Vph1 is associated with the copper homeostasis of Cryptococcus neoformans serotype D.

We clarified the roles of VPH1 in Cryptococcus neoformans serotype D by examining the detailed phenotypes of VPH1-deficient cells (Δvph1) in terms of their capability to grow in acidic and alkaline pH, at a high temperature, and under high osmotic conditions, in addition to the involvement of VPH1 in copper (Cu) homeostasis and the expression of some C. neoformans virulence factors. Δvph1 could grow well on minimal medium (YNB) but exhibited hypersensitivity to 20 µM Cu due to the failure to induce Cu-detoxifying metallothionein genes (CMT1 and CMT2). In contrast, Δvph1 exhibited defective growth on rich medium (YPD), and the induction of Cu transporter genes (CTR1 and CTR4) did not occur in this medium, implying that this strain was incapable of the uptake of Cu ions for growth. However, the addition of excess Cu promoted CTR gene expression and supported Δvph1 growth. These results suggested that the lack of the VPH1 gene disturbed Cu homeostasis in C. neoformans. Moreover, the loss of Vph1 function influenced the urease activity of C. neoformans.

Copper biology.

Metals are vital for life as they are necessary for essential biological processes. Traditionally, metals are categorized as either dynamic signals or static cofactors. Redox-inactive metals such as calcium (Ca), potassium (K), sodium (Na), and zinc (Zn) signal through large fluctuations in their metal-ion pools. In contrast, redox-active transition metals such as copper (Cu) and iron (Fe) drive catalysis and are largely characterized as static cofactors that must be buried and protected within the active sites of proteins, due to their ability to generate damaging reactive-oxygen species through Fenton chemistry. Cu has largely been studied as a static cofactor in fundamental processes from cellular respiration to pigmentation, working through cytochrome c oxidase and tyrosinase, respectively. However, within the last decade, a new paradigm in nutrient sensing and protein regulation - termed 'metalloallostery' - has emerged, expanding the repertoire of Cu beyond the catalytic proteins to dynamic signaling molecules essential for cellular processes that impact normal physiology and disease states. In this Primer we introduce both the 'traditional' and emerging roles for Cu in biology and the many ways in which Cu intersects with human health.

Biogenic copper nanoparticles produced by using the Klebsiella pneumoniae strain NST2 curtailed salt stress effects in maize by modulating the cellular oxidative repair mechanisms.

The negative effects of salinity on plant growth and physiology are well-established, which is one of the major threats to food security in semi-arid and arid regions of the world. The current research focuses on biosynthesis of copper nanoparticles (CuNPs) from a bacterial strain NST2, which was genetically identified as Klebsiella pneumoniae based on taxonomic identity of 16S rRNA gene. The strain was selected for bioprospecting of CuNPs owing to its Cu tolerance potential. The biologically-synthesized CuNPs were confirmed in culture by using ultraviolet visible spectroscopy. The material characteristics of green CuNPs were further investigated by using Fourier transform infrared spectroscopy, X-ray diffractometer, scanning electron microscopy and transmission electron microscopy, where crystallite size was ranged from 22.44 nm to 44.26 nm and particles were stabilized by various functional groups, such as carbonyl and amine groups. When 100 mg kg-1 of green CuNPs were mixed in saline soil in a pot experiment, the maize plants showed increased root and shoot length (43.52% and 44.06%, respectively), fresh weight (46.05% and 51.82%, respectively) and dry weight (47.69% and 30.63%, respectively) in comparison to control maize plants without CuNPs application. Moreover, green CuNPs at their highest treatment level (100 mg kg-1 of soil) counteracted the lipid peroxidation and oxidative damage in maize plants by promoting the activities of antioxidants and demoting the cellular levels of reactive oxygen species and ionic contents of Na+ and Cl-. Conclusively, biogenic CuNPs is an emerging and promising technique, which could replace traditional methods of salinity management in agricultural soils.

The copper economy response is partially conserved in rice (Oryza sativa L.).

Copper (Cu) is an essential element for plants, especially in photosynthesis, as it is required for plastocyanin function in electron transfer reactions at thylakoid membranes. In Arabidopsis thaliana, Cu deficiency leads to the Cu economy response, in which plants prioritize Cu usage by plastocyanin in detriment of non-essential cupric proteins. In rice (Oryza sativa), however, this response has not been characterized. Rice OsHMA5 is a Cu xylem-loading transporter involved in Cu translocation from roots to shoots, as suggested by the analysis of oshma5 mutant plants. Aiming to understand how rice plants respond to Cu deficiency and how decreased Cu translocation to shoots can affect this response, we characterized the physiological and molecular responses of WT and oshma5 plants under control and Cu deficiency treatments. We found evidence that shoots of oshma5 plants are more prone to Cu deficiency compared to shoots of WT plants, as demonstrated by decreased chlorophyll and Cu concentrations, and electron transport rate. Gene expression analysis revealed that Cu high-affinity transporters OsCOPT1 and OsCOPT5, along with a set of miRNAs and three Cu/Zn superoxide dismutases are responsive to Cu deficiency in both WT and oshma5 plants, suggesting their involvement in the Cu economy response. However, Fe superoxide dismutase was not up-regulated in rice, indicating a difference compared to the A. thaliana Cu economy model. Therefore, we provide evidence for a partially conserved Cu economy response in rice, in comparison to A. thaliana.

Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content.

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.SIGNIFICANCE STATEMENT Menkes and Wilson disease affect copper homeostasis and characteristically afflict the nervous system. However, their molecular neuropathology mechanisms remain mostly unexplored. We demonstrate that copper homeostasis in neurons is maintained by two factors that localize to the Golgi apparatus, ATP7 and the conserved oligomeric Golgi (COG) complex. Disruption of these mechanisms affect mitochondrial function and localization to synapses as well as neurotransmission and synaptic plasticity. These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

Verification of Nuclear Magnetic Resonance Characterization of Traditional Homeopathically Manufactured Metal (Cuprum metallicum) and Plant (Gelsemium sempervirens) Medicines and Controls.

BACKGROUND: Nuclear magnetic resonance (NMR) proton relaxation is sensitive to the dynamics of the water molecule, H2O, through the interaction of the spin of the proton (1H) with external magnetic and electromagnetic fields. NMR relaxation times describe how quickly the spin of 1H, forced in a direction by an external electromagnetic field, returns to a normal resting position. As a result, such measurements allow us potentially to describe higher structuring of water in homeopathic medicines. OBJECTIVE: The purpose of the present study was to verify whether specific NMR relaxation times could be measured in full lines of cH dynamizations of a metal (copper) and of a plant substance (Gelsemium sempervirens), compared with a solvent control, a potentized lactose control and a control prepared by simple dilution, in three production lines. It is aimed at verification of a previous publication (2017) on two new manufacturing lines of the same starting material and controls. MATERIALS AND METHODS: To monitor dilution and potentization processes, measurements of 1H spin-lattice T1 and spin-spin T2 relaxation times were used. T1 and T2 relaxation times were measured at 25°C with a spin analyser working at a frequency of 20 MHz. To account for its possible role as a confounding factor, free oxygen was also measured in all samples, using a MicroOptode meter. RESULTS: When the values of the three production lines were pooled, a statistically significant discrimination of NMR relaxation times between the medicines and their controls was confirmed. We found for copper cH and Gelsemium sempervirens cH a highly significant influence of the starting material (p = 0.008), a highly significant influence of level of dilution (p < 0.001), and a significant influence of the O2 concentration (p = 0.04). CONCLUSIONS: We have evidence of an obvious retention of a specific magnetic resonance signal when a substance (lactose, copper, Gelsemium) is diluted/potentized in pure water. This means that homeopathic solutions cannot be considered to be pure water. O2 is a covariant and not an explanatory variable: this factor itself is too weak to explain the NMR signal specificities in potentized samples. Homeopathic dilutions may thus have a specific material configuration governed not only by the potentized substance but also by the chemical nature of the containers, the chemical nature of dissolved gases and even by the electromagnetic environment. This sensitivity of homeopathically prepared medicines to electromagnetic fields may be amplified by the processes routinely applied during their preparation; because it occurs only when a dynamization has been performed, we may call this phenomenon "dynamic pharmacy".

Alterations of hemogram, serum biochemistry, oxidative/nitrosative balance, and copper/zinc homeostasis in dromedary camels naturally infected with poxvirus.

Camel pox (CMLP), a contagious viral disease of camels, causes considerable economic loss in terms of milk, meat, wool, and leather production besides reduction of draught power. The effect of spontaneous CMLP infection on hemogram, oxidative/nitrosative imbalance, and trace mineral homeostasis has not been studied earlier in dromedary camels. In the current study, hemogram, serum biochemistry, oxidant/antioxidant imbalance, and zinc (Zn)-copper (Cu) homeostasis were evaluated in healthy and pox-infected camels. The CMLP was confirmed from pooled samples of vesicular fluid, oral mucosa, and skin samples by polymerase chain reaction (PCR) targeting the C18L gene of CMLP virus. Hemogram was performed manually in whole blood. The serum was analyzed for biochemistry. The oxidative/nitrosative imbalance was measured by determining the concentrations of malondialdehyde (MDA), nitrite and nitrate (NOx), and glutathione S-transferase (GST) activity in serum. Simultaneously, copper (Cu) and zinc (Zn) concentrations were measured in serum. A pronounced leucopenia (p = 0.019), lymphopenia (p = 0.005), and hypoproteinemia (p = 0.014) were noted in CMLP-infected camels compared to healthy animals. The significant elevation of the MDA (p = 0.005) and NOx (p = 0.044) concentrations in serum of CMLP-infected indicated marked oxidative stress during the disease. The zinc concentration (p = 0.014) in CMLP-infected camels was significantly lower than healthy camels. The study supports that oxidative/nitrosative imbalance and Cu-Zn homeostasis are compromised and related to the pathophysiology of CMLP infection. The finding will be helpful to veterinary clinicians to adopt effective therapeutic strategies using antioxidants and trace minerals during CMLP outbreak. The timely vaccination and bio-security will be the mainstay for prevention of the diseases.

Copper and the brain noradrenergic system.

Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency (Menkes disease) or excessive Cu accumulation (Wilson disease) in the brain tissue. In either case, the loss of Cu homeostasis results in catecholamine misbalance, abnormal myelination of neurons, loss of normal brain architecture, and a spectrum of neurologic and/or psychiatric manifestations. Several metabolic processes have been identified as particularly sensitive to Cu dis-homeostasis. This review focuses on the role of Cu in noradrenergic neurons and summarizes the current knowledge of mechanisms that maintain Cu homeostasis in these cells. The impact of Cu misbalance on catecholamine metabolism and functioning of noradrenergic system is discussed.

Is brain iron trafficking part of the physiology of the amyloid precursor protein?

The amyloid precursor protein is so named, because a proteolytic fragment of it was found associated with a neuropathic disorder now known as Alzheimer's disease. This fragment, Aß, along with tau makes up the plaques and tangles that are the hallmark of AD. Iron (and other first-row transition metals) is found associated with these proteinaceous deposits. Much research has focused on the relationship of the plaques and iron to the etiology of the disease. This commentary asks another question, one only more recently addressed namely, what is the physiologic function of the amyloid precursor protein (APP) and of its secretase-generated soluble species? Overall, the data make clear that APP and its products have neurotrophic functions and some data indicate one of these may be to modulate the trafficking of iron in the brain.

De novo origination of MIRNAs through generation of short inverted repeats in target genes.

MIRNA (MIR) gene origin and early evolutionary processes, such as hairpin precursor sequence origination, promoter activity acquirement and the sequence of these two processes, are fundamental and fascinating subjects. Three models, including inverted gene duplication, spontaneous evolution and transposon transposition, have been proposed for de novo origination of hairpin precursor sequence. However, these models still open to discussion. In addition, de novo origination of MIR gene promoters has not been well investigated. Here, I systematically investigated the origin of evolutionarily young polyphenol oxidase gene (PPO)-targeting MIRs, including MIR1444, MIR058 and MIR12112, and a genomic region termed AasPPO-as-hp, which contained a hairpin-forming sequence. I found that MIR058 precursors and the hairpin-forming sequence of AasPPO-as-hp originated in an ancient PPO gene through forming short inverted repeats. Palindromic-like sequences and imperfect inverted repeats in the ancient PPO gene contributed to initiate the generation of short inverted repeats probably by causing errors during DNA duplication. Analysis of MIR058 and AasPPO-as-hp promoters showed that they originated in the 3'-flanking region of the ancient PPO gene. Promoter activities were gained by insertion of a CAAT-box and multiple-copper-response element (CuRE)-containing miniature inverted-repeat transposable element (MITE) in the upstream of AT-rich TATA-box-like sequence. Gain of promoter activities occurred before hairpin-forming sequence origination. Sequence comparison of MIR1444, MIR058 and MIR12112 promoters showed frequent birth and death of CuREs, indicating copper could be vital for the origination and evolution of PPO-targeting MIRs. Based on the evidence obtained, a novel model for plant MIR origination and evolution is proposed.

Dietary copper restriction in Wilson's disease.

Dietary copper restriction has long been considered an important aspect of treatment for Wilson's disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver).

Biological role of copper as an essential trace element in the human organism.

This paper presents an overview of the physiological properties of copper (Cu), an essential trace element playing an important role in the human metabolism, primarily as a cofactor of many metalloenzymes. The maintenance of Cu homeostasis is required for proper functioning of the human body. However, when the disturbance of Cu homeostasis occurs, strong pathological manifestations may develop. Wilsons disease and idiopathic toxicosis are examples of severe chronic liver diseases that are the results of genetic predisposition to the hepatic accumulation of copper. Conversely, congenital Menkes disease is manifested as serious Cus nutritional deficiency. Although Cu is necessary for many life processes, it is also a powerful weapon used since the ancient times against many microorganisms. Finally, the theories of Cu antimicrobial and antiviral mechanisms of action are summarized, including contemporary and potential future utilizations in medical and non-medical fields of human life. Key words: copper metalloenzymes copper toxicity copper deficiency copper-related diseases copper applications.

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells.

Copper has previously been implicated in the regulation of immune responses, but the impact of this metal on mast cells is poorly understood. In this article, we address this issue and show that copper starvation of mast cells causes increased granule maturation, as indicated by higher proteoglycan content, stronger metachromatic staining, and altered ultrastructure in comparison with nontreated cells, whereas copper overload has the opposite effects. In contrast, copper status did not impact storage of histamine in mast cells, nor did alterations in copper levels affect the ability of mast cells to degranulate in response to IgER cross-linking. A striking finding was decreased tryptase content in mast cells with copper overload, whereas copper starvation increased tryptase content. These effects were associated with corresponding shifts in tryptase mRNA levels, suggesting that copper affects tryptase gene regulation. Mechanistically, we found that alterations in copper status affected the expression of microphthalmia-associated transcription factor, a transcription factor critical for driving tryptase expression. We also found evidence supporting the concept that the effects on microphthalmia-associated transcription factor are dependent on copper-mediated modulation of MAPK signaling. Finally, we show that, in MEDNIK syndrome, a condition associated with low copper levels and a hyperallergenic skin phenotype, including pruritis and dermatitis, the number of tryptase-positive mast cells is increased. Taken together, our findings reveal a hitherto unrecognized role for copper in the regulation of mast cell gene expression and maturation.

Cytochrome b561, copper, ß-cleaved amyloid precursor protein and niemann-pick C1 protein are involved in ascorbate-induced release and membrane penetration of heparan sulfate from endosomal S-nitrosylated glypican-1.

Ascorbate-induced release of heparan sulfate from S-nitrosylated heparan sulfate proteoglycan glypican-1 takes place in endosomes. Heparan sulfate penetrates the membrane and is transported to the nucleus. This process is dependent on copper and on expression and processing of the amyloid precursor protein. It remains unclear how exogenously supplied ascorbate can generate HS-anMan in endosomes and how passage through the membrane is facilitated. Here we have examined wild-type, Alzheimer Tg2576 and amyloid precursor protein (-/-) mouse fibroblasts and human fetal and Niemann-Pick C1 fibroblasts by using deconvolution immunofluorescence microscopy, siRNA technology and [S35]sulfate-labeling, vesicle isolation and gel chromatography. We found that ascorbate-induced release of heparan sulfate was dependent on expression of endosomal cytochrome b561. Formation and nuclear transport of heparan sulfate was suppressed by inhibition of ß-processing of the amyloid precursor protein and formation was restored by copper (I) ions. Membrane penetration was not dependent on amyloid beta channel formation. Inhibition of endosomal exit resulted in accumulation of heparan sulfate in vesicles that exposed the C-terminal of the amyloid precursor protein externally. Endosome-to-nucleus transport was also dependent on expression of the Niemann-Pick C1 protein. We propose that ascorbate is taken up from the medium and is oxidized by cytochrome b561 which, in turn, reduces copper (II) to copper (I) present in the N-terminal, ß-cleaved domain of the amyloid precursor protein. Re-oxidation of copper (I) is coupled to reductive, deaminative release of heparan sulfate from glypican-1. Passage through the membrane may be facilitated by the C-terminal, ß-cleaved fragment of the amyloid precursor protein and the Niemann-Pick C1 protein.

Role of copper in the process of spermatogenesis.

Copper (Cu) is an essential trace element required for the normal development of living organisms. Due to its redox potential, copper is a cofactor in many enzymes responsible for important processes in cells. Copper deficiency has a significant influence on the reduction or the total eradication of copper-dependent enzymes in the body, thereby inhibiting cell life processes. On the other hand, copper is a very reactive element and in its free state, it can trigger the production of large amounts of free radicals, which will consequently lead to the damage of proteins and DNA. Because of those reasons, living organisms have developed precise mechanisms regulating the concentration of copper in cells. Copper also plays a very important role in male fertility. It is an essential element for the production of male gametes. The significant role of copper is also described in the processes of cell division - mitotic and meiotic. Copper-dependent enzymes such as ceruloplasmin, superoxide dismutase SOD1 and SOD3, group of metallothionein and cytochrome c oxidase are present at all stages of gametogenesis as well as in the somatic cells of the testis and in the somatic cells of epididymis. Substantial amounts of copper can also be found in liquids associated with sperm in the epididymis and prostate. Copper also affects the integral androgen distribution in terms of fertility on the line hypothalamic-pituitary-testis. Both copper increase and deficiency leads to a significant reduction in male fertility, which spans the entire spectrum of abnormalities at the sperm level, male gonad, production of hormones and distribution of micronutrients such as zinc and iron. Nowadays, the effects of copper on gametes production have become more important and are connected with the increasing levels of pollution with heavy metals in environment.

Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases.

Copper is a trace element essential for almost all living organisms. But the level of intracellular copper needs to be tightly regulated. Dysregulation of cellular copper homeostasis leading to various diseases demonstrates the importance of this tight regulation. Copper homeostasis is regulated not only within the cell but also within individual intracellular compartments. Inactivation of export machinery results in excess copper being redistributed into various intracellular organelles. Recent evidence suggests the involvement of glutathione in playing an important role in regulating copper entry and intracellular copper homeostasis. Therefore interplay of both homeostases might play an important role within the cell. Similar to copper, glutathione balance is tightly regulated within individual cellular compartments. This review explores the existing literature on the role of glutathione in regulating cellular copper homeostasis. On the one hand, interplay of glutathione and copper homeostasis performs an important role in normal physiological processes, for example neuronal differentiation. On the other hand, perturbation of the interplay might play a key role in the pathogenesis of copper homeostasis disorders.

A pilot study into a possible relationship between diet and stuttering.

PURPOSE: There are theoretical and empirical reasons to consider a potential role for copper metabolism in the brain in how it could influence stuttering. However, a link between stuttering and dietary intake has never been researched in a systematic way. This pilot study therefore aimed to explore a possible association between ingested amounts of copper and thiamine (vitamin B1) with stuttering frequency using a double blind cross-over longitudinal paradigm. METHODS: 19 adults who stutter between 20 and 51 years old filled out an online survey for 9 consecutive weeks. The survey consisted of self-assessed fluency and mood state scales, as well as food journals. After 4 weeks, the participants consumed either copper or thiamine supplements for 2 weeks, followed by a 1-week washout period, and another period of two weeks taking the other supplement. Formal speech assessments were done pre/post baseline and at the end of each supplement intake. Participants were not informed about the nature of the supplements during the experiment and the investigators were blinded to the order of the supplements. RESULTS: The results demonstrated that copper and thiamine had no measurable effect on the amount of stuttering (self and formal assessments) but there was a moderate, significant correlation between mood state and fluency. CONCLUSION: The findings do not support notions of dietary influences of ingested copper or thiamine on stuttering but do provide modest support for a relationship between variations in stuttering and self-perceived anxiety.

Perspectives on the Role and Relevance of Copper in Cardiac Disease.

Cardiac hypertrophy as a result of dietary copper deficiency has been studied for 40 plus years and is the subject of this review. While connective tissue anomalies occur, a hallmark pathology is cardiac hypertrophy, increased mitochondrial biogenesis, with disruptive cristae, vacuolization of mitochondria, and deposition of lipid droplets. Electrocardiogram abnormalities have been demonstrated along with biochemical changes especially as it relates to the copper-containing enzyme cytochrome c oxidase. The master controller of mitochondrial biogenesis, PGC1-α expression and protein, along with other proteins and transcriptional factors that play a role are upregulated. Nitric oxide, vascular endothelial growth factor, and cytochrome c oxidase all may enhance the upregulation of mitochondrial biogenesis. Marginal copper intakes reveal similar pathologies in the absence of cardiac hypertrophy. Reversibility of the copper-deficient rat heart with a copper-replete diet has resulted in mixed results, depending on both the animal model used and temporal relationships. New information has revealed that copper supplementation may rescue cardiac hypertrophy induced by pressure overload.

Synergetic Effects of K, Ca, Cu and Zn in Human Semen in Relation to Parameters Indicative of Spontaneous Hyperactivation of Spermatozoa.

We have observed that sperm quality parameters indicative of spermatozoa hyperactivation such are lower "linearity" and "straightness", and as showed by this research "elongation", were more pronounced in patients with normal spermiogram compared to the group of men with reduced sperm motility who were undergoing routine in vitro fertilisation. The research encompassed 97 men diagnosed with normozoospermia (n = 20), asthenozoospermia (n = 54) and oligoasthenozoospermia (n = 23). The findings indicate that sperm quality of patients with normal spermiogram diagnosed according to WHO criteria, may be compromised by showing premature spontaneous hyperactivation which can decrease the chances of natural conception. We assessed synergistic effects of multiple chemical elements in ejaculated semen to find if premature spontaneous hyperactivation of spermatozoa can be a sign of imbalanced semen composition especially of elements K, Ca, Cu and Zn. Human semen samples showing low or high baseline status of chemical elements concentrations were found in samples from all three diagnostic groups. However, correlation of K/Ca and Cu/Zn ratios, taking into account samples from all three groups of men, were negative at statistical significance level p = 0.01. We tested if the negative correlation between K/Ca and Cu/Zn ratio works for greater number of semen samples. We found the negative correlation to be valid for 175 semen samples at statistical significance of p = 0.00002. The ratio of K/Ca and Cu/Zn, i.e. increased concentrations of K and Zn in comparison to concentrations of Ca and Cu, were associated with a decrease of "straightness" in the group of men with normal spermiogram and pronounced spontaneous hyperactivation of spermatozoa, implying that these elements act in synergy and that the balance of elements and not their absolute concentrations plays the major role in premature spermatozoa hyperactivation in ejaculated semen.