Crucial micronutrients such as magnesium (Mg2+) are essential for correct body function. Its deficiency is associated with the development of comorbidities such as diabetes, obesity, and cardiovascular diseases (CVD, i.e., heart failure, arrhythmias, atherosclerosis, stroke, and hypertension) [1–6]. These comorbidities are frequently associated with an increase in inflammatory markers and oxidative stress (OS), in which Mg2+ deficiency may play an important role [2, 7,8]. Subclinical Mg2+ deficiency is widespread worldwide, mainly due to insufficient dietary intake [6, 9–16]. Unfortunately, this deficiency is difficult to detect but stimulates the production of cytokines in cells, causing chronic inflammation and, consequently, OS [17, 18].
This narrative review focuses on Mg2+ deficiency, its complications, and its relationship with OS and chronic inflammatory diseases. We highlight the potential importance of increasing Mg2+ intake worldwide to attenuate manifestations and symptoms derivate from Mg2+ deficiency. Our exhaustive review of the scientific literature was conducted in the “PubMed databases”. Search keyword terms included all possible combinations, abbreviations, and synonyms between “magnesium”, “magnesium deficiency”, “magnesium supplementation”, “cardiovascular diseases”, “Diabetes”, “oxidative stress”, and “inflammation.” We also considered the publication date from 1957 to 2022.
Mg2+ is the fourth most abundant intracellular ion in the human body [18, 19]. Mg2+ is essential to cellular processes, including energetic metabolism, protein and amino acid synthesis, and maintenance of the electrical potential of nerve tissues and cell membranes [18, 20]. Many enzymes that are vital for life require Mg2+. It is estimated that Mg2+ acts as a cofactor for over 600 enzymes and an activator in other 200 enzymes . Fundamentally, Mg2+ participates as a cofactor in several complex electron transport chain subunits, including methylenetetrahydrofolate dehydrogenase 2 and pyruvate dehydrogenase phosphatase . In this respect, Mg2+ is needed to feed the electron transport chain with nicotinamide adenine dinucleotide reduced (NADH) and flavine-adenine dinucleotide reduced (FADH2) due to acetyl coenzyme A (acetyl-CoA) requires Mg2+ to enter the tricarboxylic acid cycle [23, 24]. Also, Mg2+ is fundamental to signal transduction processes requiring kinases because almost all transphosphorylation reactions require Mg2+ . Mg2+ is needed for all the reactions in which ATP participates; binding sites of the substrate in kinases, ATPases, guanylyl cyclases, and adenylyl cyclases are specific to the Mg-ATP complex . In this sense, 538 kinases have been identified that comprise the human kinome, and an example of them are glycolytic enzymes, i.e., hexokinase, phosphofructokinase, aldolase, phosphoglycerate kinase, and pyruvate kinase [21, 26]. Mg2+ is also necessary for the structure and activity of DNA and RNA polymerases. Mg2+ is required for the enzyme to make conformational changes during catalytic reactions . Mg2+ also participates in muscle relaxation, neurotransmission, and stabilizing of the cellular membrane (reducing its fluidity and permeability indirectly by disturbances in lipid metabolism) [28–31]. Mg2+ is a key component in mediating protein synthesis through stabilizing the structure of ribosomes, stabilizing the secondary structure of ribosomal RNA (rRNA), and ribosomal binding proteins to rRNA . Mg2+ binds to rRNA and ribosomal proteins alleviating electrostatic phosphates repulsion; they translate the genetic information encoded by mRNA [32, 33]. When Mg2+ concentration is low (e.g., 10 mM in 70S ribosomes from Escherichia coli), the ribosome dissociates with the release of ribosomal components, stopping polypeptide synthesis [33, 34].
Moreover, Mg2+ is also necessary to transport vitamin D and activate it [35, 36]. Vitamin D binding protein (VDBP) and vitamin D receptor (VDR) are Mg2+ dependent for binding vitamin D . Also, the enzymes responsible for vitamin D metabolism require Mg2+ as a cofactor for 25 hydroxylations of vitamin D in the liver and 1 hydroxylation in the kidneys . Besides, Mg2+ may act as a second messenger in different cell signal pathways [38, 39]. For example, the Mg2+ cation has been described as a second signaling messenger in T cells [4, 21, 39]. Thus, Mg2+ has a closer relationship with adaptative immunity, mainly related to signaling and immunomodulatory pathways [20, 40, 41]. To summarize, Mg2+ has multiple functions, primarily associated with energy metabolism; its deficiency causes mitochondrial dysfunction and damage, increasing reactive oxygen species (ROS) production, which, in addition to the inflammatory response observed in Mg2+ deficiency, leads to chronic metabolic diseases [3, 17, 42, 43].
Mg2+ homeostasis is maintained by the intestine, bone, and kidneys . In the small intestine, Mg2+ reabsorption is mediated by the passive paracellular pathway dependent on an electrochemical gradient. However, a small portion is absorbed by the large intestine mediated by transient receptor potential melastatin 6 and 7 channel (TRPM6 and TRPM7), which also involve calcium absorption [21, 40]. Proteins that transport Mg2+ are required to recognize the large, hydrated cation, remove its hydration layer, and deliver the dehydrated ion to the Mg2+ transporters for transcellular transport across the membrane . It has been reported that in normal consumption of 370 mg, the intestine only absorbs between 30-50% of Mg2+, and the not absorbed Mg2+ is eliminated in the feces .
Bone is the most important Mg2+ reservoir, containing around 65%, residing in the bone at hydroxyapatite crystals surface; 34% is intracellular, less than 1% is extracellular, and only 0.3% is found in serum. Bone surface Mg2+ or exchangeable Mg2+ pool is continuously exchanged with blood Mg2+. During Mg2+ depletion, the Mg2+ concentration in bone exchangeable Mg2+ pool decreases to maintain blood Mg2+, reducing bone formation . Additionally, during Mg2+ deficiency, increased proinflammatory cytokines such as substance P, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)1 promote osteoclastic bone resorption .
The kidney maintains the serum concentration of Mg2+. Approximately 70% of the total serum Mg2+ is not protein bound, making it available for glomerular filtration. However, Mg2+ can be reabsorbed in the ascending limb of the loop of Henle (65-75%) and the proximal convoluted tubule (5-15%) using paracellular pathways. Also, the distal convoluted tubule reabsorbs 5-10% of Mg2+ through TRPM6/7 channels . Under normal conditions, 96% of the filtered Mg2+ is reabsorbed, and the body's Mg2+ balance is delicately adjusted by urinary excretion .
To summarize, the intestine, bones, and kidneys maintain the serum Mg2+ concentration; kidneys play a central role because gastrointestinal absorption is balanced by renal excretion (Fig. 1).
Fig. 1: Magnesium homeostasis (Mg2+). The Mg2+ consumed through the diet is absorbed throughout the entire gastrointestinal tract and into the blood, while that not absorbed is excreted in the feces. Once in the blood, the Mg2+ passes quickly to the different tissues. The kidney is essential to Mg2+ homeostasis since the most significant amount is filtered here, and only about 5% is excreted in the urine. Under conditions of Mg2+ deficiency, the concentration of exchangeable Mg2+ in bone decreases to maintain Mg2+ in the blood, reducing bone formation. In addition, they increase proinflammatory cytokines that promote osteoclastic bone resorption. IL: interleukins, TNFα: tumor necrosis factor-α, TRPM: transient receptor potential melastatin. Created with biorender.com (published with permission from biorender.com).
The primary source of Mg2+ is the diet . Mg2+ intake recommendations are provided in the Dietary Reference Intakes (DRI), which are developed by the Food and Nutrition Board (FNB) at the National Academies Institute of Medicine (formerly the National Academy of Sciences) . DRI is the set of reference values used to plan and assess the nutrient intake of healthy people. These values vary by age and gender and include a) the recommended dietary allowance (RDA), which refers to the average daily level of intake sufficient to meet the nutrient requirements of nearly all healthy people (97–98%); b) adequate intake (AI), which is the intake that guarantees nutritional adequacy; c) the estimated average requirement (EAR) which is equivalent to the average daily level of consumption estimated to meet the requirements of 50% of healthy individuals; and finally d) the tolerable upper intake level (UL), which refers to supplemented Mg2+, that is, that which is not consumed in food because it is more for pharmacological use [49, 50]. Table 1 lists the different reference values for Mg2+ .
Table. 1: Dietary Reference Intakes (DRI) for Magnesium Intake (Mg2+). RDA: recommended dietary intake, EAR: estimated average requirement, UL: tolerable upper intake level, NE: not established. * Adequate Intake (AI)
Whole grains are considered the best dietary source of Mg2+. In fact, Mg2+ has been linked to most of the benefits of whole grain intake, including reduced risk of diabetes, coronary heart disease, stroke, and various types of cancer . Also, leafy-green foods (e.g., chard, spinach, purslane), nuts, peas, and green lentils are good sources of Mg2+. Other foods with high levels of Mg2+ are dark chocolate, black beans, avocados, and some other fruits, also seeds such as pumpkin and chia seeds [52–55].
Mineral water is another important source of Mg2+ in the diet [56, 57]. Due to the relatively frequent consumption of water for drinking and food preparation, mineral water as a source of Mg2+ may be an essential part of the daily Mg2+ intake. However, the quality of the water is essential since the available Mg2+ content depends on it. Using hard water (calcium and Mg2+ concentration of 100-200 mg/L) to boil food rich in Mg2+ may prevent its loss, while boiling this food in soft water (calcium and Mg2+ concentration less than 100 mg/L) may leach out it . In this respect, many studies have found a relationship between drinking water mineral content and CVD risk [59–68]. Catling et al.  conclude with an extensive review of epidemiological studies that there was significant evidence of an inverse association between Mg2+ content in drinking water and cardiovascular mortality. Sabatier et al.  showed in a study with ten healthy white women (aged 25-45) that Mg2+ from Mg2+ rich mineral water (110 mg/L) is highly bioavailable, with a ≈50% Mg2+ absorption from mineral water consumed, being even better when water was consumed with a light meal (may due the transit time of Mg2+ in the intestine). Thus, mineral Mg2+-rich water is a calorie-free good source of Mg2+. Mg2+ bioavailability is comparable for mineral waters with different mineralization levels or other food such as bread and dietary supplements .
However, most of the population does not consume these rich Mg2+ foods and water daily; therefore, it is insufficient to cover the dietary reference intake (DRI), leading to Mg2+ deficiency. Blache et al.  have shown in a preclinic study that a long-term moderate Mg2+ deficiency diet is closely related to increased mortality, blood pressure, inflammation, and lipid oxidation. Also, they demonstrated that these effects were mainly due to chronic impairment of redox status associated with inflammation, and these effects can be normalized or improved with Mg2+ supplementation. In addition, it has been seen that a high intake of processed foods provides low amounts of Mg2+. Food processing, which can range from cooking to refining, causes a substantial loss of Mg2+ [71, 72]. Since a large part of the population has opted for refined cereals consumption, the intake of trace elements such as Mg2+, which are found in the pericarp of cereal grains, has decreased notably . For this reason, subclinical Mg2+ deficiency has been observed more frequently, mainly in populations that consume processed foods, such as the U.S. and countries with a Western diet [6, 10–15, 73, 74].
Mg2+ deficiency means body deficiency, including hypomagnesemia (specifically serum deficiency). Low levels of Mg2+ characterize Mg2+ deficiency and depends on its chronicity and status. For instance, Nielsen et al.  demonstrated a significant deprivation of red blood cell membrane Mg2+ in healthy postmenopausal women. They were on a restrictive diet of approximately 33% of the DRI of Mg2+ for 78 days. Thus, these authors concluded that Mg2+ deficiency is mainly associated with chronic inadequate Mg2+ intake .
Due to its facility and cost, total serum Mg2+ is the most used measure to diagnose Mg2+ deficiency clinically. The normal serum Mg2+ concentration is between 0.850 and 0.955 mmol/L ; if the serum Mg2+ concentration is below 0.7 mM, it is hypomagnesemia. According to Liu and Dudley Jr ., mild to moderate hypomagnesemia is when serum Mg2+ is between 0.5–0.69 mM, and severe hypomagnesemia is when serum Mg2+ is lower than 0.5 mM. Hypermagnesemia is characterized by high levels than normal serum concentrations of Mg2+ .
Unfortunately, even with a total serum Mg2+ level in the acceptable range, there may exist deficiency since approximately 55% of serum Mg2+ is in its bioactive form. At the same time, the rest is bound to proteins such as albumin or an anionic complex [77, 78]. Although Mg2+ serum concentrations are the main form to describe abnormalities in the Mg2+ status, these are very unspecific, providing inaccurate body Mg2+ status data. For instance, body Mg2+ homeostasis in other tissues, including bone, the main reservoir, provides Mg2+ through bone resorption during Mg2+ deficiency or insufficient Mg2+ intake, but this is related to a lower bone mineral density [79–81]. Mg2+ deficiency has detrimental effects on skeletal health, contributing to osteoporosis . Thus, normal serum Mg2+ concentrations could mask Mg2+ deficiency in other tissues like bone.
Also, some conditions affect circulating Mg2+ concentrations; an example of this is an abnormal state in the acid-base balance in the blood as slight acidosis. Defects can cause acidosis in renal tubules that facilities the reabsorption of bicarbonate or secretion of protons , also during a failure of respiratory ventilation due to carbon dioxide accumulation . Acidosis generally occurs due to increased acid production, decreased acid excretion, acid ingestion, and bicarbonate losses . That serum acid increase can release Mg2+ from the bone surface, artificially increasing the Mg2+ detected in serum that can mask hypomagnesemia . In addition, the acidosis significantly increasing urine Mg2+ excretion [28, 85]. Thus, acidosis masks hypomagnesemia and induces Mg2+ excretion, harming Mg2+ homeostasis.
The positive correlation between hypomagnesemia, higher morbidity, and mortality in hospitalized patients in an intensive care unit (ICU) [86, 87] makes it fundamental to know the general Mg2+ status. Thus preventing increased risk parameters associated with mortality (i.e., high C-reactive protein (CRP) serum levels and electrolytic abnormalities) [86, 87]. Various methods of assessing Mg2+ status, from surveys to clinical concentration data, have been extensively reviewed [88–91]. Not all the methods are of clinical utility to diagnose hypomagnesemia, but these indicate clinical or subclinical Mg2+ deficiency. These are considered measures for the evaluation of the status of the nutrient [88, 91, 92]. To obtain a valid assessment of Mg2+ status, Costello and Nielsen  proposed the combined determination of the concentration of serum Mg2+, the 24-hour urine Mg2+ excretion, and the intake diet. Due to difficulties in hypomagnesemia detection, it has proposed a sensible measurement of the bioactive form concentrations of whole blood from acute oral Mg2+ intake compared to serum and urine total Mg2+ .
Mg2+ deficiency can represent a potential risk to health [1, 4,93, 94]. An association between Mg2+ deficiency and sudden death has even been suggested . In a preclinical study by Fiset et al. , rats assigned to an Mg2+-free diet with consequent hypomagnesemia commonly died from episodes of sudden death after inadvertent startles. Because seizures preceded sudden death, the authors concluded that sudden cardiac death was probably due to a neurological trigger's interaction and ventricular repolarization dispersion . Depending on the degree of Mg2+ deficiency and its chronicity, it can present from a mild clinical presentation, such as weakness or fatigue, and escalate to severe and life-threatening complications such as arrhythmias, heart failure, or electrolyte disorders (Table 2) [3, 9,17, 18, 21, 36, 40, 93, 94, 97].
Table. 2: Mg2+ deficiency clinical presentation
Mg2+ deficiency can decrease the synthesis of proteins, carbohydrates, lipids, and genetic material . It could also affect the functioning of the other micronutrients, such as reducing the number of VDRs available in vitamin D target cells [98, 99]. When Mg2+ deficiency is acute, muscle cramps help to its diagnosis . However, in a chronic clinical deficiency, the symptoms are less severe, infrequent, and nonspecific, making its diagnosis difficult .
The causes of Mg2+ deficiency are many and very frequent
Abnormal Mg2+ levels during Mg2+ deficiency can be attributed to various factors. Intrinsic factors are insufficient intake or gastrointestinal insufficiency, decreased absorption due to injury to the intestinal epithelium (e.g., damage from alcoholism), kidney damage, and replacement therapies [17, 20, 100, 101]. At the same time, extrinsic factors may be diuretics that alter the renal tubule's reabsorption due to alterations in the electrochemical gradient. Loop diuretics decrease Mg2+ reabsorption, and thiazide diuretics reduce Mg2+ reabsorption and enhance its excretion [102, 103]. Also, some others are related to lower levels of Mg2+ in soil due to Mg2+ leaching, consequently affecting food levels . An example is the decreased mineral concentration reported in wheat for the past several decades [105–107]. Fan et al.  showed a significant decrease of 27% in the concentration of Mg2+ in wheat from 1968. The authors conclude that significant changes were made that year in cultivars due to the "Green Revolution," with higher grain yields but a dilution effect on mineral concentration.
As in wheat, other comparative studies of ancient and modern times observed a historical depletion in the concentration of minerals in food [108–110]. Unfortunately, this decrease in the concentration of Mg2+ is observed in fruits, vegetables, and cereals, affecting other food groups such as their derivatives and animal origin . The latter means that people need to eat more servings of food to obtain the same Mg2+ content as in the past, which is especially problematic due to metabolic syndrome problems in the current population .
In industrialized countries, clinical and subclinical Mg2+ deficiency is increasing, which can be associated with pathological states [1, 4,73, 74, 76, 93]. Multiple factors contribute to Mg2+ deficiency. For example, in people with diets high in phosphate (PO43-), Mg2+ absorption may be decreased due to the ability of PO43- to bind to Mg2+, reducing its availability [9, 28, 93, 111]. In general, the main source of phosphorus comes from soda (phosphoric acid) and inorganic PO43- contained in many ingredients used in processed foods (i.e., meat products). Dairy (especially cheese) also contributes to increasing Mg2+ requirements due to their phosphorus-magnesium-calcium ratio [93, 111]. Diets high in dietary fiber decrease the absorbed fraction of Mg2+. Fiber phytate decreases Mg2+ absorption because Mg2+ binds to the PO43- groups of phytic acid [28, 112]. In addition to the abovementioned cases, other factors contribute to Mg2+ deficiency, such as chronic diseases, gastrointestinal disorders, elderly age, and emotional stress (Table 3) [6, 9,17, 20, 93, 97, 100, 111]. The following list shows factors that contribute to Mg2+ deficiency:
Subclinical Mg2+ deficiency is the most common in the population, especially in countries that consume refined or ultra-processed products [9, 73, 74, 93]. The 2013-2016 National Health and Nutrition Examination Survey (NHANES) conducted on the US population showed that approximately 48% of the general population over one year does not reach the adequate intake of Mg2+. Moreover, in people older than 19 years (adult population), just over 50% of the population does not have consumption habits that cover the DRI .
According to an analysis of the 2006 national health and nutrition survey conducted on the Mexican population, 35% of adult men and women older than 20 have low serum concentrations of Mg2+ . In addition, 64.2% of women and 25.2% of men presented a low ingestion of Mg2+ compared with the DRI . Based on the same survey, Cruz-Góngora et al.  reported that in the 12 to 19-year-old population, the overall prevalence of low serum Mg2+ was 37.68%, and at least 50% of the analyzed population did not comply with the DRI . In the case of the child population, Morales-Ruán et al.  reported that the nutritional status of Mg2+ in Mexican children from 1 to 11 years old is deficient, and the prevalence of low serum Mg2+ concentrations is 22.6% for this population. The lowest prevalence (9.1%) of low serum Mg2+ concentrations is in the population 1 to 2 years old . The latter evidence shows the trend toward increasing Mg2+ deficiency prevalence with age.
At a global level, the consumption of Mg2+ in the diet is deficient and generalized in the populations (Table 4) [6, 9–16, 115]. Subclinical Mg2+ deficiency has been observed more frequently, mainly in populations consuming processed food, such as the US and countries with a Western diet [1, 4,9, 73, 74, 76, 93].
Table. 3: Mg2+ deficiency is global and general. Mg2+: magnesium; mg/d: milligrams per day; mmol/d: millimole per day; DRI: Dietary Reference Intakes; RDA: Recommended Dietary Allowances; EAR: Estimated Average Requirement
In addition to the countries mentioned above, DiNicolantonio et al.  included Japan and Ukraine as countries consuming insufficient amounts of Mg2+. The latter derives from the results obtained in the National Nutrition Survey in Japan in 2002, where it was found that for people aged 15 to 49 years, the intake of Mg2+ was below the Japanese recommended daily dose. Moreover, in Kiev (Ukraine), men between the ages of 20 and 59 years (n= 780) consumed 10% less than the recommended Mg2+ intake.
Mg2+ deficiency is difficult to detect at an early stage since bone compensation of Mg2+ maintains normal serum Mg2+ levels; and the absence of signs or symptoms [45, 116]. Knowing the general body Mg2+ status is essential to avoid other related Mg2+ deficiency complications, such as chronic inflammation and excessive production of ROS. To properly diagnose and treat Mg2+ deficiency, it is necessary to carry out more than one measurement of the Mg2+ levels method. It is suggested that due to the compensation of the homeostasis of Mg2+, the detection of low levels of Mg2+with a single method cannot be a good indicator of deficiency
In summary, many factors could contribute to developing a chronic deficiency. It is clear that Mg2+ intake is inadequate worldwide, and Mg2+ deficiency is a potential public health problem; nevertheless, the consequences of this deficiency are more frequently reflected in older adults.
Mg2+ deficiency has been widely correlated to the development of OS [3, 117]. OS is defined as “an imbalance between the generation of oxidants (ROS and reactive nitrogen species) and their removal systems (antioxidants) in favor of oxidants, leading to disruption of redox signaling and control and/or molecular damage” . Mitochondria are the primary source of ROS production, and mainly, when mitochondria suffer structural or functional damage, excessive ROS production is generated . Studies have shown that Mg2+ deficiency causes mitochondrial dysfunction [43, 120]. Mitochondria are the main reservoirs of Mg2+ in most cells (with mitochondrial Mg2+ concentrations between 0.2 and 1.5 mM) . However, intracellular Mg2+ deficiency inhibits Mg2+ transport to the mitochondria through mitochondrial RNA splicing protein 2 (MRS2) and promotes mitochondrial Mg2+ efflux via solute carrier family 41, member 3 (SLC41A3), leading to decreased mitochondrial Mg2+ . Mitochondrial Mg2+ deficiency decreases the activity of the electron transport chain, which alters coupled respiration [122–124] and increases the production of mitochondrial ROS [125, 126]. In addition, the antioxidant defense system (such as superoxide dismutase (SOD), catalase, and glutathione) is suppressed, and ATP synthase (F0F1) is downregulated, causing a decrease in ATP concentration [127–129]. In turn, the decrease in ATP causes an increase in the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) .
Mg2+ deficiency also causes depolarization of the mitochondrial membrane potential (ΔΨm)  by promoting the opening of the mitochondrial ATP-sensitive potassium (K) channel , the anion channel of the inner membrane (IMAC)  and the mitochondrial permeability transition pore (PTP) . These effects exacerbate ROS production and lead to apoptosis, where Bcl-2-associated X (Bax) and the voltage-gated anion channel (VDAC) increase cytochrome C release, leading to apoptosome formation . In addition, antiapoptotic proteins such as the Bcl-2 family are decreased, and proapoptotic proteins such as HIF-1α and p38/JNK are increased .
On the other hand, Mg2+ deficiency also increases the concentration of calcium (Ca) in the mitochondria through the mitochondrial Ca uniporter (MCU) [131, 137], which could alter ΔΨm. In contrast, Ca leakage from mitochondria via VDAC increases with apoptosis induced by Mg2+ deficiency. Other mechanisms that explain the increase in intracellular calcium in situations of Mg2+ deficiency include the activation of N-methyl-D-aspartate (NMDA) receptors in neural cells and L-type calcium channels in adipose tissue [2, 138].
The excess of intracellular Ca results in the activation of Ca-dependent processes, such as the release of inflammatory cytokines and the activation of NOX by phosphorylation of protein kinase C (PKC), the activation of nitric oxide synthase (NOS) and the calcium-dependent calmodulin complex, which exacerbates ROS production . Likewise, the increase in Ca stimulates the release of catecholamines, and it has been proven that catecholamines increase the production of ROS . Furthermore, elevated levels of catecholamines, such as epinephrine, cause Mg2+ deficiency to intensify, creating a vicious circle .
Likewise, Zheltova et al.  suggest that Mg2+ deficiency and Ca increase cause an increase in the number of available substrates for radical oxidation. A greater amount of Ca stimulates the activity of phospholipase A2 , an enzyme responsible for mobilizing unsaturated fatty acids (UFA) from phospholipids. UFAs, either free or bound to triglycerides and phospholipids, can be readily oxidized by ROS to form lipid hydroperoxides. In turn, hydroperoxides can decompose to form new radicals, thus initiating branching chain reactions that lead to self-sustaining peroxidation [142, 143].
OS can also be generated because the renin-angiotensin-aldosterone system (RAAS) is activated by Mg2+ deficiency [138, 144]. It is well established that angiotensin II activates NOX, monocytes, macrophages, and endothelial cells to produce ROS [145, 146]. In addition, RAAS has been shown to decrease the expression of TRPM6 and TRPM7, Mg2+ transporters, which further increases intracellular Mg2+ deficiency . Fig. 2 shows the possible mechanisms by which Mg2+ deficiency increases ROS production.
Fig. 2: Magnesium deficiency (Mg2+) and oxidative stress (OS). Mg2+ deficiency in mitochondria leads to the inhibition of the electron transport chain (ETC) and the opening of different channels, decreasing the mitochondrial membrane potential (ΔψM), Bax recruitment and calcium efflux (Ca2+). These factors increase the production of reactive oxygen species (ROS) in mitochondria and induce apoptosis. Intracellular Mg2+ deficiency activates N-methyl-D-aspartate (NMDA) receptors, contributing to the increase in Ca2+. High concentrations of Ca2+ they increase ROS through calmodulins, catecholamines, nitric oxide synthase (NOS), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). NOX is also activated by decreased production of adenosine triphosphate (ATP) and the renin-angiotensin-aldosterone system (RAAS). NMDA also activates phospholipase A, increasing the concentration of free fatty acids (FFA) and ROS. Low concentrations of Mg2+ are enhanced by inhibition of mitochondrial RNA splicing protein 2 (MRS2), activation of solute transporter family 41 member 3 (SLC41A3), RAAS, and catecholamines. Bax: Bcl-2 associated X, CAT: catalase, Cyc c: cytochrome c, IMAC: inner membrane anion channel, K: potassium, MCU: mitochondrial Ca2+ uniporter, PKC: protein kinase C phosphorylation, PTP: pore permeability transition, SOD: superoxide dismutase, TRPM9: melastatin transient receptor potential, VDAC: voltage-gated anion channel. Created with biorender.com (published with permission from biorender.com).
On the other hand, inflammation is also a highly reported consequence in situations where the concentration of Mg2+ is insufficient [7, 148]. In addition, the OS generated by low concentrations of Mg2+ could have a strong relationship with inflammation [3, 149]. As mentioned above, Mg2+ deficiency causes excessive ROS production mainly due to mitochondrial dysfunction, abnormal calcium homeostasis, and RAAS activation. The increase in ROS activates transcription factors such as NF-κB . For example, Mg2+ deficiency has been shown to induce lipid peroxidation and NF-κB activation in cultured canine cerebral vascular tissue . NF-κB is inactive in the cytoplasm, and its activation generates the transcription of proinflammatory cytokines such as TNF-α and interleukins (IL-1 and 6) [150, 152]. Bussière et al.  showed that an early consequence of Mg2+ deficiency is the activation of polymorphonuclear leukocyte activity and elevated circulating levels of IL-6. Likewise, Malpuech-Brugère et al.  observed macrophage activation and an elevation of IL-6 in rats after a few days of Mg2+ deficiency. Therefore, Mg2+ deficiency induces an acute phase inflammatory response that turns into chronic inflammation [7, 153].
In the brain, NF-κB can also be activated by substance P (SP), vascular cell adhesion molecule-1, and inhibitor of plasminogen activator-1, which is induced by NMDA activation and the increased intracellular calcium by decreasing the concentration of Mg2+ . Indeed, in a mouse model of Mg2+ deficiency, immunochemistry revealed that substance P is increased by 230 and 200% in megakaryocytes and lymphocytes, respectively, after 1 day of Mg2+ depletion . Furthermore, SP has a direct role in promoting the activation of neutrophils and endothelium and inducing nitric oxide (NO) production; these processes could participate in the OS that contributes to the depletion of blood glutathione .
Mg2+ deficiency also increases endothelin levels, an endothelial cell-derived cytokine . Likewise, it has been reported that animals with Mg2+ deficiency present greater recruitment and activity of phagocytic cells [1, 158]. The origin of this phenomenon is not well understood, but it is probably also related to OS . Finally, inflammation related to Mg2+ deficiency is also generated by reducing anti-inflammatory mediators such as NO, lipoxins, resolvins, and protectins [159, 160].
In summary, Mg2+ deficiency is strongly related to OS due to impaired calcium homeostasis, mitochondrial dysfunction, and RAAS activation. OS can cause inflammation, and inflammation, in turn, improves OS (Fig. 3). However, some aspects of this relationship are not yet fully elucidated. Therefore, more preclinical and clinical studies are needed to clarify the mechanisms involved in the relationship between Mg2+ deficiency with OS and inflammation.
Fig. 3: Relationship between magnesium (Mg2+) deficiency with oxidative stress (OS) and inflammation. Mg2+ deficiency causes an increase in reactive oxygen species (ROS) due to mitochondrial damage, an increase in N-methyl-D-aspartate (NMDA), and the activation of the renin-angiotensin-aldosterone system (RAAS). The latter also increases the recruitment of phagocytic cells, which exacerbates ROS. ROS activates the transcription factor nuclear transcription factor kappa B (NF-κB), which increases the transcription of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (1 and 6). This leads to inflammation. NF-κB is also activated by substance P (SP). Finally, Mg2+ deficiency causes a decrease in anti-inflammatory factors, exacerbating inflammation. Ca: calcium, mt: mitochondria, NOX: adenine dinucleotide phosphate (NADPH) oxidase. Created with biorender.com (published with permission from biorender.com).
Mg2+ deficient diets lead to low Mg2+ body concentrations, decreased antioxidants, and OS that progresses to oxidative damage, such as lipid peroxidation [2, 4,75, 161–163]. Also, there is evidence that low Mg2+ body concentrations are associated with increased OS and cytokine storm due to the alteration of antioxidant and immune defenses [111, 162, 164, 165]. Thus, Mg2+ deficiency is strongly associated with increased OS and metabolic syndrome mainly associated with low-grade systemic inflammation, such as obesity, diabetes, and CVD [2–4, 166]. These CVD includes heart failure, arrhythmias, atrial fibrillation, atherosclerosis, hypertension, and preeclampsia [3–5].
Mg2+ deficiency and cardiovascular diseases
Low serum Mg2+ levels have been associated with increased cardiovascular mortality by causing cardiovascular problems and exacerbating pre-existing ones [3, 5,8, 43, 75, 93, 120, 167–169]. In contrast, restoration of adequate Mg2+ levels or supplementation has been associated with improvements in CVD [3, 5,43, 75, 120, 169–171]. In a preclinical study with mice, Liu et al.  observed that a low Mg2+ diet for six weeks significantly decreased serum Mg2+ concentration. In addition, as a consequence, cardiac functions were affected with prolonged QTc intervals; mitochondrial dysfunction was observed in mouse cardiomyocytes with low cellular ATP production, overproduction of mitochondrial ROS, and mitochondrial membrane depolarization. Finally, normalizing these affectations with the replacement of Mg2+ . In another study by Watanabe et al. , similar results were observed since an Mg2+ deficient diet for eight weeks significantly decreased plasma Mg2+ levels. In addition to increased systolic and diastolic blood pressure, left ventricular hypertrophy, macrocytic anemia, and impaired basal cardiac contractile activities. Similarly, observing that with the replacement of Mg2+, the conditions described above were normalized .
One of the causes of these CVDs is that intracellular Mg2+ deficiency leads to inflammation and cardiovascular fibrosis. The latter was identified thanks to the anti-inflammatory and anti-fibrotic role of coenzyme TRPM7 mediated partly through Mg2+ dependent mechanisms since mice deficient in TRPM7 presented significant cardiac hypertrophy, fibrosis, and inflammation; Mg2+ treatment at a cellular level ameliorated effects . Also, the electrophysiologic changes resulting from Mg2+ deficiency can increase the risk of malignant ventricular arrhythmias and sudden cardiac death [173, 174].
A higher incidence of sudden death in some geographic regions attracts attention, and researchers begin to relate them to geological environments such as drinking water due to their mineral content . Residents in soft water areas presented higher sudden death rates due to an increased susceptibility to lethal arrhythmias [62, 63, 95]. Electrolyte disturbances are a frequent complication of chronic heart failure . Patients with isolated hypomagnesemia (without other electrolyte disturbance) frequently present electrocardiogram disturbances with a P wave, corrected QT, and corrected T peak-to-end-interval duration prolonged, suggesting atrial depolarization and ventricular repolarization dispersion increased . Even though the electrophysiologic action on cellular function is unclear, it suggests that these disturbances may have importance in the relationship between hypomagnesemia and sudden death . Mg2+ deficiency has been implicated in sudden death, and it is suspected that the electrophysiological changes induced by calcium are involved [177, 178].
Mg2+ deficiency and diabetes
Mg2+ deficiency is widely associated with diabetes, mainly in type 2 diabetes [179–186]. Hypomagnesemia is frequently identified in diabetic patients and contributes to the progression of diabetes complications [187, 188]. Also, numerous studies have described a high prevalence of Mg2+ deficiency in diabetic patients [6, 180, 185, 189–192]. There has been evidence that Mg2+ deficiency alters calcium homeostasis by competitively inhibiting the voltage-dependent calcium channel, leading to lower insulin secretion [42, 193]. Mg2+ deficiency also may influence the insulin signaling pathway, modifying sensitivity to insulin, such as increasing the association between insulin receptor substrate-1 and p58 subunit of phosphatidyl-inositol 3 kinase or reducing the phosphorylation of protein kinase B (Akt), leading to a diminished response to insulin [194, 195]. As if that were not enough, it has been observed that Mg2+ excretion is more significant in diabetic patients than in healthy subjects due to type 2 diabetes frequently causing damage to the glomerular filtration barrier, altering Mg2+ reabsorption [196–198]. The latter indicates that Mg2+ deficiency is promoted by diabetes, and at the same time, Mg2+ lack exacerbates IR and impaired insulin secretion diabetes.
Also, as mentioned previously, inflammation and OS are related to the incidence of diabetes, a consequence of cellular signaling pathways interference [179, 199, 200]. The secretion of IL-1, IL-6, IL-8, IL-18, TNF-α, beta-adrenergic, and ROS in IR is enhanced in Mg2+ deficiency . King et al.  observed that diabetic patients with elevated glycated hemoglobin levels present elevated CRP concentrations, indicating systemic inflammation. Han et al.  even suggest that inflammation is essential in diabetic pathogenesis and a high CRP level increases the risk of developing diabetes. Although the linking mechanisms of inflammation and IR are unclear, inflammation plays an important role via cytokines and molecular pathways .
Fortunately, Mg2+ replenishment in inflammatory pathologies associated with Mg2+ deficiency through supplementation is favorable. Clinic and pre-clinic studies showed decreased inflammatory biomarkers and disease improvement (Table 5) [8, 170, 171, 204–211]. These optimistic and encouraging results suggest using Mg2+ as an immunomodulatory agent, a regulator of inflammation and associated conditions, thus preventing the development of severe or chronic inflammation [3, 163, 205]. Mg2+ therapy decreases nuclear transcription factor kappa B (NF-κB), IL-6, TNF-α, and CRP and enhances vitamin D functionality [36, 99, 111, 212].
Table. 4: Diseases associated with Mg2+ deficiency and the effect of supplementation. BDSW: Balanced Deep Water, hs-CRP: High Sensitivity Serum C-Reactive Protein, IL-1: Interleukin 1, Mg2+: Magnesium, OGTT: Oral Glucose Tolerance Test, PCO: Protein Carbonyl, TAC: plasma total antioxidant capacity, TNF-α: tumor necrosis factor-alpha, ICU: intensive care unit
Also, Mg2+ supplementation has been observed to be effective as a treatment in diabetic rats due to increased insulin receptors and glucose transporter-4 improving glucose tolerance and lowering blood glucose levels almost to the normal range . Even it has observed reduced oxidative damage and increased glutathione concentrations . Liu et al.  also observed that Mg2+ supplementation positively affects insulin sensitivity by increasing insulin receptor expression. Additionally, Kamran et al.  observed that Mg2+ supplementation improved blood glucose levels and intraperitoneal glucose tolerance test of diabetic rats and improved Akt-2 and insulin receptor substrate-1 gene and protein expression, increasing glucose transportation in skeletal muscle. In summary, Mg2+ supplementation promotes the correct insulin signaling pathway increasing the expression of proteins involved in enhancing its activity.
Although it is still uncertain whether Mg2+ deficiency is the origin or consequence of diseases associated with OS and inflammation, there is clear evidence that it represents a greater risk for their development, in addition to the high prevalence of Mg2+ deficiency in these patients and that this leads to exacerbating clinical symptoms. So, maintaining optimal Mg2+ body concentration may be favorable in preventing of OS, inflammation, and, thus, chronic comorbidities. Furthermore, Mg2+ deficiency is directly associated with physiological mechanisms such as electrophysiology, insulin excretion, and sensitivity. Therefore, it is associated with an increased risk of developing or exacerbating diabetes and CVD. Although favorable results have been observed with Mg2+ supplementation in inflammatory markers, more specific studies are required to evaluate and understand the Mg2+ supplementation effect as a joint therapy in comorbidities and to prevent disease development. Also, assessing the impact of Mg2+ supplementation in healthy subjects as a preventive treatment is necessary.
This research was funded by Consejo Nacional de Ciencia y Tecnología (CONACYT) México, Grants Numbers A1-S-7495, by Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT), Grant Numbers IN202219 and IN200922 of the Universidad Nacional Autónoma de México (UNAM), and by Programa de Apoyo a la Investigación y el Posgrado (PAIP), Grant Number 5000-9105. Estefani Yaquelin Hernández-Cruz is a doctoral student from Programa de Doctorado en Ciencias Biológicas from the National Autonomous University of Mexico (UNAM), and she received a fellowship from CONACYT (779741).
The authors declare no conflicts of interest.
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