Role for calcium signaling in manganese neurotoxicity

Ijomone, Omamuyovwi M.; Aluko, Oritoke Modupe; Okoh, Comfort O A; Martins, Airton C.; Aschner, Michael

doi:10.1016/j.jtemb.2019.08.006

Cited by 36 publications

(27 citation statements)

References 169 publications

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“…In view of the significant neurological effects of Mn exposure, the mechanisms of Mn-induced neurotoxicity have been extensively studied. Key mechanisms include neuroinflammation, impaired calcium homeostasis [ 24 ], dysregulation of mitochondrial function and redox homeostasis [ 25 ], altered proteostasis [ 26 ], impaired microRNAs (miRNA) function [ 27 ], and altered neurotransmitter metabolism [ 28 ], to name a few. Additionally, reports suggest that Mn homeostasis is affected by low dose cadmium feeding [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

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Section: Introductionmentioning

confidence: 99%

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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“…An important exception is the brain where a transient and limited Mn 2+ uptake may become a safe tool in functional MRI while a persistent Mn elevation in basal ganglia may induce oxidative injuries. Also Parkinson-like symptoms are feared outcomes from long term exposure to Mn metal whether being environmental, following total parenteral nutrition, or being caused by liver failure [ 33 , 44 , 45 ]. Importantly, with MnDPDP, single doses up to 25 μ mol/kg were applied in phase II trials without reported signs of Parkinsonism [ 6 ], and based on the success with MEMRI for study of brain physiology in animals [ 14 , 15 ] Reich and Koretsky are exploring the possibility of using MnDPDP to image neuronal activity and neural tracts in patients with multiple sclerosis [ 46 ].…”

Section: Basic Propertiesmentioning

confidence: 99%

“…After 8 months, the patient developed a mild hand tremor as a potential early sign of Parkinsonism. Then, MRI of the brain ( Figure 13 ) showed widely distributed Mn deposits [ 44 , 45 ] with maximal SI in basal ganglia including dentate nucleus and globus pallidum. As recently discussed by Blomlie et al [ 90 ] these basal ganglia sites are also noted for deposition of Gd 3+ [ 91 ] indicating a common, possibly Ca 2+ related, pathway for focal brain storage of these metals.…”

Section: Therapy In Humansmentioning

confidence: 99%

MnDPDP: Contrast Agent for Imaging and Protection of Viable Tissue

Jynge¹,

Skjold

Falkmer

et al. 2020

Contrast Media & Molecular Imaging

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The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T1 mapping and, to a lesser degree, T1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.

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“…Mn-induced oxidative stress in neurodegenerative diseases can also be secondary to a mitochondrial dysfunction, which plays a central role in PD and AD [47,48,49]. Mn 2+ interferes with Ca 2+ homeostasis within the mitochondria by occupying Ca 2+ binding sites [50,51], triggering an increase in mitochondrial Ca 2+ levels, which interfere with oxidative respiration and induce oxidative stress [52]. The ROS generated by excessive Mn levels promote the opening of the mitochondrial permeability transition pore, causing a loss of membrane potential and impairing ATP synthesis and mitochondrial swelling, thereby contributing to cellular apoptosis [53,54]).…”

Section: Oxidative Stress and Mitochondrial Dysfunctionmentioning

confidence: 99%

New Insights on the Role of Manganese in Alzheimer’s Disease and Parkinson’s Disease

Martins

Morcillo

Ijomone

et al. 2019

IJERPH

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Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.

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Role for calcium signaling in manganese neurotoxicity

Cited by 36 publications

References 169 publications

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

MnDPDP: Contrast Agent for Imaging and Protection of Viable Tissue

New Insights on the Role of Manganese in Alzheimer’s Disease and Parkinson’s Disease

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