Ferroptosis inhibitor, liproxstatin-1, protects the myocardium against ischemia/reperfusion injury by decreasing VDAC1 levels and rescuing GPX4 levels (2025)

Abstract

Ferroptosis is a distinct iron-dependent mechanism of regulated cell death recognized in cancer and ischemia/reperfusion (I/R) injury of different organs. It has been reported that molecules such as liproxstatin-1 (Lip-1) inhibit ferroptosis and promote cell survival however, the mechanisms underlying this action are not clearly understood. We investigated the role and mechanism of Lip-1 in reducing cell death in the ischemic myocardium. Using an I/R model of isolated perfused mice hearts in which Lip-1 was given at the onset of reperfusion, we found that Lip-1 protects the heart by reducing myocardial infarct sizes and maintaining mitochondrial structural integrity and function. Further investigation revealed that Lip-1-induced cardioprotection is mediated by a reduction of VDAC1 levels and oligomerization, but not VDAC2/3. Lip-1 treatment also decreased mitochondrial reactive oxygen species production and rescued the reduction of the antioxidant GPX4 caused by I/R stress. Meanwhile, mitochondrial Ca2+ retention capacity needed to induce mitochondrial permeability transition pore opening did not change with Lip-1 treatment. Thus, we report that Lip-1 induces cardioprotective effects against I/R injury by reducing VDAC1 levels and restoring GPX4 levels.

Keywords: Ferroptosis, ischemia, reperfusion, mitochondria, reactive oxygen species

1. Introduction

Ferroptosis is a uniquely regulated mechanism for cell death that results from iron-dependent lipid peroxidation [1]. Ferroptosis particularly differs from other forms of regulated cell death in that it is caspase-independent and has neither nuclear morphology alterations nor aberrant mitochondrial morphology [1, 2]. Compounds that selectively induce ferroptosis include erastin, buthioninesulfoxomine and other Ras-selective lethal small molecules, while inhibitors include ferrostatins and liproxstatin-1, which reduce accumulation of ROS from lipid peroxidation (reviewed in [3]). In particular, liproxstatin-1 (Lip-1) is a spiroquinoxalinamine derivative, which potently and specifically inhibits ferroptosis [4]. However, although models of ferrostain-1 action have been proposed [5], the mechanism of Lip1 protection, is yet to be elucidated [6]. Nevertheless, ferroptosis is commonly observed in cancer cells and has also been shown in brain, kidney and liver cells, especially after ischemia/reperfusion (I/R) injury, hence ferroptosis is a recognized significant cause of cell death [7].

Devolution of mitochondrial structure is a key ferroptosis characteristic. Although ferroptosis involves production of reactive oxygen species (ROS) from extra-mitochondrial iron-mediated lipid peroxidation, it results in shrinkage of mitochondria, reduction in cristae and rupture of the outer mitochondrial membrane (OMM) [4, 8]. Additionally, erastin-initiated ferroptosis is also mediated by a direct interaction between erastin and the OMM protein, voltage-dependent anion channel (VDAC) isoforms 2 and 3 [9]. And upstream of mitochondria, glutathione peroxidase 4 (GPX4), is a vital antioxidant enzyme that regulates ferroptosis by sensing and transducing oxidative stress [10]. GPX4 operates by catalyzing the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG) in a reaction that also reduces phospholipid hydroperoxides to less harmful alcohols [3, 11]. Recently, knockdown of GPX4 in a glutathione-independent manner was shown to lead to mitochondrial morphology destruction and an increase in mitochondrial ROS production [12].

Further, mitochondria are a critical target of cardiac I/R damage, particularly through VDAC1 regulation, and opening of the mitochondrial permeability transition pore (mPTP), an event known to cause cell death [1315]. And although ferroptosis is a recognized contributor to cell death during cardiac I/R injury (reviewed in [7]), little is known about the protective mechanisms utilized by ferroptosis inhibitors, especially Lip-1.

In this study, the objective was to investigate whether Lip-1, a potent inhibitor of ferroptosis, can protect the heart against I/R injury. Following this, we sought to determine the mechanism by which such cardioprotection may be elicited. We found that Lip-1 indeed mitigates cardiac damage caused by I/R insult via the reduction of VDAC1 protein levels, without affecting VDAC 2/3. Further, we show an increase in GPX4 protein levels accompanied by a reduction of mitochondrial ROS production by the NADH-ubiquinone oxidoreductase (ETC complex I). All these Lip-1 effects are elicited without impacting the amount of Ca2+ required to trigger opening of the mPTP.

2. Materials and Methods

2.1. Animals

Male adult mice (C57BL/6J, Jackson Labs) 9–12 weeks old were used. Protocols were approved by the UT Health Science Center at San Antonio Institutional Animal Care and Use Committee and conformed to the Guide for the Care and Use of Laboratory Animals: Eighth Edition (2011) from the National Research Council.

2.2. Langendorff heart perfusion system

All reagents were purchased from Sigma Aldrich, unless otherwise stated. Mice were anesthetized with ketamine (80 mg/kg i.p.) and xylazine (8 mg/kg i.p.) as previously described [15]. Hearts were excised and arrested in cold (4C) Krebs Henseleit (KH) buffer (in mM): glucose 11, NaCl 118, KCl 4.7, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25 and CaCl2 3, pH 7.4. Hearts were retrograde perfused (3 ml/min) through the aorta with KH buffer bubbled with 95% O2/5% CO2 at 37°C on the Langendorff apparatus. Following 30 min equilibration, normothermic ischemia was induced by stopping buffer follow for 35 min. Reperfusion followed with KH buffer + Lip-1 (200 nM) or vehicle (DMSO), for 30 min (to isolate mitochondria) or 2 h (for infarct size measurement). This protocol typically results in ~50% infarct size. Sham hearts were not subjected to I/R.

2.3. Myocardial infarct size measurements

Following 2 h reperfusion, hearts were sliced into 4 transverse sections parallel to the atrio-ventricular groove as described in [16]. Samples were then incubated for 10 min with 2% triphenyltetrazolium chloride at 37°C to identify viable (red) from infarcted (white) heart tissue. Adobe Photoshop CS6 planimetry was used to quantify necrotic area by a blinded investigator.

2.4. Transmission electron microscopy (TEM)

TEM was used for ultrastructural analysis of tissue samples as previously described [14]. Samples were fixed in 4% formaldehyde with 1% glutaraldehyde overnight at 4°C before being washed and post-fixed for 2 h at room temperature in 2% osmium tetroxide. Sections were dehydrated in a graded alcohol series then embedded in Eponate 12 medium and cured for 48 h at 60°C. Sections were then sliced, mounted and stained with uranyl acetate and lead citrate and then viewed on a JEOL 1230 electron microscope.

2.5. Western blot analysis

As recently described in [17], we loaded equal concentrations of lysed tissue in 4–20% Tris-glycine gels (Bio-Rad). We carried out electrophoresis for 120 min at 90 V, then transfer onto nitrocellulose membranes for 80 min at 90 V. Membranes were blocked using 5% blocker solution (Bio-Rad), then probed overnight at 4°C using primary antibodies for the following targets: VDAC1 (Santa Cruz Biotechnology, sc390996), VDAC2 (Cell Signaling Technology, 9412s), VDAC3 (LifeSpan BioSciences, LS®C80113), cyclophilin D (Thermo Fisher, 455900), GPX4 (Abcam, ab125066) and GAPDH (Cell Signaling Technology, 97166S). Ponceau staining was also used to determine total protein quantities. Visualization was done on an Odyssey CLx system using IRDye secondary antibodies (LI-COR, 926–32211 and 926–68070).

2.6. Mitochondrial Isolation

Crude mitochondria were isolated from ischemic (30 min reperfusion) and sham hearts as described in [14]. Tissue was minced and homogenized in isolation buffer A (in mM): sucrose 70, mannitol 210, EDTA 1 and Tris-HCl 50, pH 7.4, at 0.1 g of tissue/ml of buffer. The homogenate was centrifuged at 3,000 rpm for 3 min, then the supernatant for 10 min at 13,000 rpm in a Galaxy 20R centrifuge (VWR). The resultant mitochondrial pellet was resuspended in isolation Buffer B (in mM): sucrose 150, KCl 50, KH2PO4 2, succinic acid 5 and Tris/HCl 20, pH 7.4. Concentration was determined using the DC assay kit (Bio-Rad).

2.7. Mitochondrial H2O2 measurement

Mitochondria ROS production was measured spectrofluorometrically at 560/590 nm (excitation/emission) in 100 ug of mitochondrial protein in a buffer: (in mM): 20 Tris, 250 sucrose, 1 EGTA, 1 EDTA, and 0.15% bovine serum albumin adjusted to pH 7.4 at 30°C with continuous stirring. Amplex red dye (1 uM) (Thermofisher) and horseradish peroxidase (0.345 U/mL) were used to monitor H2O2 production, an analog for ROS generation [15]. H2O2 levels were calculated using a standard curve of H2O2 concentration and fluorescence intensity and a sodium salt of glutamate/malate (3 mM) was used to activate ETC complex I.

2.8. Ca2+-induced mitochondrial permeability transition

Mitochondrial resistance to Ca2+ overload-induced formation of the mitochondrial permeability transition pore (mPTP) was measured as described in [18, 19]. Isolated mitochondria (500 ug) were suspended in isolation Buffer B with the dye, calcium green-5N (0.1 uM) (ThermoFisher). Samples were placed in a fluorescence spectrophotometer (Hitachi F2710) at 500/530 nm (excitation/emission) at 30°C and incubated for 90 seconds followed by injections of CaCl2 (10 μmoles) pulses at 60 second intervals. Pulses induce a fluorescence peak of extra-mitochondrial Ca2+ + dye, which returns to baseline as mitochondria absorb Ca2+. Calcium uptake reduces as more Ca2+ pulses are added, and eventually, a large release of mitochondrial Ca2+ occurs, signaling opening of the mPTP. Calcium retention capacity (CRC) was defined as the amount of Ca2+ required to initiate mPTP opening and was expressed in nmol of CaCl2 per mg of mitochondrial protein.

2.9. Statistical Analysis

Data is shown in bar graphs expressed as means with error bars that are the standard errors of the mean (±SEM). Student’s t-test was used for comparisons using Prism 6 (Graphpad Software). A difference of p<0.05 was considered to be statistically significant.

3. Results

3.1. Post-ischemic Lip-1 administration reduces myocardial infarct size and protects mitochondrial structural integrity

Inhibiting ferroptosis using Lip-1 reduces I/R damage in the liver [4]. We found that administering Lip-1 at the start of reperfusion induced cardiprotective effects against I/R injury in mice (Fig. 1). Myocardial infarct size measured at the end of reperfusion was significantly reduced in the I/R+Lip-1 group compared to the I/R control group (53% in I/R versus 30% in I/R+Lip-1) (Fig. 1B). Further, analysis of tissue structure using electron microscopy revealed that Lip-1 protective effects directly result in protection of mitochondrial structural integrity, as well as preservation of cardiac contraction machinery (Fig. 1C).

Fig. 1. Post-ischemic Lip-1 treatment reduces myocardial infarct size and helps maintain mitochondrial structural integrity.

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3.2. Post-ischemic Lip-1 treatment reduces protein levels of VDAC1 and VDAC1 oligomers, but not VDAC2 or VDAC3

Erastin, a potent ferroptosis instigator, has been reported to act directly via binding to VDAC2/3 in BJeLR cells [9]. To assess the protective Lip-1 effects on mitochondria, we assessed expression levels of all the VDAC isoforms 1, 2 and 3. We found that although VDAC 2 (Fig. 2EF) and VDAC 3 (Fig. 2GH) levels remained the same after 2 h reperfusion, levels of VDAC1 were significantly reduced in the I/R+Lip-1 group (Fig. 2AB). Further, we also found that VDAC1 oligomerization, an occurrence tied to increasing cell death [20], was actually reduced with Lip-1 treatment (Fig. 2D). Taken together, these results suggest that Lip-1 treatment leads to the increased degradation of VDAC1 and its oligomers.

Fig. 2. Post-ischemic Lip-1 treatment reduces VDAC1 protein levels and oligomerization, but not VDAC2/3.

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3.3. Post-ischemic Lip-1 treatment increases GPX4 protein levels and decreases ROS production

Lip-1 is known to inhibit ferroptosis by preventing lipid ROS build-up and cell death in inducible Gpx4−/− mice [4]. As shown in Fig. 3A, we found that I/R decreases levels of the cytosolic antioxidant, GPX4, responsible for removing lipid peroxides, but that Lip-1 treatment restores GPX4 levels. Furthermore, in order to assess if Lip-1 had any effects on mitochondrial ROS production, we stimulated complex I (using glutamate/malate) in isolated mitochondria. Here, we found that post-ischemic Lip-1 treatment results in significantly reduced generation of ROS from this complex (253 pmol/min/mg of mito protein for I/R versus 153 pmol/min/mg of mito protein for I/R+Lip-1) (Fig. 3B). From our previous studies, we have shown that reduction of ROS from complex I following I/R is cardio-beneficial [15], hence these results are in line with the notion of Lip-1 actions resulting in cardioprotection.

Fig. 3. Post-ischemic Lip-1 treatment increases GPX4 protein levels and decreases mitochondrial ROS production, but does not impact Ca2+-induced mPTP opening.

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3.4. Post-ischemic Lip-1 treatment does not affecting Ca2+-induced mPTP opening

Opening of the mPTP results in mitochondrial depolarization and subsequently cell death by apoptosis and necrosis. Previously, VDAC was postulated to be a component of the pore itself, but it has since been shown to be dispensable for mPTP formation [21]. In light of the protection of mitochondrial cristae and reduction of VDAC1 levels we observed, we next sought to assess mPTP opening in Lip-1 treated hearts. As shown in Fig. 4, we did not observe any significant changes in the Ca2+ required to trigger mPTP opening in isolated mitochondria (145 nmol/mg of mito protein for I/R versus 160 nmol/mg of mito protein for I/R+Lip-1). From this, we concluded that Lip-1 protection of mitochondria does not involve delaying mPTP opening.

4. Discussion

In this study, we have shown that post-ischemic treatment of isolated mice hearts with the ferroptosis inhibitor, liproxstatin-1, results in cardioprotective effects by reducing myocardial infarct size and protection of mitochondrial structural integrity and function. On examining the mechanisms involved in Lip1-induced cardioprotection after I/R, we showed that protection of mitochondria is associated with a significant decrease in the pro-cell death VDAC1, but does not involve the ferroptotic targets VDAC 2/3. Further, we showed that Lip-1 treatment leads to an increase in levels of the antioxidant GPX4 and a reduction of mitochondrial ROS production by complex I, without delaying Ca2+-induced mPTP opening.

Induction of cell death is carried out by a variety of regulated pathways such as caspase-mediated (apoptosis), ROS-induced (oxeiptosis), inflammasome-activated (pyroptosis), and iron/lipid dependent (ferroptosis) pathways (reviewed in [22]). Despite ferroptosis being a recognized contributor to cell death in cardiac I/R injury [23], understanding the mechanisms of anti-ferroptotic compounds has largely gone understudied, with a few studies focusing on ferrostatin-1 [22]. Here, we show that post-ischemic application of Lip-1 to mice myocardium results in decreased I/R injury as shown by decreased infarct sizes (Fig. 1). Given that ferrostatin-1 and Lip-1 both reduce lipid peroxidation, this result is in line with Lip-1 reducing ferroptosis following I/R injury in other organs such as the liver and kidneys [4, 24]. Furthermore, our studies remarkably found that protection of mitochondrial structure is an important outcome for Lip-1 cardioprotective effects (Fig. 1), contrary to the often-implied suggestions that mitochondrial damage is a secondary component of ferroptosis [3, 9]. This observation led us to conclude that Lip-1 cardioprotection against ferroptosis is facilitated via direct mitochondrial effects.

The potent ferroptosis-inducer, erastin, both interferes with the cystine/glutathione antiporter system (system Xc-) and binds directly with the mitochondrial outer membrane (OMM) channel, VDAC2/3, leading to OMM rupture [9]. In evaluating the impact of Lip-1 protection of mitochondria, we measured protein levels of the VDAC isoforms 1, 2 and 3, but notably observed decreases only in VDAC1 content and VDAC 1 oligomerization (Fig. 2). The role of open/closed VDAC in cardiac I/R has long been debated, but generally VDAC1 is thought to promote injury, while VDAC2 may be protective [25]. Increasing intracellular Ca2+ enhances VDAC1 oligomerization and subsequently apoptosis [20], and our results show that Lip-1 reduces VDAC1 oligomerization. Knockdown of VDAC1, a highly Ca2+-permeable channel, increases cell death by reducing low-amplitude apoptotic Ca2+ signals being conveyed from the endoplasmic reticulum to mitochondria via the VDAC1/GRP75/IP3R1 complex [26, 27]. Hence, it is plausible that Lip-1 cardioprotection is mediated by the decline of VDAC1 expression, without affecting VDAC 2/3.

Lip-1 actions are presumed to be downstream of the cytosolic GPX4 antioxidant system that also converts reduced GSH to oxidized GSSH [3]. Adding to the complexity of ferroptosis pathways, mitochondria have recently been suggested to be important for cysteine-deprivation-induced ferroptotsis, but dispensable for GPX4 inhibition-induced ferroptosis [12, 28]. Here it is worth noting that cysteine is the precursor to GSH, the substrate of GPX4; and that Lip-1 was discovered via its inhibition of ferroptosis in a Gpx4−/− mouse model [4]. In our studies however, Lip-1 treatment resulted in increased GPX4 levels in the 2 h reperfusion window (Fig. 3), suggesting that Lip-1 actions may not be restricted to downstream lipid peroxidation outcomes. Further, as shown in Fig. 3B, we also found that Lip-1 treatment reduced mitochondrial ROS production by the NADH-ubiquinone oxidoreductase (complex I). This is in contrast to studies that have not observed mitochondrial complex I ROS changes in erastin-induced or ferrostatin-inhibited ferroptosis [1, 5]. While it has also been shown that erastin-insitgated ferroptosis can also increase intra-mitochondrial ROS in the form of lipid peroxides [29]. Overall, it appears that the impact of GPX4 and ferroptosis on mitochondrial ROS may be dependent on the particular trigger or inhibitor of ferroptosis being studied.

Lastly, opening of the mPTP in cardiac I/R injury because of Ca2+ overload and/or increased ROS production causes cell death [17]. Our results show that decreased mitochondrial ROS and VDAC1 levels do not coincide with effects on Ca2+ needed to induce mPTP opening (Fig. 3C). In fact, Lip-1 treatment showed no impact on mitochondrial calcium retention capacity, which along with reduction of VDAC1, is in line with reports discounting VDAC as being part of the mPTP [21]. Ferroptosis inhibition by ferrostatin-1 has not been linked with delaying mPTP opening except with the addition of mPTP inhibitors, similar to the no-effect on Ca2+-induced mPT pore opening we observed with Lip-1 (Fig. 3C).

In conclusion, our study is the first to demonstrate the post-ischemic cardioprotective effects of Lip-1 in the myocardium against I/R injury via its reduction of infarct size and preservation of mitochondrial structure and function. The mechanism of this protection involves reducing VDAC1 levels and oligomerization, without affecting VDAC2/3, and reduction of mitochondrial ROS generation. These effects are complemented by the increase in GPX4 levels and no changes to Ca2+ levels required to induce mPTP opening.

Highlights.

  • Lip-1 protects the myocardium and mitochondria from ischemia/reperfusion injury

  • Lip-1 reduces VDAC1 levels but not VDAC2/3

  • Treatment rescues GPX4 levels and reduces mitochondrial ROS production

  • Lip-1 does not impact Ca2+-induced mPTP opening

Acknowledgements

This work was supported by the National Institutes of Health [grant HL138093 (JCB)], )]; and the AHA award [18PRE34030307 (NBM)].

Abbreviations:

I/R

ischemia/reperfusion

ROS

reactive oxygen species

VDAC

voltage-dependent anion channel

GPX4

glutathione peroxidase 4

mPTP

mitochondrial permeability transition pore

IP3R1

inositol triphosphate receptor 1

GRP75

glucose-regulated protein 75

Footnotes

Conflicts of Interest

The authors declare no conflicts of interest.

I declare that the manuscript, or part of it, neither has been published nor is currently under consideration for publication by any other journal. All the co-authors have read the manuscript and approved its submission to Biochemical and Biophysical Research Communications. The corresponding author agrees to pay the cost of printing the color figures and will do so upon manuscript acceptance.

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Reference List

  • [1].Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell, 149 (2012) 1060–1072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Dolma S, Lessnick SL, Hahn WC, Stockwell BR, Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells, Cancer Cell, 3 (2003) 285–296. [DOI] [PubMed] [Google Scholar]
  • [3].Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D, Ferroptosis: process and function, Cell Death Differ, 23 (2016) 369–379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Radmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Forster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O’Donnell VB, Kagan VE, Schick JA, Conrad M, Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice, Nat Cell Biol, 16 (2014) 1180–1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A, Stockwell BR, Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models, J Am Chem Soc, 136 (2014) 4551–4556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Cao JY, Dixon SJ, Mechanisms of ferroptosis, Cell Mol Life Sci, 73 (2016) 2195–2209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN, Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease, Physiol Rev, 99 (2019) 1765–1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Park EJ, Park YJ, Lee SJ, Lee K, Yoon C, Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells, Toxicol Lett, 303 (2019) 55–66. [DOI] [PubMed] [Google Scholar]
  • [9].Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR, RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels, Nature, 447 (2007) 864–868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Radmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M, Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death, Cell Metab, 8 (2008) 237–248. [DOI] [PubMed] [Google Scholar]
  • [11].Thomas JP, Geiger PG, Maiorino M, Ursini F, Girotti AW, Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins, Biochim Biophys Acta, 1045 (1990) 252–260. [DOI] [PubMed] [Google Scholar]
  • [12].Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R, Diederich WE, Culmsee C, Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis, Free Radic Biol Med, 117 (2018) 45–57. [DOI] [PubMed] [Google Scholar]
  • [13].Lin D, Cui B, Ren J, Ma J, Regulation of VDAC1 contributes to the cardioprotective effects of penehyclidine hydrochloride during myocardial ischemia/reperfusion, Exp Cell Res, 367 (2018) 257–263. [DOI] [PubMed] [Google Scholar]
  • [14].Feng Y, Madungwe NB, da Cruz Junho CV, Bopassa JC, Activation of G protein-coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy, Br J Pharmacol, 174 (2017) 4329–4344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Madungwe NB, Zilberstein NF, Feng Y, Bopassa JC, Critical role of mitochondrial ROS is dependent on their site of production on the electron transport chain in ischemic heart, Am J Cardiovasc Dis, 6 (2016) 93–108. [PMC free article] [PubMed] [Google Scholar]
  • [16].Feng Y, Bopassa JC, Oxygen surrounding the heart during ischemic conservation determines the myocardial injury during reperfusion, Am J Cardiovasc Dis, 5 (2015) 127–139. [PMC free article] [PubMed] [Google Scholar]
  • [17].Kabir ME, Singh H, Lu R, Olde B, Leeb-Lundberg LM, Bopassa JC, G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3beta Pathway after Ischemia/Reperfusion, PLoS One, 10 (2015) e0135988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M, PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning, Cardiovasc Res, 69 (2006) 178–185. [DOI] [PubMed] [Google Scholar]
  • [19].Ferrera R, Bopassa JC, Angoulvant D, Ovize M, Post-conditioning protects from cardioplegia and cold ischemia via inhibition of mitochondrial permeability transition pore, J Heart Lung Transplant, 26 (2007) 604–609. [DOI] [PubMed] [Google Scholar]
  • [20].Keinan N, Pahima H, Ben-Hail D, Shoshan-Barmatz V, The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis, Biochim Biophys Acta, 1833 (2013) 1745–1754. [DOI] [PubMed] [Google Scholar]
  • [21].Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD, Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death, Nat Cell Biol, 9 (2007) 550–555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G, The molecular machinery of regulated cell death, Cell Res, 29 (2019) 347–364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Fang X, Wang H, Han D, Xie E, Yang X, Wei J, Gu S, Gao F, Zhu N, Yin X, Cheng Q, Zhang P, Dai W, Chen J, Yang F, Yang HT, Linkermann A, Gu W, Min J, Wang F, Ferroptosis as a target for protection against cardiomyopathy, Proc Natl Acad Sci U S A, 116 (2019) 2672–2680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, Prokai A, Zuchtriegel G, Krombach F, Welz PS, Weinlich R, Vanden Berghe T, Vandenabeele P, Pasparakis M, Bleich M, Weinberg JM, Reichel CA, Brasen JH, Kunzendorf U, Anders HJ, Stockwell BR, Green DR, Krautwald S, Synchronized renal tubular cell death involves ferroptosis, Proc Natl Acad Sci U S A, 111 (2014) 16836–16841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ, VDAC2 inhibits BAK activation and mitochondrial apoptosis, Science, 301 (2003) 513–517. [DOI] [PubMed] [Google Scholar]
  • [26].De Stefani D, Bononi A, Romagnoli A, Messina A, De Pinto V, Pinton P, Rizzuto R, VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria, Cell Death Differ, 19 (2012) 267–273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Paillard M, Tubbs E, Thiebaut PA, Gomez L, Fauconnier J, Da Silva CC, Teixeira G, Mewton N, Belaidi E, Durand A, Abrial M, Lacampagne A, Rieusset J, Ovize M, Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury, Circulation, 128 (2013) 1555–1565. [DOI] [PubMed] [Google Scholar]
  • [28].Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, Jiang X, Role of Mitochondria in Ferroptosis, Mol Cell, 73 (2019) 354–363e353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Yuan H, Li X, Zhang X, Kang R, Tang D, CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation, Biochem Biophys Res Commun, 478 (2016) 838–844. [DOI] [PubMed] [Google Scholar]
Ferroptosis inhibitor, liproxstatin-1, protects the myocardium against ischemia/reperfusion injury by decreasing VDAC1 levels and rescuing GPX4 levels (2025)
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