed food, higher intake of fructose corn syrup, juices, soft drinks, and sweets , and many other processed foods Dornas et al.

Moreover, pollution and exposure to obesogens such as endocrine-disrupting chemicals EDC will increase the fat amount, inflammation, and adipocyte dysfunction Uzunlulu et al. Other less cited, modern factors are involved. Loneliness and chronic social isolation are also associated with upregulated lipid synthesis and a metabolic switch from OXPHOS to aerobic glycolysis and glycolytic pathway gene expression Williams et al.

Social interactions should be considered a basic need, just as other human needs, such as eating, breathing, and sleeping Shen et al. The benefits of social interaction include better mental health, improved sleep quality, increased life expectancy, and improved immunological and metabolic health Xiong et al.

Related to metabolic changes observed in loneliness or chronic isolation, HPA axis chronic activation leads to the elevated secretion of cortisol, increased blood glucose, glycogenolysis, and insulin resistance that ends up in engaging in unhealthy habits and decreasing satiety signaling.

New insights into the way mitochondria respond to social behavior include mitochondria-derived stress mediators steroid hormones produced by mitochondria and blood mitokines. An emerging circulating mitokine is cell-free mtDNA cf-mtDNA present in human blood, which activates immune receptors and triggers inflammatory responses.

Acute psychological stress Trumpff et al. Interdisciplinary approaches that involve mitochondrial signaling in resilience, aging, and metabolism are needed, and perhaps mitochondria should be defined as social organelles Picard and Sandi, Not only should the modern lifestyle be considered toxic for cell and mitochondrial functioning, but also medication can induce mitochondrial toxicity and a metabolic switch to glycolysis because of the impairment of OXPHOS.

Many drugs have been reported to cause mitochondrial harm and damage, including benfluorex, rosiglitazone, celecoxib, ponatinib, etoricoxib, diclofenac, and remdesivir Tang et al. Oncological drugs are reported to cause structural damage to mitochondria, including downregulated ferroptosis, accumulation of lipid peroxides, mitochondrial swelling, cristae disappearance, and matrix cavitation, as found in research with the oncological medicine doxorubicin DOX Tadokoro et al.

Related to mitochondrial complexes, zoniporide, naproxen, dronedarone, and mubritinib inhibit complex I Tang et al. Complex II is compromised by propranolol and atenolol. Celecoxib suppresses complex IV, and As 2 O 3 inhibits complexes I, III, and IV. Non-steroidal anti-inflammatory drugs NSAIDs , such as nimesulide, meloxicam, and acetylsalicylate, also o inhibit OXPHOS.

Lipophilic drugs can damage phospholipids on the IMM, especially cardiolipin, or activate the mitochondrial permeability transition pore mPTP Tang et al.

Studies have demonstrated the presence of mitochondria-induced myopathies caused by reduced respiratory enzyme activity, calcium leakage, and oxidative stress in patients treated with statins in addition to rhabdomyolysis reported in 1 in 10, patients Stoker et al. Cancer radiation therapy in animal models induces aerobic glycolysis through ROS Zhong et al.

Chemical cancer therapies, antiviral or antiretroviral drugs, antibiotics, antidiabetic drugs, non-steroidal anti-inflammatory agents, anesthetics, and many others, impair healthy mitochondrial function altering the metabolism of many cell types, including those of the immune system Stoker et al.

Almost all mentioned risk factors leading to the Warburg effect and long-term aerobic glycolysis are characterized by high blood glucose levels and an abundance of free fatty acids.

The use of hormetic triggers could serve as an antidote against modern life because of a rerouting of cellular metabolism from cytosolic glycolysis to mitochondrial OXPHOS Bianchi et al.

Intermittent fasting alone already induces an anti-Warburg effect Bianchi et al. Cancer is considered a disease characterized by hallmarks such as aerobic glycolysis in most, if not all types of, cancers.

Cancer manipulates its own metabolism and the metabolism of cells surrounding a tumor, making it a selfish-metabolic disease Vaupel and Multhoff, Therefore, not only does the tumor cell itself depend on aerobic glycolysis for the initiation and progression of cancer, but also the tumor activates the Warburg effect in cells of the tumor microenvironment TME , including immune cells and cancer-affected fibroblasts.

By doing so, the tumors cells create a hyper-acidic, nutrient-deficient environment combined with changes in glutamine load, fatty acid metabolism, and hypoxic states that support tumor aggressivity and growth Correnti et al. Different from what was earlier assumed, the acceleration of aerobic glycolysis is not a consequence of dysfunctional mitochondria perse and a compensation for the poor ATP yield per molecule of glucose.

Instead, in most tumors, the Warburg effect is an essential part of selfish metabolic reprogramming. As discussed earlier, mitochondria play an important role in cell fate.

The exclusion of mitochondria from the metabolism prevents the cell and its cancer from being killed by the cell fate mechanisms of mitochondria. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival Vaupel and Multhoff, The metabolic transformation leading to the Warburg effect we observe in cancer also underlies neuronal degeneration in sporadic AD Traxler et al.

Strategies intervening in this metabolic switch, inhibiting glycolysis and glutaminolysis, and promoting OXPHOS—keeping mitochondria healthy—could be interesting strategies in the fight against these conditions and others related to the Warburg effect Manzi et al.

Besides preventing pro-apoptotic pathways mediated by mitochondria, aerobic glycolysis enables a list of other malignant progression and survival advantages for cancer cells.

Examples are accelerated glycolytic fluxes, ATP generation, a backup and diversion of glycolytic intermediates, the biosynthesis of nucleotides, the production of non-essential amino acids, lipids and hexosamines, maintenance of cellular redox homeostasis, low ROS formation, inhibition of pyruvate entry into mitochondria, lactate accumulation, stimulating sustained proliferation and suppression of anti-tumor immunity, and extracellular acidosis, which accelerates malignant progression and drives resistance to conventional therapies Vaupel and Multhoff, As the metabolic shift seems an important stone early in the domino effect of cancer initiation, preventing or intervening in this switch seems an important intervention for primary and secondary prevention of cancer.

The Warburg effect results from an interplay of different mechanisms and driving processes. Furthermore, the functions of tumor suppressors mutant p53, mutant PTEN, and microRNAs 29, , and , Sirtuins 3 and 6, and the AMPK signaling pathway Kumar et al.

The metabolic changes belonging to the Warburg effect can be influenced by the known physiological hormetic triggers that could serve as primary and perhaps secondary preventive interventions Jazvinšćak Jembrek et al. For instance, intermittent fasting programs could perhaps serve as Warburg antidote, blocking enzymatic pathways and creating amino-acid and glucose starvation Lee et al.

Glutamine executes multiple functions in cancer cells. Besides being an energy source, glutamine is a so-called anaplerotic molecule.

Glutamine can replenish the TCA cycle with intermediates extracted for biosynthesis. In this regard, glutamine is an alternative source for the TCA cycle. Thereby, glutamine uptake by the energetically transformed cell contributes to the formation of nucleotides and fatty acids and has an important role in the homeostasis of ROS Alhayaza et al.

Another important oncometabolite is leucine, which, together with glutamine, can activate the mTOR complex cell growth master Scalise et al. As aforementioned, intermittent fasting could serve as an mTOR antidote. When glutamine is absorbed by metabolically transformed cells, it is converted into glutamate.

Thereafter, glutamate is converted into α-ketoglutarate, which enters the TCA in the mitochondria, where the reaction is catalyzed by succinyl-CoA synthetase with the resulting production of ATP. In the above process, one of the five carbon atoms of glutamine is released as CO 2.

The remaining four carbon atoms of glutamine are exported to the cytosol as malate, which, in turn, can give rise to different metabolic pathways useful for cancer cells, including the conversion into pyruvate Scalise et al. Pyruvate can be converted into lactate for aerobic glycolysis and ATP production.

The conversion of glutamine into glutamate is regulated by an oxidative reaction orchestrated by glutaminase Zhang et al. Alternatively, malate can enter the TCA cycle as a molecule with four carbon atoms, including asparagine alanine-serine cysteine-preferring transporter 2 ASCT2 substrates Scalise et al.

Malate is converted into oxaloacetate via malate dehydrogenase and then into aspartate via aspartate aminotransferase Scalise et al. The enzymes mentioned serve as important targets in the development of anticancer therapies.

The glutaminase enzyme is produced by two different genes: GLS1 and GLS2 Scalise et al. These genes are important therapeutic targets, and inhibition could serve as a promising cancer intervention. Other targets of cancer preventive interventions are glucose and glutamine transporters and their increase in the cancer process.

Cancer cells overexpress glucose transporters GLUTs , sodium-dependent amino acid transporters such as ASCT2, and sodium-independent amino acid transporters for signaling, such as LAT1 Scalise et al.

Glutamine is also recognized at the plasma membrane by SLC receptors including members, e. Within this family, the major and best-characterized glutamine transporter is SLC1A5.

SLC1A5 is currently known as ASCT based on preliminary observations of substrate specificity, although the actually preferred substrate is now known to be glutamine Scalise et al.

The most likely exchanged amino acids by SLC1A5 are asparagine, threonine, or serine, and their transport, together with glutamine, allows the entry of 1—2 carbon atoms into the cell, which can then be oxidized in the TCA with ATP production in the mitochondria.

The increase in the plasmatic concentration of serine and threonine is well-described in cancer Scalise et al. It seems clear that amino acids are involved in cancer metabolic rewiring, and several are essential for the initiation and progress of cancer Scalise et al.

As touched upon briefly, the metabolic transformation seen in tumor cells also enhances a favorable ROS environment. ROS accumulation can directly affect DNA integrity, and ROS-mediated DNA damage could favor the initiation stage of tumorigenesis.

ROS have also been associated with epigenetic alterations that favor oncogenic transformation. ROS-induced hypermethylation of the promoter region of tumor suppressor genes has been shown to promote carcinogenesis.

Cancer cells also need to keep ROS production under control, and glutamine converted in glutamate serves the synthesis of glutathione peroxidase as a major anti-oxidative enzyme from glutamine.

Intervening in this pathway also seems important Shi et al. Oncometabolites are signaling molecules derived from mitochondria dysfunction. Others are gain-of-function mutations in cytosolic and mitochondrial isocitrate dehydrogenase IDH isoforms 1 and 2 with the production of 2-hydroxyglutarate 2-HG.

These combinations lead to the loss of α-ketoglutarate α-KG production and simultaneous gain of 2-HG that alters transcriptional patterns of histone methylation regulation and whole DNA methylation in favor of tumor growth Cassim et al.

Pyruvate kinase M PKM is the glycolytic enzyme that converts phosphoenolpyruvate to pyruvate. The PKM gene codes for two isoforms, PKM1 and PKM2, which code for 22 different amino acids. PKM2 is the most common isoform of this enzyme in cancer van Niekerk and Engelbrecht, ; Li et al. The pathological isoform of PKM toward the cancer-associated PKM2 isoform causes metabolic and transcriptional changes.

These alterations occur through the lack of metabolic activity of PKM2. PKM2 specifically interacts with the STAT3 and HIF1a transcription factors and enhances them, together exerting pro-oncogenic programs in which HIF1a is aberrantly activated despite a normoxic environment Traxler et al.

Altogether, pro-carcinogenic changes have a solid metabolic basis, and changes in metabolism are a leading therapeutic target for the treatment of patients with cancer, which is among the leading causes of mortality and, in many countries, risk factor number one Bray et al.

As many processes are involved at the same time, primary and perhaps secondary prevention should be achieved by multiple lifestyle interventions. In the scope of this review, the use of physiological hormetic triggers possibly stops the domino cascade, leading to the development of neoplasms.

Intestinal barrier dysfunction results from food poisoning, dietary factors, and dysbiosis, and increased permeability leads to the translocation of sterile toxins and living or dormant microbes and lipopolysaccharides LPS into the bloodstream de Punder and Pruimboom, ; de Punder and Pruimboom, b.

The resulting endotoxemia leads to a sustained or low inflammatory and stress response. Translocation of intestinal xenotoxins and micro-organisms should be considered one of the main pathways leading to low-grade inflammation Laugerette et al.

The immune, mitochondrial, and metabolic characteristics of the gut environment will depend on the enterotype distribution taxonomic classification of microbial families, mucus quality, and diversity of each intestine Pimentel and Lembo, A gut pathological microbiome has been related to chronic disease, LGI, and mitochondrial dysfunction, and the so-called atopbiome in other tissues is frequently recognized as a risk factor for chronic diseases.

Our industrialized society, with the presence of a wide range of toxic chemicals, metals, and antibiotics, has completely changed the microbiome, which affects mitochondrial functionality and organ function Demeneix, ; Martel et al.

Modern life also comes with environmental exposure to many pathogenic microorganisms and resistant microbes exposed to insecticides or pesticides. Dysbiosis caused by pathobionts impairs mitochondrial integrity through multiple pathways, impairing healing mechanisms and promoting chronicity.

In other words, strengthening mitochondria as much as possible helps us deal with the deteriorating consequences of modern life. An acute infection induces dysregulation in mitochondria-nuclear communication, which is part of the resolving response when it is time-restricted.

In an LGI, this dysregulation lasts long and should be considered one of the most important steps in the development of chronic diseases Sureshbabu et al. Mitochondria are a major location for the production of ROS, which is necessary to fight infections.

Evolutionary pressure made pathogens exploit the mitochondrial influence in killing and developed mechanisms to disturb mitochondrial—nucleus communication in fighting infections and increased the survival of the struggling pathogens Andrieux et al.

The existence and optimal functioning of pattern-recognizing receptors PRRs are essential for optimal immune functionality. There are four families of PRRs distributed throughout all types of cells in the human body, namely, TOLL-like receptors TLRs , NOD-like receptors NLRs , retinoic acid-inducible gene I-like receptors RIG-I RLRs , RIG-I receptors, and C-type lectin receptors CLR.

Each PRR can trigger a response through the nuclear transcription factor Kappa beta nfKb that allows the transcription of interferon and pro-inflammatory cytokines dependent on the pathogen that activated the PRR Sandhir et al.

In the antiviral response, the mitochondrial antiviral signaling protein MAVS —located in the outer membrane of the mitochondria—is involved in the recognition and detection of viruses via the RLR receptor signaling pathway.

The interaction between MAVS and the mitochondrial outer membrane protein mitofusin MFN and mitochondrial fusion are required in the RLR signaling pathway.

In animal models with the deletion of MFN1 and MFN2, responses via RLR are reduced and impair the antiviral response. ROS are essential in antimicrobial signaling and efficiency because macrophages and dendritic cells eliminate microorganisms by phagocytosis.

The proximity between the alpha-phagosomes and the mitochondria allows mtROS to cross the phagosome and eliminate the pathogen Sandhir et al. It allows the recruitment of other immune cells to improve anti-infective efficiency.

The activation of the NLRP3 inflammasome is related to the triggering of TLRs and the production of pro-IL1b and pro-IL18 via caspase-1 activation in response to microbial infection and cellular damage PAMP and DAMP signaling. Free mtDNA, ROS, and the MAVS pathway are required for the recruitment of NLRP3 to mitochondrial membranes.

The phospholipid cardiolipin translocates from the inner to the outer membrane of the mitochondria to bind to NLRP3 and promote its activation. The accumulation of mtDNA in the cytosol results in an antiviral immune response, and the oxidation of mtDNA and cardiolipin leads to the activation of the inflammasome that ultimately induces a pro-inflammatory response that should resolve in time Kelley et al.

Besides the necessity of mitochondrial involvement in eliminating pathogens, damaged mitochondria can be the cause of inflammation due to their prokaryotic bacterial origin.

Damage causes free mtDNA, which is perceived as DAMP, and triggers inflammation. Therefore, infection is not the only cause of inflammation; mitochondrial damage could be a cause as well Tan et al.

The role of mitochondria in the antibacterial response is evidenced by their role in apoptotic regulation. Host cells and their mitochondria produce ROS to damage the lipids, proteins, and nucleic acids of some bacteria. In addition, mitochondrial fission via dynamin-related protein 1 DRP1 maintains cell homeostasis during infection to prevent propagation by modulating cell apoptosis because if the cell dies, the infection can spread Andrieux et al.

Pathogen infection changes the mitochondrial- metabolic- and oxidative profile of cells. Infected cells cause dysregulation of several nuclear genes through retrograde signaling.

When pathogens exploit and eliminate mitochondrial defense mechanisms, they are much more efficient in bypassing immune mechanisms. Pathogens have learned to use pathways that avoid both immune and mitochondrial anti-infective effects. The treatment of mitochondrial damage and gut permeability and the restoration of gut equilibrium are promising targets for optimizing and resolving infection at the time.

Mitochondria are vital in triggering the immune response related to RLR, NLR, or TLR against viruses, protozoa, bacteria, fungi, or damage Kelley et al. The persistence of pathological microbes harms the integrity of the intestinal barrier, mediating immune and mitochondrial failure.

Even biomechanical disorders, such as intervertebral discopathies, seem to be associated with disc infection caused by oral and skin-derived pathogens Rajasekaran et al. Besides the aforementioned mechanisms, dysbiosis reduces the supply of calcium to the bone and impairs the ability to manufacture vitamins K2 and D and other important immuno-metabolic substances.

Dysbiosis mediates more aggressive immunological disorders in genetically predisposed individuals, and dysbiosis is related to Multiple immune pathologies.

Examples are multiple sclerosis Opazo et al. The interconnection between endotoxemia, mitochondrial dysfunction, LGI, and even non-resolved infection demands more integrative interventions. Lifestyle interventions and the use of physiological hormetic stress triggers could serve as interventions for primary and secondary prevention of chronic diseases, the scope of this review.

The metabolic activity of brain neurons is, together with the activity in the lungs and kidneys, the highest in the human body. The disruption of any of the mitochondrial dynamics or alteration of functions, such as energy production, ROS production, calcium homeostasis, control of epigenetic and nuclear transcriptional processes, immune defense, lipid regulation, and glucose regulation, can have deleterious effects on neurons and neuroglial cells Fairbrother-Browne et al.

Although neurological diseases vary in terms of their underlying risk factors and mechanisms, mitochondrial dysfunction is common in most, if not all, of them.

Mitochondria are necessary for the energy supply of neurological cells, as their energy consumption is incredibly high, with the brain as one of the most specialized and metabolically active organs. In basal conditions, neurons and astrocytes will use the same amount of energy sources.

Although neurons synthesize ATP through OXPHOS, astrocytes are specialized in metabolizing glucose through aerobic glycolysis, resulting in an enormous amount of lactate and pyruvate generation from glucose that can be transported to neurons by MCTs and hydrocarboxylic acid receptors 1 HCAR1 Sharma et al.

One of the mitochondrial mechanisms involved in PD is related to the function DJ-1 protein. DJ-1 is an oxidative stress sensor that prevents neuronal death induced by oxidative stress and inhibits the aggregation of α-synuclein via its chaperone activity.

Dj-1 mutation causes mitochondrial dysfunction and accumulation of α-synuclein, the hallmark of PD Dolgacheva et al. This could also lead to complex I deficiency in muscular and immune cells, substantia nigra, and platelets, as seen in patients with PD Rey et al.

MAM and ER defects induce translocation of the MAM components, such as IP3R, VDAC, and MFN1 and MFN This can lead to disturbed calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death Sunanda et al.

Alterations in mitochondrial-located sirtuins SIRT3, SIRT4, and SIRT5 induce mitochondrial transcriptional problems, which might result in pathologies He et al. Iron is a key element for mitochondrial function and homeostasis, which is also crucial for the maintenance of the neuronal system.

However, too much iron promotes oxidative stress, immune response, and altered mitochondrial proteins. Patients with PD show an over-storage of iron compared with controls that could be caused by blood barrier dysfunction and subsequently lead to iron storage in the substantia nigra Cheng et al.

Another explanation can be an upregulation of some iron-storage proteins such as mitoferritin, lactoferrin, and transferrin or increased expression of DMT1 in dopamine neurons and ceruloplasmin dysfunction, observed in multiple neurodegenerative diseases Zhang et al.

In ALS, mitophagy and increased ROS are markedly involved in its pathogenesis, resulting in a reduced number of phagosomes at the neuromuscular junction Tsitkanou et al.

Mutations acquired or congenital in the genes for the production of mitochondrial proteins FUS, TDP, SOD1, and C9ORF72 have been reported Wong and Venkatachalam, ; Rey et al.

More than SOD1 mutations are associated with ALS. SOD1 codes for Cu-Zn superoxide dismutase, which is responsible for neutralizing superoxide radicals by catalyzing molecular oxygen and hydrogen peroxide. Mutations in FUS, TDP, SOD1, and C9ORF72 increase DNA damage, alter mitochondria fusion and fission, alter calcium homeostasis, and reduce the activity of respiratory chain complexes II and IV Kodavati et al.

This leads to structural abnormalities, such as swollen mitochondria, impaired MAM functions, augmented mitochondrial fragmentation, progressive loss of membrane potential, increased ROS production, and defective mitochondrial axonal transport Kodavati et al. Dysregulations of the cytoskeletal network, mitochondrial localization, and homeostasis are involved pathways in the initial steps for the development of neurodegeneration.

In ALS, mitochondrial dysfunction increases mtROS and decreases ATP production. Dysregulation of mitochondrial proteins that impair fission, fusion, and mitophagy is responsible for disruptions of axonal transport and defects of the cytoskeletal organization Petrozziello et al.

Furthermore, mitochondrial dysfunction leads to impaired binding of motor proteins to microtubules, altered activities of kinases, and destabilization of the motor cargo binding. ALS further shows dysregulated PKN1 activity Petrozziello et al. PKN1 elevates excitatory amino acid transporter-3 EAAT3 and other glutamate transporters.

The resulting excitotoxic levels of glutamate disrupt the axonal trafficking of neurofilaments and may contribute to irreversible neurodegeneration Petrozziello et al. Mitochondrial dysfunction is also seen as a primary cause of AD.

The brains of patients with AD show impaired glucose and oxygen metabolism and impaired activity of pyruvate dehydrogenase, ketoglutarate dehydrogenase, and cytochrome oxidase. Furthermore, mtDNA alterations, dysfunctional transmembrane amyloid beta, and tau protein accumulation are found, together with altered mitochondria morphology and respiratory chain dysfunction Chen et al.

The two pathologies show common mechanisms with neuroinflammatory diseases, such as depression, fibromyalgia, and migraine. Some of the shared mechanisms are altered brain activity or morphology in several regions; alterations of the HPA axis; genetic susceptibilities; inflammatory signaling mediated by several cytokines, ROS, NRS, and chemokines; altered neuroglial cell functions including indolamine dioxygenase and neurotrophic factors ; dysregulation in monoamines; increase in substance P; altered galanin and opiate signaling; and excessive excitatory glutamatergic transmission and compromised GABA mediated inhibition Maletic and Raison, In particular, MAVS could protect patients with CFS from viral-related infections, which is essential in a progressive disease related to severe immune alteration Rasa et al.

The observed mitochondrial alterations are the suppression of the PDC, thereby lowering the conversion of pyruvate to acetyl-CoA and diminished mitochondrial ATP production from OXPHOS and glycolysis. In addition, the reduction in acetyl-CoA prevents melatonin-mediated cellular and mitochondrial protection.

Acetyl-CoA is important for aralkylamine N-acetyltransferase AANAT activity, which converts serotonin to N- acetylserotonin NAS that is then converted to melatonin by acetyl-serotonin methyltransferase ASMT Anderson and Maes, Melatonin has immune plus antioxidative effects and optimizes mitochondrial OXPHOS Acuña-Castroviejo et al.

Neuroinflammation is an important mechanism related to pain syndromes such as fibromyalgia and CFS. Various pathways are associated with neuroinflammation, including increased oxidative stress, peripheral inflammation, and changes in the gut microbiome.

The long-lasting neuroinflammation leads to sensitization of the CNS, with chronic pain as a consequence Chen et al. Neuroinflammation in the CNS is mediated by neuroglia cells, found in high numbers in the brain and spinal cord. Glial cells oligodendrocytes, astrocytes, microglia, and ependymal cells can be activated by inappropriate dietary patterns, another possible cause of neuroinflammation.

The most relevant diet-related risk factors for Glia-cell induced neuroinflammation are the imbalance of anti-inflammatory fatty acids omega 3 and pro-inflammatory fatty acids omega 6 , energy-dense diets excess sugar , a diet poor in micronutrients vitamins and minerals , and diets low in polyphenols Chen et al.

Microglia are macrophages residing in the CNS and responsible for the regulation of homeostasis. They interact dynamically with synapses and induce synaptic pruning in stages of healthy brain development. Glia cells contribute to the pathogenesis of brain diseases through neuroinflammation.

The role of mitochondrial dysfunction is central to Glial function and even development Chen et al. Shifts in mitochondrial metabolism are crucial in the regulation of glial immune cell phenotypes.

Perhaps melatonin should be considered the main regulator of glia cell inflammatory activity. Many protective mechanisms against neuroinflammation have been attributed to melatonin functioning. Autocrine melatonin switches immune cells from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype and produces a change in reactivity from cellular to humoral Carrillo-vico et al.

Besides the switch in phenotype, melatonin interacts in multiple ways with microglia. It acts as a protector and an antioxidant and, by this means, inhibits processes that cause, promote, or propagate oxidative stress and neurodegeneration, resulting in excitatory overactivity, toxicological aggressions, viral and bacterial infections, and inflammation Carrillo-vico et al.

Melatonin also has several other mitochondrial mechanisms that interfere with pathways leading to chronic pain. Melatonin can eliminate mitochondrial free radicals and inhibit the activity of mitochondrial nitric oxide synthase.

It restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, improves the integrity of the blood—brain barrier, and counteracts neuroinflammation and glutamate excitotoxicity Morris et al.

Furthermore, melatonin and its derivatives act as natural electron donors, being, therefore, highly efficient substances against oxidative stress Manchester et al. Melatonin-induced Bmal1 drives the night-time dampening of immune cells.

Under challenging conditions at night, when immune cell activity is required, an increase in pro-inflammatory cytokines suppresses pineal melatonin production, called the immune-pineal axis Markus et al. As already mentioned, dysbiosis is involved in many or all neurological pathologies.

Dysbiosis can signal to the CNS through the production of neuromodulators, such as GABA, tryptophan, choline, serotonin, butyrate, and short-chain fatty acids SCFA Rea et al. Dysregulation of the gut—brain axis can contribute to the development of several neurodegenerative, neuropsychiatric, neurodevelopmental, and neuroinflammatory diseases Mezzelani et al.

Gut microbiome-generated metabolites, such as colonic acid, D-lactic acid, D amino acids, and methyl metabolites, can pass the blood—brain barrier and modulate neuronal behavior. In this way, they influence neuronal development and brain mitochondrial dynamics.

Strategies to enhance melatonin production and or exogenous delivery are described in PART III. Figure 4 Understanding the different components of mitochondrial dynamics and their influence on health and disease enables the implementation of specific and targeted interventions.

As mitochondria play a key role in health and disease, maintenance or recovery of mitochondrial function could or even should be considered a root cause prevention and root cause medicine.

FIGURE 4. Lifestyle interventions based on this principle are also known as hormetic strategies. At the mitochondrial level: mitohormetic strategies.

Mitohormesis could support mitochondrial resilience and health, especially preventing CNCDs or premature and failed aging. A phenomenon called hormesis is important in the maintenance of mitochondrial health. Hormesis refers to the evolutionary conserved adaptive responses of all living organisms to mild environmental, nutritional, or even voluntary challenges, through which the system amends its tolerance to more toxic stress factors Pruimboom and Muskiet, Subsequently, treatments and lifestyle interventions based on this principle are also known as hormetic strategies Lee and Lee, ; Bongiovanni et al.

Substances producing hormetic responses are called hormetins Gezer, ; Nunn et al. The application of hormetic strategies and combination thereof might lead to increased lifespan and disease resistance, which is evidenced in different animal studies Schmeisser et al.

Hormesis is the result of an upregulation of stress response genes. Triggering or stressing these mitochondrial control systems enables the expression of certain genes and results in the production of protective substances and activation of longevity-related mechanisms Blagosklonny, ; Lee and Lee, ; Calabrese and Kozumbo, The positive impact of the use of mitohormetic stimuli has been shown in studies on animals in early life.

Mitohormetic triggers applied in early life could support mitochondrial resilience and prevent early and unsuccessful aging Yun and Finkel, ; Merry and Ristow, ; Bárcena et al. One of the mitochondrial stress responses is characterized by the induction of specific heat shock protein HSP genes in the nucleus and the subsequent effects of the HSPs on mitochondrial functioning, called the mitochondrial unfolded protein response UPRmt Tower, ; Inigo and Chandra, HSPs induce mitophagy and thus influence mitochondrial dynamics that enable the breakdown and replacement of abnormal mitochondria, including those destructed or with mutated mitochondrial genomes Tower, The activation of HSPs and the clearance of damaged mitochondria could be a possible solution for heteroplasmy explained earlier in this document.

HSPs are involved in immune function, cell cycle regulation, and proteome homeostasis. They facilitate cell function by translocating proteins to other sites within the cell, escorting proteins across cell membranes, stabilizing various proteins and receptors, and identifying and repairing damaged proteins Brunt and Minson, HSPs are also associated with other proteins in the ER and in close proximity to the plasma membrane, nucleus, cytosol, or regulation of mitochondrial proteostasis Brunt and Minson, Hormetins induce responses to HSP through the stimulation of kinases and transcription factors Lee and Lee, ; Nunn et al.

Examples of these are the co-transcription factors PGC1α, SIRT1, and SIRT3. They code for proteins that protect mitochondrial dynamics and thus functioning. They are known to prevent the transition from acute to chronic pathologies in kidney disease models Aparicio-Trejo et al.

Restored expression of PGC-1α in cells ameliorates defective FA oxidation and corrects ATP depletion by reversing changes in damaged tissues through mitochondrial recovery Fontecha-Barriuso et al. In addition, mitochondrial protectors and antioxidants, such as N-acetyl cysteine, are frequently used to prevent kidney damage.

Their efficacy is shown in models of folic acid-induced kidney damage. They are also a good example of interventions that could support mitochondrial health and induce the production of mitochondrial antioxidants for injury prevention Aparicio-Trejo et al.

Hormetic triggers also influence retrograde signaling nuclear—mitochondrial , a phenomenon discussed earlier. Retrograde signaling influences mitochondrial dynamics, replacement, and health. Important proteins here are HIF1, nuclear factor kappa B NFkB , PPARs, NRF1, and NRF2.

All of these promote the transcription of TFAM and PGC-1α responses. They migrate and bind to target genes, eliciting the expression of cytoprotective molecules Pruimboom and Muskiet, and facilitating mitochondrial dynamics and mitochondrial health.

Examples of hormetins as hormetic triggers are exercise, controlled oxidative stress, calory restriction CR , temperature stressors such as heat and cold, and the use of phytochemicals.

These and their relation to mitochondrial health will be discussed hereafter. Fasting is an effective way to recover mitochondrial efficiency, and multiple human studies have shown its ability to restore metabolic pathways in people suffering from chronic pathologies.

Fasting regimens are promising primary and secondary prevention strategies in patients suffering from metabolic and cardiovascular diseases Oliveira et al.

During nutrient deprivation, the fusion rate increases and the fission rate decreases, leading to increased bioenergetic efficiency Cuevas-Sierra et al. CR, another way to create hormetic stress, induces remodeling of the ETC architecture and cristae morphology.

This remodeling of the ECT architecture might be driven by ER stress Balsa et al. Eukaryotic cells have evolved a conserved pathway called the unfolded protein response aimed to re-establish ER homeostasis.

These substances can re-establish ER homeostasis and support proper protein folding. A properly functioning ER enables the OXPHOS system to increase ATP supply and promote protein homeostasis Balsa et al.

Studies suggest that fasting supports the balance between the fusion and fission states and homeostasis in the mitochondrial network in multiple cells and organs Liesa and Shirihai, ; Yu and Pekkurnaz, Research shows an increased expression of mitochondrial fusion-related proteins, MFN 1 and MFN 2.

In an experimental model that studied the influence of CR on mitochondrial morphology and dynamics in muscle cells, it was reported that CR reduced fission Cuevas-Cervera et al.

As we explain above, fasting induces an ANTI-Warburg effect Bianchi et al. Protein and biomass accumulation is treatable, improving autophagia, for example, with fasting Gherardi et al. The positive effects of IF and CR and the timing of food intake on mitochondria are related to oxidative stress Savencu et al.

Numerous studies on animals and humans have shown the beneficial effects of diet interventions on mitochondria-related ROS production. Thus, CR and IF seem able to influence ROS generation and the antioxidative capacity of mitochondria Cuevas-Cervera et al.

Nuclear erythroid-related factor 2 NRF2 is a transcription factor encoded by the NFE2L2 gene. Phytochemicals seem to reverse conditions involved in extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA Biagiotti et al. Optimization of the activity of NRF1 and NRF2 is a very efficient strategy for rehabilitating mitochondrial function.

NRF2 activation is inversely related to mtROS generation. PGC1α, in collaboration with NRF2, increases mitochondrial biogenesis to supply healthier mitochondria. NRF2 further supports the maintenance of the mitochondrial membrane potential, OXPHOS, ATP synthesis, fatty acid synthesis, and oxidation Buttari et al.

Under stress conditions, cells activate the regulatory enhancer sequence of the NRF2 pathway—antioxidant response element ARE —to promote the expression of antioxidant genes.

This decreases the expression of pro-inflammatory mediators and increases the detoxifying capacity of all cell types. Phytochemicals are involved in the regulation of NRF2. They are plant antinutrients and are present in the human diet. There are thousands of different phytochemicals in commonly consumed plants.

These phytochemicals can be subdivided into four classes based on their chemical structure: phenols and polyphenols, terpenoids, alkaloids, and sulfur-containing compounds Clifford et al.

Multiple dietary phytochemicals are useful in regulating NRF and the subsequent activation of cytoprotective effects Cuadrado et al. Some useful phytochemicals investigated are naringenin in citrus fruits and tomatoes Lim et al.

Another example is sulforaphane present in broccoli, brussels sprouts, cabbage, and cauliflower Santín-Márquez et al. Civil Law. Company and Commercial Law. Commercial Law. Company Law.

Comparative Law. Systems of Law. Competition Law. Constitutional and Administrative Law. Government Powers. Judicial Review. Local Government Law. Military and Defence Law. Parliamentary and Legislative Practice. Social Law. Construction Law. Contract Law.

Criminal Law. Criminal Procedure. Criminal Evidence Law. Sentencing and Punishment. Employment and Labour Law. Environment and Energy Law. EU Law. Family Law. Financial Law. Banking Law. Insolvency Law. Tax Law. History of Law.

Human Rights and Immigration. Intellectual Property Law. International Law. Private International Law and Conflict of Laws. Public International Law. IT and Communications Law. Jurisprudence and Philosophy of Law. Law and Politics.

Law and Society. Legal System and Practice. Courts and Procedure. Legal Skills and Practice. Primary Sources of Law. Regulation of Legal Profession.

Media Law. Medical and Healthcare Law. Criminal Investigation and Detection. Police and Security Services. Police Procedure and Law. Police Regional Planning. Property Law. Land Law. Personal Property Law. Study and Revision.

Terrorism and National Security Law. Tort Law. Trusts Law. Wills and Probate or Succession. Medicine and Health. Allied Health Professions. Arts Therapies. Clinical Science. Dietetics and Nutrition. Occupational Therapy. Operating Department Practice. Speech and Language Therapy.

General Anaesthesia. Clinical Medicine. Acute Medicine. Cardiovascular Medicine. Clinical Genetics. Clinical Pharmacology and Therapeutics. Endocrinology and Diabetes. Genito-urinary Medicine. Geriatric Medicine. Infectious Diseases. Medical Oncology. Medical Toxicology.

Pain Medicine. Palliative Medicine. Rehabilitation Medicine. Respiratory Medicine and Pulmonology. Sleep Medicine. Sports and Exercise Medicine. Clinical Neuroscience. Community Medical Services.

Critical Care. Emergency Medicine. Forensic Medicine. History of Medicine. Medical Dentistry. Oral and Maxillofacial Surgery. Paediatric Dentistry. Restorative Dentistry and Orthodontics. Surgical Dentistry. Medical Ethics. Medical Skills. Clinical Skills. Communication Skills. Nursing Skills. Surgical Skills.

Medical Statistics and Methodology. Clinical Neurophysiology. Nursing Studies. Obstetrics and Gynaecology.

Occupational Medicine. Otolaryngology ENT. Chemical Pathology. Clinical Cytogenetics and Molecular Genetics. Medical Microbiology and Virology.

Patient Education and Information. Popular Health. Caring for Others. Complementary and Alternative Medicine. Self-help and Personal Development. Preclinical Medicine. Cell Biology. Molecular Biology and Genetics. Reproduction, Growth and Development. Primary Care.

Professional Development in Medicine. Addiction Medicine. Child and Adolescent Psychiatry. Forensic Psychiatry. Learning Disabilities. Old Age Psychiatry. Public Health and Epidemiology. Public Health. Clinical Radiology. Interventional Radiology. Nuclear Medicine.

Radiation Oncology. Reproductive Medicine. Cardiothoracic Surgery. Gastro-intestinal and Colorectal Surgery. General Surgery. Paediatric Surgery. Peri-operative Care. Plastic and Reconstructive Surgery. Surgical Oncology. Transplant Surgery. Trauma and Orthopaedic Surgery. Vascular Surgery.

Science and Mathematics. Biological Sciences. Aquatic Biology. Bioinformatics and Computational Biology. Developmental Biology.

Ecology and Conservation. Evolutionary Biology. Genetics and Genomics. Molecular and Cell Biology. Natural History. Plant Sciences and Forestry. Research Methods in Life Sciences. Structural Biology. Systems Biology. Zoology and Animal Sciences. Analytical Chemistry. Computational Chemistry.

Environmental Chemistry. Industrial Chemistry. Inorganic Chemistry. Materials Chemistry. Medicinal Chemistry. Mineralogy and Gems. Organic Chemistry. Physical Chemistry. Polymer Chemistry. Study and Communication Skills in Chemistry. Theoretical Chemistry. Computer Science.

Artificial Intelligence. Computer Architecture and Logic Design. Game Studies. Human-Computer Interaction. Mathematical Theory of Computation. Programming Languages. Software Engineering.

Systems Analysis and Design. Virtual Reality. Business Applications. Computer Security. Computer Games. Computer Networking and Communications. Digital Lifestyle. Graphical and Digital Media Applications. Operating Systems.

Earth Sciences and Geography. Atmospheric Sciences. Environmental Geography. Geology and the Lithosphere.

Maps and Map-making. Meteorology and Climatology. Oceanography and Hydrology. Physical Geography and Topography. Regional Geography. Soil Science. Urban Geography. Engineering and Technology. Agriculture and Farming. Biological Engineering. Civil Engineering, Surveying, and Building.

Electronics and Communications Engineering. Energy Technology. Engineering General. Environmental Science, Engineering, and Technology.

History of Engineering and Technology. Mechanical Engineering and Materials. Technology of Industrial Chemistry. Transport Technology and Trades. Environmental Science. Applied Ecology Environmental Science.

Conservation of the Environment Environmental Science. Environmental Sustainability. Environmentalist Thought and Ideology Environmental Science.

Management of Land and Natural Resources Environmental Science. Natural Disasters Environmental Science. Nuclear Issues Environmental Science.

Pollution and Threats to the Environment Environmental Science. Social Impact of Environmental Issues Environmental Science. History of Science and Technology. Materials Science. Ceramics and Glasses. Composite Materials.

Metals, Alloying, and Corrosion. Applied Mathematics. Biomathematics and Statistics. History of Mathematics. Mathematical Education.

Mathematical Finance. Mathematical Analysis. Numerical and Computational Mathematics. Probability and Statistics. Pure Mathematics. Cognition and Behavioural Neuroscience.

Development of the Nervous System. Disorders of the Nervous System. History of Neuroscience. Invertebrate Neurobiology. Molecular and Cellular Systems. Neuroendocrinology and Autonomic Nervous System.

Neuroscientific Techniques. Sensory and Motor Systems. Astronomy and Astrophysics. Atomic, Molecular, and Optical Physics. Biological and Medical Physics. Classical Mechanics.

Computational Physics. Condensed Matter Physics. Electromagnetism, Optics, and Acoustics. History of Physics. Mathematical and Statistical Physics. Measurement Science. Nuclear Physics. Particles and Fields. Plasma Physics. Quantum Physics. Relativity and Gravitation. Semiconductor and Mesoscopic Physics.

Affective Sciences. Clinical Psychology. Cognitive Neuroscience. Cognitive Psychology. Criminal and Forensic Psychology. Developmental Psychology. Educational Psychology. Evolutionary Psychology. Health Psychology. History and Systems in Psychology. Music Psychology.

Organizational Psychology. Psychological Assessment and Testing. Psychology of Human-Technology Interaction. Psychology Professional Development and Training. Research Methods in Psychology.

Social Psychology. Social Sciences. Anthropology of Religion. Human Evolution. Medical Anthropology. Physical Anthropology.

Regional Anthropology. Social and Cultural Anthropology. Theory and Practice of Anthropology. Business and Management. Business Strategy. Business History.

Business Ethics. Business and Government. Business and Technology. Business and the Environment. Comparative Management. Corporate Governance. Corporate Social Responsibility. Health Management. Human Resource Management. Industrial and Employment Relations. Industry Studies. Information and Communication Technologies.

International Business. Knowledge Management. Management and Management Techniques. Operations Management. Organizational Theory and Behaviour.

Pensions and Pension Management. Public and Nonprofit Management. Strategic Management. Supply Chain Management. Criminology and Criminal Justice. Criminal Justice. Forms of Crime. International and Comparative Criminology.

Youth Violence and Juvenile Justice. Development Studies. Agricultural, Environmental, and Natural Resource Economics. Asian Economics. Behavioural Finance. Behavioural Economics and Neuroeconomics. Econometrics and Mathematical Economics. Economic Systems.

Economic Methodology. Economic History. Economic Development and Growth. Financial Markets. Financial Institutions and Services. General Economics and Teaching. Health, Education, and Welfare. History of Economic Thought. International Economics. Labour and Demographic Economics.

Law and Economics. Macroeconomics and Monetary Economics. Public Economics. Urban, Rural, and Regional Economics. Welfare Economics. Adult Education and Continuous Learning. Care and Counselling of Students.

Early Childhood and Elementary Education. Educational Equipment and Technology. Educational Strategies and Policy. Higher and Further Education.

Organization and Management of Education. Philosophy and Theory of Education. Schools Studies. Secondary Education. Teaching of a Specific Subject. Teaching of Specific Groups and Special Educational Needs.

Teaching Skills and Techniques. Applied Ecology Social Science. Climate Change. Conservation of the Environment Social Science.

Environmentalist Thought and Ideology Social Science. Social Impact of Environmental Issues Social Science. Human Geography. Cultural Geography. Economic Geography.

Political Geography. Interdisciplinary Studies. Communication Studies. Museums, Libraries, and Information Sciences. African Politics. Asian Politics. Chinese Politics. Comparative Politics. Conflict Politics.

Elections and Electoral Studies. Environmental Politics. European Union. Foreign Policy. Gender and Politics.

Human Rights and Politics. Indian Politics. International Relations. International Organization Politics. International Political Economy. Irish Politics. Latin American Politics.

Middle Eastern Politics. Political Methodology. Political Communication. Political Philosophy. Political Sociology. Political Theory. Political Behaviour. Political Economy. Political Institutions. Politics and Law. Public Administration.