Cu loading alters expression of non-IRE regulated, but not IRE regulated, Fe dependent proteins in HepG2 cells

Fosset, Cédric; Danzeisen, Ruth; Gambling, Lorraine; McGaw, Brian A.; McArdle, Harry J

doi:10.1016/j.jinorgbio.2009.01.007

Cited by 10 publications

(6 citation statements)

References 43 publications

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“…Ferroportin expressed in the pre-synaptic vesicles indicate that it is a vesicular transporter protein carrying α-synuclein and iron to synaptic terminals. It is also an important retrograde solute carrier, not only binding iron, but also other metals (calcium, manganese, copper, cadmium, and aluminum) [78,79]. In human brain, ferroportin is expressed in medium spiny neurons (SMNs) of the striatum, mainly containing γ-aminobutric acid (GABA), and in dopaminergic neurons containing melanin pigments.…”

Section: Discussionmentioning

confidence: 99%

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Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases

Raha

Henderson

Chakraborty

et al. 2022

IJMS

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Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain.

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Section: Discussionmentioning

confidence: 99%

“…Conversely, α-synuclein expression was consistent in control samples and higher in PD brains. It was reported that the 5 -UTR of α-synuclein gene contains a putative iron responsive element [79]. Therefore, increase in iron may lead to a post-transcriptional upregulation of α-synuclein protein [80].…”

Section: Discussionmentioning

confidence: 99%

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases

Raha

Henderson

Chakraborty

et al. 2022

IJMS

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“…A recent in vitro study in fact provides support for this hypothesis, because it was demonstrated that Cp protein expression increased in copper-loaded HepG2 cells with no corresponding changes in mRNA expression. 46 Whether such a phenomenon occurs in vivo in other mammalian species is unknown, but the authors note a published report that documented increased Cp activity in a human patient suffering from acute copper toxicosis. 47 Perhaps the most common clinical condition in which patients present with liver copper loading is Wilson disease, 48 in which the ATP7B copper exporter is dysfunctional.…”

Section: Discussionmentioning

confidence: 99%

Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

Ranganathan

Jiang

et al. 2011

Blood

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Increases in serum and liver copper content are noted during iron deficiency in mammals, suggesting that copper-dependent processes participate during iron deprivation. One point of intersection between the 2 metals is the liver-derived, multicopper ferroxidase ceruloplasmin (Cp) that is important for iron release from certain tissues. The current study sought to explore Cp expression and activity during physiologic states in which hepatic copper loading occurs (eg, iron deficiency). Weanling rats were fed control or low iron diets containing low, normal, or high copper for ∼ 5 weeks, and parameters of iron homeostasis were measured. Liver copper increased in control and iron-deficient rats fed extra copper. Hepatic Cp mRNA levels did not change; however, serum Cp protein was higher during iron deprivation and with higher copper consumption. In-gel and spectrophotometric ferroxidase and amine oxidase assays demonstrated that Cp activity was enhanced when hepatic copper loading occurred. Interestingly, liver copper levels strongly correlated with Cp protein expression and activity. These observations support the possibility that liver copper loading increases metallation of the Cp protein, leading to increased production of the holo enzyme. Moreover, this phenomenon may play an important role in the compensatory response to maintain iron homeostasis during iron deficiency.

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“…It has been shown in rats, for example, that copper deficiency during pregnancy can result in reduced iron status and vice versa, and that copper overload induces iron overload, by interfering with the iron regulatory mechanism. 27,28 Others have demonstrated interactions between iron and zinc. 29 During the third trimester, fetal growth is at its most rapid.…”

Section: Discussionmentioning

confidence: 99%

The relationship between dietary supplement use in late pregnancy and birth outcomes: a cohort study in British women

Alwan¹,

Greenwood²,

Simpson

et al. 2010

BJOG

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ObjectiveTo examine the relationship between dietary supplement use during pregnancy and birth outcomes.DesignA prospective birth cohort.SettingLeeds, UK.SampleOne thousand two hundred and seventy-four pregnant women aged 18–45 years.MethodsDietary supplement intake was ascertained using three questionnaires for the first, second and third trimesters. Dietary intake was reported in a 24-hour dietary recall administered by a research midwife at 8–12 weeks of gestation. Information on delivery details and antenatal pregnancy complications was obtained from the hospital maternity records.Main outcome measuresBirthweight, birth centile and preterm birth.ResultsReported dietary supplement use declined from 82% of women in the first trimester of pregnancy to 22% in the second trimester and 33% in the third trimester. Folic acid was the most commonly reported supplement taken. Taking any type of daily supplement during any trimester was not significantly associated with size at birth taking into account known relevant confounders. Women taking multivitamin-mineral supplements in the third trimester were more likely to experience preterm birth (adjusted OR = 3.4, 95% CI 1.2, 9.6, P= 0.02).ConclusionsRegular multivitamin–mineral supplement use during pregnancy, in a developed country setting, is not associated with size at birth. However, it appears to be associated with preterm birth if taken daily in the third trimester. The mechanism for this is unclear and our study’s findings need confirming by other cohorts and/or trials in developed countries.

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Cu loading alters expression of non-IRE regulated, but not IRE regulated, Fe dependent proteins in HepG2 cells

Cited by 10 publications

References 43 publications

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases

Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

The relationship between dietary supplement use in late pregnancy and birth outcomes: a cohort study in British women

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