Mitochondria as multifaceted regulators of ferroptosis

Abstract

Mitochondria are well known to be “energy factories” of the cell as they provide intracellular ATP via oxidative phosphorylation. Interestingly, they also function as a “cellular suicidal weapon store” by acting as a key mediator of various forms of regulated cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis. Ferroptosis, distinct from the other types of regulated cell death, is characterized by iron-dependent lipid peroxidation and subsequent plasma membrane rupture. Growing evidence suggests that an impaired ferroptotic response is implicated in various diseases and pathological conditions, and this impaired response is associated with dramatic changes in mitochondrial morphology and function. Mitochondria are the center of iron metabolism and energy production, leading to altered lipid peroxidation sensitivity. Although a growing number of studies have explored the inextricable link between mitochondria and ferroptosis, the role of this organelle in regulating ferroptosis remains unclear. Here, we review recent advances in our understanding of the role of mitochondria in ferroptosis and summarize the characteristics of this novel iron-based cellular suicide weapon and its arsenal. We also discuss the importance of ferroptosis in pathophysiology, including the need for further understanding of the relationship between mitochondria and ferroptosis to identify combinatorial targets that are essential for the development of successful drug discovery.

Key words： mitochondria; ferroptosis; lipid peroxidation; iron; ROS

References

1 Nunnari J , Suomalainen A . Mitochondria: in sickness and in health. Cell 2012; 148: 1145- 59.

2 Friedman JR , Nunnari J . Mitochondrial form and function. Nature 2014; 505: 335- 43.

3 Westermann B . Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010; 11: 872- 84.

4 Ying Z , Chen K , Zheng L et al. Transient activation of mitoflashes modulates nanog at the early phase of somatic cell reprogramming. Cell Metab 2016; 23: 220- 6.

5 Ying Z , Xiang G , Zheng L et al. Short-term mitochondrial permeability transition pore opening modulates histone lysine methylation at the early phase of somatic cell reprogramming. Cell Metab 2018; 28: 935- 45.e5.

6 Xiang G , Yang L , Long Q et al. BNIP3L-dependent mitophagy accounts for mitochondrial clearance during 3 factors-induced somatic cell reprogramming. Autophagy 2017; 13: 1543- 55.

7 Li L , Chen K , Wang T et al. Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade. Nat Metab 2020; 2: 882- 92.

8 Tang D , Kang R , Berghe TV et al. The molecular machinery of regulated cell death. Cell Res 2019; 29: 347- 64.

9 Bock FJ , Tait SWG . Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol 2020; 21: 85- 100.

10 Li S , Guo J , Ying Z et al. Valproic acid-induced hepatotoxicity in Alpers syndrome is associated with mitochondrial permeability transition pore opening-dependent apoptotic sensitivity in an induced pluripotent stem cell model. Hepatology 2015; 61: 1730- 9.

11 Shi J , Gao W , Shao F . Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 2017; 42: 245- 54.

12 Li Q , Shi N , Cai C et al. The role of mitochondria in pyroptosis. Front Cell Dev Biol 2020; 8: 630771.

13 Yuan J , Amin P , Ofengeim D . Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 2019; 20: 19- 33.

14 Gong Y , Fan Z , Luo G et al. The role of necroptosis in cancer biology and therapy. Mol Cancer 2019; 18: 100.

15 Xue C , Gu X , Li G et al. Mitochondrial mechanisms of necroptosis in liver diseases. Int J Mol Sci 2020; 22: 66.

16 Dixon SJ , Lemberg KM , Lamprecht MR et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060- 72.

17 Kagan VE , Mao G , Qu F et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13: 81- 90.

18 Gaschler MM , Andia AA , Liu H et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018; 14: 507- 15.

19 Chen X , Li J , Kang R et al. Ferroptosis: machinery and regulation. Autophagy 2021; 17: 2054- 81.

20 Stockwell BR , Friedmann Angeli JP , Bayir H et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171: 273- 85.

21 Stockwell BR . Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022; 185: 2401- 21.

22 Brigelius-Flohe R , Maiorino M . Glutathione peroxidases. Biochim Biophys Acta 2013; 1830: 3289- 303.

23 Jiang L , Kon N , Li T et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520: 57- 62.

24 Jiang L , Hickman JH , Wang SJ et al. Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle (Georgetown, Tex) 2015; 14: 2881- 5.

25 Yang WS , SriRamaratnam R , Welsch ME et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317- 31.

26 Doll S , Freitas FP , Shah R et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019; 575: 693- 8.

27 Bersuker K , Hendricks JM , Li Z et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019; 575: 688- 92.

28 Warner GJ , Berry MJ , Moustafa ME et al. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine. J Biol Chem 2000; 275: 28110- 9.

29 Venkatesh D , O’Brien NA , Zandkarimi F et al. MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes Dev 2020; 34: 526- 43.

30 Mao C , Liu X , Zhang Y et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 2021; 593: 586- 90.

31 Ta N , Qu C , Wu H et al. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 2022; 119: e2117396119.

32 Kraft VAN , Bezjian CT , Pfeiffer S et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci 2020; 6: 41- 53.

33 Doll S , Proneth B , Tyurina YY et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 2017; 13: 91- 8.

34 Zou Y , Palte MJ , Deik AA et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun 2019; 10: 1617.

35 Dixon SJ , Winter GE , Musavi LS et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol 2015; 10: 1604- 9.

36 Jiang X , Stockwell BR , Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22: 266- 82.

37 Wu H , Wang F , Ta N et al. The multifaceted regulation of mitochondria in ferroptosis. Life (Basel, Switzerland) 2021; 11: 222.

38 Frazer DM , Anderson GJ . The regulation of iron transport. BioFactors (Oxford, England) 2014; 40: 206- 14.

39 Hou W , Xie Y , Song X et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016; 12: 1425- 8.

40 Yu F , Zhang Q , Liu H et al. Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis. Cell Discov 2022; 8: 40.

41 Chen Y , Zhu G , Liu Y et al. O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer. Cell Signal 2019; 63: 109384.

42 Hirschhorn T , Stockwell BR . The development of the concept of ferroptosis. Free Radic Biol Med 2019; 133: 130- 43.

43 Muckenthaler MU , Rivella S , Hentze MW et al. A red carpet for iron metabolism. Cell 2017; 168: 344- 61.

44 Chen X , Yu C , Kang R et al. Iron metabolism in ferroptosis. Front Cell Dev Biol 2020; 8: 590226.

45 Kuang F , Liu J , Tang D et al. Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol 2020; 8: 586578.

46 Chen X , Kang R , Kroemer G et al. Organelle-specific regulation of ferroptosis. Cell Death Differ 2021; 28: 2843- 56.

47 Xie Y , Hou W , Song X et al. Ferroptosis: process and function. Cell Death Differ 2016; 23: 369- 79.

48 Friedmann Angeli JP , Schneider M , Proneth B et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180- 91.

49 Gan B . Mitochondrial regulation of ferroptosis. J Cell Biol 2021; 220: e202105043.

50 Gaschler MM , Hu F , Feng H et al. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem Biol 2018; 13: 1013- 20.

51 Wang H , Liu C , Zhao Y et al. Mitochondria regulation in ferroptosis. Eur J Cell Biol 2020; 99: 151058.

52 van Meer G , Voelker DR , Feigenson GW . Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 2008; 9: 112- 24.

53 Boonnoy P , Karttunen M , Wong-Ekkabut J . Alpha-tocopherol inhibits pore formation in oxidized bilayers. Phys Chem Chem Phys 2017; 19: 5699- 704.

54 Niu B , Lei X , Xu Q et al. Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury. Cell Biol Toxicol 2022; 38: 505- 30.

55 Tyurina YY , Shrivastava I , Tyurin VA et al. “Only a life lived for others is worth living”: redox signaling by oxygenated phospholipids in cell fate decisions. Antioxid Redox Signal 2018; 29: 1333- 58.

56 Shoshan-Barmatz V , De Pinto V , Zweckstetter M et al. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 2010; 31: 227- 85.

57 DeHart DN , Fang D , Heslop K et al. Opening of voltage dependent anion channels promotes reactive oxygen species generation, mitochondrial dysfunction and cell death in cancer cells. Biochem Pharmacol 2018; 148: 155- 62.

58 Yagoda N , von Rechenberg M , Zaganjor E et al. RAS-RAF-MEKdependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864- 8.

59 Ma Q , Zhang W , Zhu C et al. FUNDC2 regulates platelet activation through AKT/GSK-3beta/cGMP axis. Cardiovasc Res 2019; 115: 1672- 9.

60 Li S , Han S , Zhang Q et al. FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion. Nat Commun 2022; 13: 3486.

61 Yuan H , Li X , Zhang X et al. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 2016; 478: 1338- 43.

62 Yan S , Yang XF , Liu HL et al. Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. World J Gastroenterol 2015; 21: 3492- 8.

63 Quan J , Bode AM , Luo X . ACSL family: the regulatory mechanisms and therapeutic implications in cancer. Eur J Pharmacol 2021; 909: 174397.

64 Wang M , Su Y , Hou C et al. Targeted lipidomics analysis of lysine 179 acetylation of ACSF2 in rat hepatic stellate cells. Prostaglandins Other Lipid Mediat 2022; 163: 106671.

65 Magtanong L , Ko PJ , To M et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol 2019; 26: 420- 32.e9.

66 Eaton S . Control of mitochondrial beta-oxidation flux. Prog Lipid Res 2002; 41: 197- 239.

67 Nassar ZD , Mah CY , Dehairs J et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.Elife 2020; 9: e54166.

68 Blomme A , Ford CA , Mui E et al. 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nat Commun 2020; 11: 2508.

69 Vander Heiden MG , Cantley LC , Thompson CB . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029- 33.

70 Li XB , Gu JD , Zhou QH . Review of aerobic glycolysis and its key enzymes - new targets for lung cancer therapy. Thorac Cancer 2015; 6: 17- 24.

71 Wang X , Lu S , He C et al. RSL3 induced autophagic death in glioma cells via causing glycolysis dysfunction. Biochem Biophys Res Commun 2019; 518: 590- 7.

72 Gao M , Yi J , Zhu J et al. Role of mitochondria in ferroptosis. Mol Cell 2019; 73: 354- 63.e3.

73 Zdralevic M , Vucetic M , Daher B et al. Disrupting the ‘Warburg effect’ re-routes cancer cells to OXPHOS offering a vulnerability point via ‘ferroptosis’-induced cell death. Adv Biol Regul 2018; 68: 55- 63.

74 Song X , Liu J , Kuang F et al. PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep 2021; 34: 108767.

75 Dan Dunn J , Alvarez LA , Zhang X et al. Reactive oxygen species and mitochondria: a nexus of cellular homeostasis. Redox Biol 2015; 6: 472- 85.

76 Fang X , Wang H , Han D et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 2019; 116: 2672- 80.

77 Krainz T , Gaschler MM , Lim C et al. A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis. ACS Cent Sci 2016; 2: 653- 9.

78 Zhang W , Gai C , Ding D et al. Targeted p53 on small-molecules-induced ferroptosis in cancers. Front Oncol 2018; 8: 507.

79 Xie Y , Zhu S , Song X et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 2017; 20: 1692- 704.

80 Venkatesh S , Li M , Saito T et al. Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo. J Mol Cell Cardiol 2019; 128: 38- 50.

81 Shimada K , Skouta R , Kaplan A et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 2016; 12: 497- 503.

82 Boukalova S , Hubackova S , Milosevic M et al. Dihydroorotate dehydrogenase in oxidative phosphorylation and cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866: 165759.

83 Tadokoro T , Ikeda M , Ide T et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020; 5: e132747.

84 Yang L , Venneti S , Nagrath D . Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng 2017; 19: 163- 94.

85 Gao M , Monian P , Quadri N et al. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 2015; 59: 298- 308.

86 Lill R , Dutkiewicz R , Freibert SA et al. The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron-sulfur proteins. Eur J Cell Biol 2015; 94: 280- 91.

87 Stehling O , Wilbrecht C , Lill R . Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 2014; 100: 61- 77.

88 Maher P , van Leyen K , Dey PN et al. The role of Ca²⁺ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium 2018; 70: 47- 55.

89 Thorn CF , Oshiro C , Marsh S et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011; 21: 440- 6.

90 Do Van B , Gouel F , Jonneaux A et al. Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis 2016; 94: 169- 78.

91 Dai E , Meng L , Kang R et al. ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem Biophys Res Commun 2020; 522: 415- 21.

92 Pedrera L , Espiritu RA , Ros U et al. Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ 2021; 28: 1644- 57.

93 Xu T , Ding W , Ji X et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 2019; 23: 4900- 12.

94 Thomas C , Mackey MM , Diaz AA et al. Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 2009; 14: 102- 8.

95 Chang HC , Wu R , Shang M et al. Reduction in mitochondrial iron alleviates cardiac damage during injury. EMBO Mol Med 2016; 8: 247- 67.

96 Geldenhuys WJ , Leeper TC , Carroll RT . mitoNEET as a novel drug target for mitochondrial dysfunction. Drug Discov Today 2014; 19: 1601- 6.

97 Yuan H , Li X , Zhang X et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun 2016; 478: 838- 44.

98 Sohn YS , Tamir S , Song L et al. NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci USA 2013; 110: 14676- 81.

99 Kim EH , Shin D , Lee J et al. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett 2018; 432: 180- 90.

100 Li Y , Wang X , Huang Z et al. CISD3 inhibition drives cystine-deprivation induced ferroptosis. Cell Death Dis 2021; 12: 839.

101 Ward DM , Cloonan SM . Mitochondrial iron in human health and disease. Annu Rev Physiol 2019; 81: 453- 82.

102 Wachnowsky C , Fidai I , Cowan JA . Iron-sulfur cluster biosynthesis and trafficking - impact on human disease conditions. Metallomics 2018; 10: 9- 29.

103 Alvarez SW , Sviderskiy VO , Terzi EM et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 2017; 551: 639- 43.

104 Du J , Wang T , Li Y et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med 2019; 131: 356- 69.

105 Colin F , Martelli A , Clemancey M et al. Mammalian frataxin controls sulfur production and iron entry during de novo Fe₄S₄ cluster assembly. J Am Chem Soc 2013; 135: 733- 40.

106 Gomes CM , Santos R . Neurodegeneration in Friedreich’s ataxia: from defective frataxin to oxidative stress. Oxid Med Cell Longev 2013; 2013: 487534.

107 Cotticelli MG , Xia S , Lin D et al. Ferroptosis as a novel therapeutic target for Friedreich’s ataxia. J Pharmacol Exp Ther 2019; 369: 47- 54.

108 Tang D , Chen X , Kroemer G . Cuproptosis: a copper-triggered modality of mitochondrial cell death. Cell Res 2022; 32: 417- 8.

109 Tsvetkov P , Coy S , Petrova B et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 2022; 375: 1254- 61.

110 van der Bliek AM , Sedensky MM , Morgan PG . Cell biology of the mitochondrion. Genetics 2017; 207: 843- 71.

111 Reznik E , Miller ML , Senbabaoglu Y et al. Mitochondrial DNA copy number variation across human cancers. Elife 2016; 5: e10769.

112 Yang L , Lin X , Tang H et al. Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/ NAD⁺ redox. Aging Cell 2020; 19: e13206.

113 Yang L , Long Q , Liu J et al. Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA. Cell Mol Life Sci 2015; 72: 2585- 98.

114 Yang L , Mei T , Lin X et al. Current approaches to reduce or eliminate mitochondrial DNA mutations. Sci China Life Sci 2016; 59: 532- 5.

115 El-Hattab AW , Scaglia F . Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 2013; 10: 186- 98.

116 Guo J , Duan L , He X et al. A combined model of human iPSC-derived liver organoids and hepatocytes reveals ferroptosis in DGUOK mutant mtDNA depletion syndrome. Adv Sci (Weinh) 2021; 8: 2004680.

117 Chen X , Zeh HJ , Kang R et al. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol 2021; 18: 804- 23.

118 Li C , Zhang Y , Liu J et al. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy 2021; 17: 948- 60.

119 Dai E , Han L , Liu J et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun 2020; 11: 6339.

120 Zhang R , Kang R , Tang D . The STING1 network regulates autophagy and cell death. Signal Transduct Target Ther 2021; 6: 208.

121 Chan DC . Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol 2020; 15: 235- 59.

122 Li C , Liu J , Hou W et al. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion. Front Cell Dev Biol 2021; 9: 698679.

123 Yu R , Lendahl U , Nister M et al. Regulation of mammalian mitochondrial dynamics: opportunities and challenges. Front Endocrinol (Lausanne) 2020; 11: 374.

124 Zhang L , Wang Q , Liu W et al. The orphan nuclear receptor 4a1: a potential new therapeutic target for metabolic diseases. J Diabetes Res 2018; 2018: 9363461.

125 Liu M , Fan Y , Li D et al. Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS-mitochondrial fission-mitophagy axis. Mol Oncol 2021; 15: 2084- 105.

126 Zhou Y , Long Q , Wu H et al. Topology-dependent, bifurcated mitochondrial quality control under starvation. Autophagy 2020; 16: 562- 74.

127 Liu J , Kuang F , Kroemer G et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol 2020; 27: 420- 35.

128 Basit F , van Oppen LM , Schockel L et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis 2017; 8: e2716.

129 Chen X , Kang R , Kroemer G et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol 2021; 18: 280- 96.

130 Alberio S , Mineri R , Tiranti V et al. Depletion of mtDNA: syndromes and genes. Mitochondrion 2007; 7: 6- 12.

131 Li J , Cao F , Yin HL et al. Ferroptosis: past, present and future. Cell Death Dis 2020; 11: 88.

132 Fang X , Cai Z , Wang H et al. Loss of cardiac ferritin H facilitates cardiomyopathy via slc7a11-mediated ferroptosis. Circ Res 2020; 127: 486- 501.

133 Tang LJ , Zhou YJ , Xiong XM et al. Ubiquitin-specific protease 7 promotes ferroptosis via activation of the p53/TfR1 pathway in the rat hearts after ischemia/reperfusion. Free Radic Biol Med 2021; 162: 339- 52.

134 Song Y , Wang B , Zhu X et al. Human umbilical cord blood-derived MSCs exosome attenuate myocardial injury by inhibiting ferroptosis in acute myocardial infarction mice. Cell Biol Toxicol 2021; 37: 51- 64.

135 Park TJ , Park JH , Lee GS et al. Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes. Cell Death Dis 2019; 10: 835.

136 Bai T , Li M , Liu Y et al. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med 2020; 160: 92- 102.

137 Wang H , An P , Xie E et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 2017; 66: 449- 65.

138 Martinet W , Coornaert I , Puylaert P et al. Macrophage death as a pharmacological target in atherosclerosis. Front Pharmacol 2019; 10: 306.

139 NaveenKumar SK , SharathBabu BN , Hemshekhar M et al. The role of reactive oxygen species and ferroptosis in heme-mediated activation of human platelets. ACS Chem Biol 2018; 13: 1996- 2002.

140 Liu J , Liu W , Liu Y et al. New thiazolidinones reduce iron overload in mouse models of hereditary hemochromatosis and beta-thalassemia. Haematologica 2019; 104: 1768- 81.

141 Matsushita M , Freigang S , Schneider C et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med 2015; 212: 555- 68.

142 Weiland A , Wang Y , Wu W et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol 2019; 56: 4880- 93.

143 Li Q , Han X , Lan X et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight 2017; 2: e90777.

144 Alim I , Caulfield JT , Chen Y et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell 2019; 177: 1262- 79.e25.

145 Shinde A , Paez JS , Libring S et al. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche. Oncogenesis 2020; 9: 16.

146 Bao WD , Zhou XT , Zhou LT et al. Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model. Aging Cell 2020; 19: e13235.

147 Rui T , Wang H , Li Q et al. Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis. J Pineal Res 2021; 70: e12704.

148 Zhou J , Jin Y , Lei Y et al. Ferroptosis is regulated by mitochondria in neurodegenerative diseases. Neurodegener Dis 2020; 20: 20- 34.

149 Reichert CO , de Freitas FA , Sampaio-Silva J et al. Ferroptosis mechanisms involved in neurodegenerative diseases. Int J Mol Sci 2020; 21: 8765.

150 Bao WD , Pang P , Zhou XT et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ 2021; 28: 1548- 62.

151 Wang M , Liu CY , Wang T et al. (+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis. Cell Death Dis 2020; 11: 781.

152 Yamada N , Karasawa T , Takahashi M . Role of ferroptosis in acetaminophen-induced hepatotoxicity. Arch Toxicol 2020; 94: 1769- 70.

153 Song H , Zhang S , Sun X et al. Distinct iron deposition profiles of liver zones in various models with iron homeostasis disorders. Adv Sci (Weinh) 2018; 5: 1800866.

154 Yang L , Wang H , Yang X et al. Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms. Signal Transduct Target Ther 2020; 5: 138.

155 Yu Y , Jiang L , Wang H et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 2020; 136: 726- 39.

156 You Y , Liu C , Liu T et al. FNDC3B protects steatosis and ferroptosis via the AMPK pathway in alcoholic fatty liver disease. Free Radic Biol Med 2022; 193: 808- 19.

157 Li X , Wang TX , Huang X et al. Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity. Liver Int 2020; 40: 1378- 94.

158 Tsurusaki S , Tsuchiya Y , Koumura T et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis 2019; 10: 449.

159 Chen J , Li X , Ge C et al. The multifaceted role of ferroptosis in liver disease. Cell Death Differ 2022; 29: 467- 80.

160 Wang Y , Quan F , Cao Q et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J Adv Res 2021; 28: 231- 43.

161 Guo L , Zhang T , Wang F et al. Targeted inhibition of Rev-erbalpha/beta limits ferroptosis to ameliorate folic acid-induced acute kidney injury. Br J Pharmacol 2021; 178: 328- 45.

162 Su L , Jiang X , Yang C et al. Pannexin 1 mediates ferroptosis that contributes to renal ischemia/reperfusion injury. J Biol Chem 2019; 294: 19395- 404.

163 Deng F , Sharma I , Dai Y et al. Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. J Clin Invest 2019; 129: 5033- 49.

164 Zhang J , Bi J , Ren Y et al. Involvement of GPX4 in irisin’s protection against ischemia reperfusion-induced acute kidney injury. J Cell Physiol 2021; 236: 931- 45.

165 Li Y , Cao Y , Xiao J et al. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/ reperfusion-induced acute lung injury. Cell Death Differ 2020; 27: 2635- 50.

166 Wang M , Mao C , Ouyang L et al. Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ 2019; 26: 2329- 43.

167 Yoshida M , Minagawa S , Araya J et al. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat Commun 2019; 10: 3145.

168 Wang Y , Chen D , Xie H et al. AUF1 protects against ferroptosis to alleviate sepsis-induced acute lung injury by regulating NRF2 and ATF3. Cell Mol Life Sci 2022; 79: 228.

169 Wei S , Qiu T , Yao X et al. Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway. J Hazard Mater 2020; 384: 121390.

170 Li D , Jiang C , Mei G et al. Quercetin alleviates ferroptosis of pancreatic beta cells in type 2 diabetes. Nutrients 2020; 12: 2954.

171 Kuang F , Liu J , Li C et al. Cathepsin B is a mediator of organelle-specific initiation of ferroptosis. Biochem Biophys Res Commun 2020; 533: 1464- 9.

172 Liu K , Liu J , Zou B et al. Trypsin-mediated sensitization to ferroptosis increases the severity of pancreatitis in mice. Cell Mol Gastroenterol Hepatol 2022; 13: 483- 500.

173 Wilmanski T , Zhou X , Zheng W et al. Inhibition of pyruvate carboxylase by 1alpha,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression. Cancer Lett 2017; 411: 171- 81.

174 Ye X , Weinberg RA . Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol 2015; 25: 675- 86.

175 Shinde A , Libring S , Alpsoy A et al. Autocrine fibronectin inhibits breast cancer metastasis. Mol Cancer Res 2018; 16: 1579- 89.

176 Shinde A , Wilmanski T , Chen H et al. Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer. Breast Cancer Res 2018; 20: 76.

177 Ma S , Dielschneider RF , Henson ES et al. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS One 2017; 12: e0182921.

178 Palmer LD , Jordan AT , Maloney KN et al. Zinc intoxication induces ferroptosis in A549 human lung cells. Metallomics 2019; 11: 982- 93.

179 Probst L , Dachert J , Schenk B et al. Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. Biochem Pharmacol 2017; 140: 41- 52.

180 Montes de Oca Balderas P . Mitochondria-plasma membrane interactions and communication. J Biol Chem 2021; 297: 101164.

181 Hu X , Duan T , Wu Z et al. Intercellular mitochondria transfer: a new perspective for the treatment of metabolic diseases. Acta Biochim Biophys Sin (Shanghai) 2021; 53: 958- 60.

182 Ng MYW , Wai T , Simonsen A . Quality control of the mitochondrion. Dev Cell 2021; 56: 881- 905.