Lipid storage and lipophagy regulates ferroptosis

Bai, Yuansong; Meng, Lingjun; Han, Leng; Jia, Yuanyuan; Zhao, Yanan; Gao, Huan; Kang, Rui; Wang, Xiaofeng; Tang, Daolin; Dai, Enyong

doi:10.1016/j.bbrc.2018.12.039

Cited by 343 publications

(250 citation statements)

References 46 publications

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“…Lipophagy, intracellular lipid droplets degradation by autophagy, promotes ferroptotic cell death through induction of lipid peroxidation in hepatocytes, both in vivo and in vitro (Bai et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

Han

Jiang

et al. 2020

Journal Cellular Physiology

161

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Ferroptosis, an autophagy‐dependent cell death, is characterized by lipid peroxidation and iron accumulation, closely associated with pathogenesis of gestational diabetes mellitus (GDM). Sirtuin 3 (SIRT3) has positive regulation on phosphorylation of activated protein kinase (AMPK), related to maintenance of cellular redox homeostasis. However, whether SIRT3 can confer autophagy by activating the AMPK‐mTOR pathway and consequently promote induction of ferroptosis is unknown. We used human trophoblastic cell line HTR8/SVneo and porcine trophoblastic cell line pTr2 to deterimine the mechanism of SIRT3 on autophagy and ferroptosis. The expression of SIRT3 protein was significantly elevated in trophoblastic cells exposed to high concentrations of glucose and ferroptosis‐inducing compounds. Increased SIRT3 expression contributed to classical ferroptotic events and autophagy activation, whereas SIRT3 silencing led to resistance against both ferroptosis and autophagy. In addition, autophagy inhibition impaired SIRT3‐enhanced ferroptosis. On the contrary, autophagy induction had a synergistic effect with SIRT3. Based on mechanistic investigations, SIRT3 depletion inhibited activation of the AMPK‐mTOR pathway and enhanced glutathione peroxidase 4 (GPX4) level, thereby suppressing autophagy and ferroptosis. Furthermore, depletion of AMPK blocked induction of ferroptosis in trophoblasts. We concluded that upregulated SIRT3‐enhanced autophagy activation by promoting AMPK‐mTOR pathway and decreasing GPX4 level to induce ferroptosis in trophoblastic cells. SIRT3 deficiency was resistant to high glucose‐ and erastin‐induced autophagy‐dependent ferroptosis and is, therefore, a potential therapeutic approach for treating GDM.

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Section: Discussionmentioning

confidence: 99%

SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

Han

Jiang

et al. 2020

Journal Cellular Physiology

161

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“…42 Moreover, lipophagy, the degradation of intracellular lipid droplets (LDs) via autophagy, promotes ferroptosis induced by RSL3 in hepatocytes by decreasing lipid storage, and subsequent lipid peroxidation. 43 Specific lipids, such as cis-unsaturated fatty acids and free fatty acids, can induce, modulate, or suppress both apoptotic and nonapoptotic cell death pathways. [44][45][46] It has been demonstrated that oxidized arachidonic and adrenic phosphatidylethanolamine (PEs) navigate cells to ferroptosis.…”

Section: Lipid Metabolism Regulates Ferroptosismentioning

confidence: 99%

The interaction between ferroptosis and lipid metabolism in cancer

2020

Sig Transduct Target Ther

426

285

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Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides. Recent discoveries have focused on alterations that occur in lipid metabolism during ferroptosis and have provided intriguing insights into the interplay between ferroptosis and lipid metabolism in cancer. Their interaction regulates the initiation, development, metastasis, therapy resistance of cancer, as well as the tumor immunity, which offers several potential strategies for cancer treatment. This review is a brief overview of the features characterizing the interaction between ferroptosis and lipid metabolism, and highlights the significance of this interaction in cancer.

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“…While autophagy plays an adaptive role in protecting cells from environmental stress, it can promote ferroptosis in many cases (Zhou et al, 2019;. Specifically, selective autophagy (e.g., ferritinophagy, lipophagy, and clockophagy) is involved in mediating ferroptotic cell death through the degradation of antiferroptosis regulators (Gao et al, 2016;Hou et al, 2016;Bai et al, 2019;Yang et al, 2019). Autophagy regulators, such as beclin 1 (BECN1) (Song et al, 2018), mechanistic target of rapamycin kinase (MTOR) (Liu Y. et al, 2020), and a lysosomal protease cathepsin B (CTSB) (Gao et al, 2018) contribute to ferroptotic cell death through affecting lipid peroxidation.…”

Section: Introductionmentioning

confidence: 99%

Iron Metabolism in Ferroptosis

Chen

Kang

et al. 2020

Front. Cell Dev. Biol.

Self Cite

594

382

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Ferroptosis is a form of regulated cell death that is characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures and the release of damage-associated molecular patterns. Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, ferroptosis is strictly controlled by regulators involved in many aspects of iron metabolism, such as iron uptake, storage, utilization, and efflux. Translational and transcriptional regulation of iron homeostasis provide an integrated network to determine the sensitivity of ferroptosis. Impaired ferroptosis is implicated in various iron-related pathological conditions or diseases, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. Understanding the molecular mechanisms underlying the regulation of iron metabolism during ferroptosis may provide effective strategies for the treatment of ferroptosis-associated diseases. Indeed, iron chelators effectively prevent the occurrence of ferroptosis, which may provide new approaches for the treatment of iron-related disorders. In this review, we summarize recent advances in the theoretical modeling of iron-dependent ferroptosis, and highlight the therapeutic implications of iron chelators in diseases.

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Lipid storage and lipophagy regulates ferroptosis

Cited by 343 publications

References 46 publications

SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

The interaction between ferroptosis and lipid metabolism in cancer

Iron Metabolism in Ferroptosis

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