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Mechanisms of Ferritinophagy and Ferroptosis in Diseases

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Abstract

The discovery of the role of autophagy, particularly the selective form like ferritinophagy, in promoting cells to undergo ferroptosis has inspired us to investigate functional connections between diseases and cell death. Ferroptosis is a novel model of procedural cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS), mitochondrial dysfunction, and neuroinflammatory response. Based on ferroptosis, the study of ferritinophagy is particularly important. In recent years, extensive research has elucidated the role of ferroptosis and ferritinophagy in neurological diseases and anemia, suggesting their potential as therapeutic targets. Besides, the global emergence and rapid transmission of COVID-19, which is caused by SARS-CoV-2, represents a considerable risk to public health worldwide. The potential involvement of ferroptosis in the pathophysiology of brain injury associated with COVID-19 is still unclear. This review summarizes the pathophysiological changes of ferroptosis and ferritinophagy in neurological diseases, anemia, and COVID-19, and hypothesizes that ferritinophagy may be a potential mechanism of ferroptosis. Advancements in these fields will enhance our comprehension of methods to prevent and address neurological disorders, anemia, and COVID-19.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

ACSL4:

acyl CoA synthase long-chain family member 4

ACE2:

angiotensin-converting enzyme 2

ATP:

abundant adenosine triphosphate

AD:

Alzheimer’s disease

Aβ:

amyloid-β

ALS:

amyotrophic lateral sclerosis

BH4:

tetrahydrobiopterin

BH2:

dihydrobiopterin

BBB:

blood-brain barrier

CoQ10:

ubiquinone 10

COVID-19:

coronavirus disease 2019

CQ:

chloroquine

DMT1:

divalent metal transporter 1

DFP:

deferiprone

FTH1:

ferritin heavy chain 1

FPN:

ferroportin

FSP1:

ferroptosis suppressor protein 1

FTMT:

mitochondrial ferritin

FALS:

familial ALS

Fer-1:

Ferrostatin-1

GSH:

glutathione

GPX4:

glutathione peroxidase 4

HSC:

hepatic stellate cell

HD:

Huntington’s disease

HTT:

Huntington

HO-1:

heme-oxygenase-1

IREBP2:

iron response element binding protein 2

IS:

ischemic stroke

IRE:

iron response element

IRP1/2:

iron regulatory protein-1and -2

IL-6:

inflammatory cytokines interleukin

ICP-MS:

inductively coupled plasma mass spectrometry

JNK:

c-Jun N-terminal kinase

LPCAT3:

lysophosphatidylcholine acyltransferase 3

LIP:

labile iron pool

LA:

α-lipoic acid

LAP:

α-Lipoic acid-plus

MAPK8:

mitogen-activated protein kinase 8

MCAO/R:

middle cerebral artery occlusion/reoxygenation

MDA:

malondialdehyde

MRI:

magnetic resonance imaging

mHTT:

mutant huntingtin

NCOA4:

nuclear receptor coactivator 4

Nrf2:

Nuclear Factor Erythroid 2-Related Factor 2

ND:

neurodegenerative diseases

NBIA:

neurodegenerative with brain accumulation

NFTs:

neurofibrillary tangles

OGD/R:

oxygen-glucose deprivation/reoxygenation

8-OHdG:

8-Hydroxy-2-deoxyguanine

PUFAs:

polyunsaturated fatty acids

PLOOHs:

phospholipid hydroperoxides

PD:

Parkinson’s disease

ROS:

reactive oxygen species

RSL3:

RAS-selective lethal 3

STEAP3:

six transmembrane epithelial antigens of the prostate 3

SARS-CoV-2:

syndrome coronavirus 2

SENDA:

static encephalopathy of childhood with neurodegeneration in adulthood

SPs:

senile plaques

SALS:

sporadic ALS

SAH:

subarachnoid hemorrhage

TEM:

transmission electron microscopy

TF:

transferrin

TfR1:

transferrin receptor 1

TBI:

traumatic brain injury

TNF-α:

tumor necrosis factor alpha

WDR45:

WD repeat domain 45

Zip8/14:

Zinc-Iron regulatory protein family 8/14

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82374326), and the Zhejiang Provincial Science and Technology Innovation Leading Talent Project of “Ten Thousand Talents Plan” (2019).

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  1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Siqi Li, Ping Huang, Feifan Lai, Ting Zhang, Jiaqi Guan & Yu He

  2. School of Basic Medicine Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Haitong Wan

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  1. Siqi Li
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The contribution of each author in this manuscript is as follows: Yu He contributes to the conception. Siqi Li writes the initial draft. Ping Huang and Feifan Lai modify the manuscript. Ting Zhang, Jiaqi Guan, Haitong Wan, and Yu He review and edit the manuscript. All authors read and approved the final manuscript. The corresponding authors attest that all listed authors meet the authorship criteria.

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Li, S., Huang, P., Lai, F. et al. Mechanisms of Ferritinophagy and Ferroptosis in Diseases. Mol Neurobiol 61, 1605–1626 (2024). https://doi.org/10.1007/s12035-023-03640-0

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