Dataset Information

The degree and position of phosphorylation determine the impact of toxic and trace metals on phosphoinositide containing model membranes

ABSTRACT: Highlights • Metal induced changes of membrane fluidity in phosphoinositide dependent manner.• Metals induced phase separation and cluster formation in PI containing membranes.• Metal induced liposome aggregation in phosphoinositide dependent manner. This work assessed effects of metal binding on membrane fluidity, liposome size, and lateral organization in biomimetic membranes composed of 1 mol% of selected phosphorylated phosphoinositides in each system. Representative examples of phosphoinositide phosphate, bisphosphate and triphosphate were investigated. These include phosphatidylinositol-(4,5)-bisphosphate, an important signaling lipid constituting a minor component in plasma membranes whereas phosphatidylinositol-(4,5)-bisphosphate clusters support the propagation of secondary messengers in numerous signaling pathways. The high negative charge of phosphoinositides facilitates electrostatic interactions with metals. Lipids are increasingly identified as toxicological targets for divalent metals, which potentially alter lipid packing and domain formation. Exposure to heavy metals, such as lead and cadmium or elevated levels of essential metals, like cobalt, nickel, and manganese, implicated with various toxic effects were investigated. Phosphatidylinositol-(4)-phosphate and phosphatidylinositol-(3,4,5)-triphosphate containing membranes are rigidified by lead, cobalt, and manganese whilst cadmium and nickel enhanced fluidity of membranes containing phosphatidylinositol-(4,5)-bisphosphate. Only cobalt induced liposome aggregation. All metals enhanced lipid clustering in phosphatidylinositol-(3,4,5)-triphosphate systems, cobalt in phosphatidylinositol-(4,5)-bisphosphate systems, while all metals showed limited changes in lateral film organization in phosphatidylinositol-(4)-phosphate matrices. These observed changes are relevant from the biophysical perspective as interference with the spatiotemporal formation of intricate domains composed of important signaling lipids may contribute to metal toxicity. Graphical abstracts Image, graphical abstract

SUBMITTER:

PROVIDER: S-EPMC10074965 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The contamination of toxic trace metals in the food chain is one of the major threats to human health. Milk is part of a balanced diet, which is essential for proper growth, but the ingestion of contaminated milk may cause chronic health disorders. The present study is focused on the assessment of contamination of toxic trace metals in buffalo milk and the associated health risks to the consumers of Abbottabad, Pakistan. Standard analytical methods were employed to quantify the metal contents in the milk samples collected from various shops and homes in the months from June 2021 to October 2021. Health risk assessment was accomplished by computing estimated daily intake (EDI), health risk index (HRI), target hazard quotient (THQ), hazard index (HI), and target cancer risk (TCR). On a comparative basis, the mean concentration of Cr was found to be highest in both shop and home milk samples (101.3 ± 45.33 and 54.11 ± 24.20 mg/L, respectively), followed by Pb, Zn, Ni, and Cd levels. In buffalo milk collected from homes, the highest concentration of the metals was found in October, followed by July, September, June, and August. In shop milk, the increasing trend of metal contents was July > October > September > June > August. Significantly strong positive relationships were noted between the metal concentrations in the milk samples. Multivariate cluster analysis and principal component analysis exhibited significant anthropogenic contributions of the metals in buffalo milk. Mostly, the EDI and HRI values were exceeding the recommended limits; however, THQ, HI, and TCR showed that the intake of these metals through milk consumption was within the safe limit and thus revealed no significant carcinogenic or non-carcinogenic risks to the consumers. It is high time to ensure the continuous monitoring of organic/inorganic toxins in the milk and concerned authorities should take strict measures to control the contamination of milk and other food products.

Project description:OBJECTIVE:Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the characteristic widespread multifocal pathology in these disorders could be due to damage to different subsets of locus ceruleus neurons. Previous studies have shown that only certain locus ceruleus neurons accumulate the neurotoxic metal mercury. To find out if concentrations of other toxic metals or of essential trace elements also vary between individual locus ceruleus neurons, we used synchrotron X-ray fluorescence microscopy on frozen sections of locus ceruleus neurons taken from people with multiple sclerosis, in whom the locus ceruleus is structurally intact. MATERIALS AND METHODS:Paraffin embedded sections containing the locus ceruleus from seven people with multiple sclerosis were stained with autometallography that demonstrates accumulations of mercury, silver and bismuth. These were compared to maps of multiple elements obtained from frozen sections of locus ceruleus neurons from the same people using X-ray fluorescence microscopy. Neurons in the anterior pons from three of these donors were used as internal controls. RESULTS:Autometallography staining was observed in scattered locus ceruleus neurons from three of the seven donors. X-ray fluorescence microscopy showed variations among individual locus ceruleus neurons in levels of mercury, selenium, iron, copper, lead, bromine, and rubidium. Variations between donors of locus ceruleus neuronal average levels of mercury, iron, copper, and bromine were also detected. Anterior pons neurons contained no mercury, had varied levels of iron, and had lower copper levels than locus ceruleus neurons. CONCLUSIONS:Individual human locus ceruleus neurons contain varying levels of toxic metals and essential trace elements. In contrast, most toxic metals are absent or at low levels in nearby anterior pons neurons. The locus ceruleus plays a role in numerous central nervous system functions, including maintaining the blood-brain-barrier and limiting neuroinflammation. Toxic metals, or alterations in essential trace metals within individual locus ceruleus neurons, could be one factor determining the non-random destruction of locus ceruleus neurons in normal aging and neurodegenerative diseases, and subsequently the sites of the widespread multifocal central nervous system pathology in these disorders.

Project description:Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) is a plasma-membrane (PM)-specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly "inactivated" at the PM, we studied PIP(2) modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PM-localized, TRPML1 is active with PI(3,5)P(2), a lysosome-specific PIP(2), as the underlying positive cofactor. Here we found that "silent" PM-localized TRPML1 could be activated by depleting PI(4,5)P(2) levels and/or by adding PI(3,5)P(2) to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P(2). Conversely, depletion of PI(4,5)P(2) by either depolarization-induced activation or chemically induced translocation of 5'-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P(2) activation and PI(4,5)P(2) inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP(2)-interacting domain. Thus, PI(4,5)P(2) may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters.

Dataset Information

The degree and position of phosphorylation determine the impact of toxic and trace metals on phosphoinositide containing model membranes

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets