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Autophagy and Ferroptosis - What's the Connection?

ABSTRACT: PURPOSE OF REVIEW:Autophagy is a conserved intracellular degradation system and plays a dual role in cell death, depending on context and phase. Ferroptosis is a new form of regulated cell death that mainly depends on iron accumulation and lipid peroxidation. In this review, we summarize the processes of autophagy and ferroptosis and discuss their crosstalk mechanisms at the molecular level. RECENT FINDINGS:The original study shows that ferroptosis is morphologically, biochemically, and genetically distinct from autophagy and other types of cell death. However, recent studies demonstrate that activation of ferroptosis is indeed dependent on the induction of autophagy. Additionally, many ferroptosis regulators such as SLC7A11, GPX4, NRF2, p53, HSPB1, CISD1, FANCD2, and ACSL4 have been identified as potential regulators of autophagy. SUMMARY:This review not only highlights the importance of autophagy as an emerging mechanism of ferroptosis, but also raises new insights regarding regulated cell death.

SUBMITTER: Kang R

PROVIDER: S-EPMC5640172 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Autophagy and Ferroptosis - What's the Connection?

Kang Rui R Tang Daolin D

Current pathobiology reports 20170420 2

<h4>Purpose of review</h4>Autophagy is a conserved intracellular degradation system and plays a dual role in cell death, depending on context and phase. Ferroptosis is a new form of regulated cell death that mainly depends on iron accumulation and lipid peroxidation. In this review, we summarize the processes of autophagy and ferroptosis and discuss their crosstalk mechanisms at the molecular level.<h4>Recent findings</h4>The original study shows that ferroptosis is morphologically, biochemicall ...[more]

PMID: 29038744

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Project description:Macroautophagy (hereafter referred to as "autophagy") is a lysosome-mediated degradation process that plays a complex role in cellular stress, either promoting survival or triggering death. Early studies suggest that ferroptosis, an iron-dependent form of regulated cell death, is not related to autophagy. Conversely, recent evidence indicates that the molecular machinery of autophagy facilitates ferroptosis through the selective degradation of anti-ferroptosis regulators. However, the mechanism of autophagy-dependent ferroptosis remains incompletely understood. Here, we examine the early dynamic change in protein expression of autophagic (e.g., MAP1LC3B and SQSTM1) or ferroptotic (e.g., SLC7A11 and GPX4) regulators in 60 human cancer cell lines in response to two classical ferroptosis activators (erastin and RSL3) in the absence or presence of the lysosomal inhibitor chloroquine. Compared to erastin, RSL3 exhibits wider and stronger activity in the upregulation of MAP1LC3B-II or downregulation of SQSTM1 in 80% (48/60) or 63% (38/60) of cell lines, respectively. Both RSL3 and erastin failed to affect SLC7A11 expression, but they led to GPX4 downregulation in 12% (7/60) and 3% (2/60) of cell lines, respectively. Additionally, the intracellular iron exporter SLC40A1/ferroportin-1 was identified as a new substrate for autophagic elimination, and its degradation by SQSTM1 promoted ferroptosis in vitro and in xenograft tumor mouse models. Together, these findings show tumor heterogeneity in autophagy-dependent ferroptosis, which might have different biological behaviors with regard to the dynamic characteristics of cell death.Abbreviations: ATG: Autophagy-related; CQ: Chloroquine; GPX4: Glutathione peroxidase 4; MAP1LC3B/LC3: Microtubule-associated protein 1 light chain 3 beta: NCOA4: Nuclear Receptor Coactivator 4; ROS: Reactive Oxygen Species; SLC40A1/ferroportin-1: Solute Carrier family 40 Member 1; SLC7A11: Solute Carrier Family 7 Member 11; SQSTM1/p62: Sequestosome 1.

Project description:BackgroundImplementation science and health services outcomes research each focus on many constructs that are likely interrelated. Both fields would be informed by increased understanding of these relationships. However, there has been little to no investigation of the relationships between implementation outcomes and service outcomes, despite general acknowledgement that both types of outcomes are important in the pathway to individual and population health outcomes. Given the lack of objective data about the links between implementation and service outcomes, an initial step in elucidating these relationships is to assess perceptions of these relationships among researchers and practitioners in relevant fields. The purpose of this paper is to assess perceived relationships between Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework outcomes and service outcomes, testing five a priori hypotheses about which perceived relationships may be strongest.MethodsA cross-sectional online survey was administered to a convenience sample of implementation scientists, health services researchers, and public health and medical practitioners from a variety of settings. Respondents provided information on their discipline, training, practice and research settings, and levels of experience in health service outcomes research, implementation science, and the RE-AIM framework. Next, they rated perceived relationships between RE-AIM and service outcomes. Repeated measures analysis of variance were used to test a priori hypotheses. Exploratory analyses assessed potential differences in mean ratings across groups of respondents categorized by discipline, setting, and levels of implementation science, health services, and RE-AIM experience.ResultsSurveys were completed by 259 respondents, most of whom were employed in academic and medical settings. The majority were doctoral-level researchers and educators or physicians. Reported levels of experience with implementation research, health services research, and the RE-AIM framework varied. The strongest perceived relationships overall were between Implementation/Fidelity and Effectiveness (as a service outcome); Maintenance and Efficiency; Reach and Equity; Adoption and Equity; Implementation/Adaptation and Patient-Centeredness; Adoption and Patient-Centeredness; and Implementation/Fidelity and Safety. All but one of the a priori hypotheses were supported. No significant differences in ratings of perceived relationships were observed among subgroups of respondents.ConclusionsThis study is an initial step in developing conceptual understanding of the links between implementation outcomes, health services outcomes, and health outcomes. Our findings on perceived relationships between RE-AIM and services outcomes suggest some areas of focus and identify several areas for future research to advance both implementation science and health services research toward common goals of improving health outcomes.

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Autophagy and Ferroptosis - What's the Connection?

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Autophagy and Ferroptosis - What's the Connection?

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