Activation of Nrf2/Keap1 signaling and autophagy induction against oxidative stress in heart in iron deficiency

Inoue, Hirofumi; Kobayashi, Kenichi; Ndong, Moussa; Yamamoto, Yuji; Katsumata, Seishi; Suzuki, Kazuharu; Uehara, Mariko

doi:10.1080/09168451.2015.1018125

Cited by 22 publications

(13 citation statements)

References 16 publications

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“…Iron is an essential element for cellular responses, including immune response and oxidative metabolism (7,25). Previously, we reported that iron deficiency induced oxidative stress in the liver and heart (10,34). However, limited information is available on the molecular mechanisms underlying the association between oxidative stress and autophagy during iron deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Iron deficiency increases oxidative stress in NIH3T3 cells (10). First, we examined to clarify accumulated intracellular ROS levels using the same cell line.…”

Section: Iron Deficiency Increased Cellular Ros Productionmentioning

confidence: 99%

“…Iron deficiency leads to health problems such as cardiovascular diseases, blood loss, and anemia (8,13,18). We previously reported that iron deficiency increased the levels of phosphatidylcholine hydroperoxide (a primary peroxide in biological membranes) and copper in the liver of rats and increased the carboxylation of proteins in the heart of rats (10,34). Iron deficiency induces oxidative stress in many tissues.…”

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confidence: 99%

“…Total RNA was extracted and was reverse transcribed to complementary DNA as described previously (10). Thermal cycling was performed using a 7500/7900 real-time polymerase chain reaction (PCR) system with a SYBR green PCR protocol (Applied Biosystems, Foster City, CA).…”

mentioning

confidence: 99%

“…The stained cells were observed under FV500-IX confocal fluorescence microscope. cent study showed that dietary iron deficiency activated nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) system and autophagy to eliminate abnormal proteins in the heart and NIH3T3 cells (10). However, molecular mechanisms underlying the association between Nrf2 signaling and autophagy during iron deficiency are unclear.…”

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Iron deficiency induces autophagy and activates Nrf2 signal through modulating p62/SQSTM

et al. 2017

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Iron is an essential trace metal in almost all organisms and plays an important role in the redox system. We previously reported that iron deficiency activated autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling for oxidative stress. However, regulatory mechanisms underlying the association between autophagy and Nrf2 signaling are unclear. In this study, we found that treatment of cells with an iron-specific chelator deferoxamine (DFO) increased reactive oxidative species (ROS) production by elevating the expression of p47 phox and p67 phox compared with that in untreated cells. The DFO treatment also induced protein aggregation and formed aggresome, which is a cellular response to misfolded protein. In addition, DFO treatment upregulated the expression of the autophagic gene p62/SQSTM1, which in turn activated intracellular proteolysis during autophagy. DFO treatment phosphorylated p62/SQSTM1 (Thr351) to activate Nrf2. However, silencing of p62/SQSTM1 followed by DFO treatment attenuated Nrf2 activation and resulted in the accumulation of carboxyl proteins compared with DFO treatment alone. These results indicated that iron deficiency activates Nrf2 signaling by modulating p62/SQSTM1 during autophagy.

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Section: Discussionmentioning

confidence: 99%

“…Iron deficiency increases oxidative stress in NIH3T3 cells (10). First, we examined to clarify accumulated intracellular ROS levels using the same cell line.…”

Section: Iron Deficiency Increased Cellular Ros Productionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Iron deficiency induces autophagy and activates Nrf2 signal through modulating p62/SQSTM

et al. 2017

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Reduced iron and cobalt levels in response to curcumin supplementation are not responsible for the prolonged larval development and do not affect the oxidative stress tolerance and polyamine status of D. melanogaster

Lüersen,

Jöckel,

Chin

et al. 2023

BioFactors

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Recent reports indicated that the phytochemical curcumin possesses iron‐chelating activity. Here, by employing the fruit fly Drosophila melanogaster, we conducted feeding studies supplementing curcumin or, as a control, the iron chelator bathophenanthroline (BPA). First, the absorption and further metabolization of dietary curcuminoids were proved by metabolomics analyses. Next, we found that 0.2% dietary curcumin, similar to BPA, lowered the iron but also the cobalt content, and to a lesser extent affected the manganese and zinc status. Supplementation during larval stages was required and sufficient for both compounds to elicit these alterations in adult animals. However, curcumin‐induced retarded larval development was not attributable to the changed trace metal status. In addition, a reduction in the iron content of up to 70% by curcumin or BPA supplementation did not reduce heme‐dependent catalase activity and tolerance toward H2O2 in D. melanogaster. Moreover, polyamines were not influenced by curcumin treatment and decreased iron levels. This was confirmed for selected organs from 0.2% curcumin‐treated mice, except for the spleen. Here, elevated spermidine level and concomitant upregulation of genes involved in polyamine production were associated with a putatively anemia‐derived increased spleen mass. Our data underline that the metal‐chelating property of curcumin needs to be considered in feeding studies.

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Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions

Fisher

Babitt

2021

Developmental Dynamics

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Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)‐SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP‐SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP‐SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.

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Activation of Nrf2/Keap1 signaling and autophagy induction against oxidative stress in heart in iron deficiency

Cited by 22 publications

References 16 publications

<b>Iron deficiency induces autophagy and activates Nrf2 signal through modulating </b><b>p62/SQSTM </b>

<b>Iron deficiency induces autophagy and activates Nrf2 signal through modulating </b><b>p62/SQSTM </b>

Reduced iron and cobalt levels in response to curcumin supplementation are not responsible for the prolonged larval development and do not affect the oxidative stress tolerance and polyamine status of D. melanogaster

Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions

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