Mitochondrial Lipid Peroxidation Is Responsible for Ferroptosis

Lyamzaev, Konstantin G.; Panteleeva, Alisa A.; Simonyan, Ruben A.; Avetisyan, Armine V.; Chernyak, Boris V.

doi:10.3390/cells12040611

Cited by 31 publications

(18 citation statements)

References 46 publications

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“…On the other hand, it is well established that excessive labile iron within mitochondria contributes to mitochondrial ROS production [48,49], leading to devastating damage of mitochondrial function and integrity. Recent studies con rmed that mitochondrial lipid peroxidation was critical in ferroptosis by using a uorescent mitochondria-targeted dye that is sensitive to lipid peroxidation [50]. Our results show that Drp1 de ciency prevented ferroptosis-mediated accumulation of mitochondrial ROS and mitochondrial lipid peroxidation (Fig.…”

Section: Discussionsupporting

confidence: 62%

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis

Culmsee,

Tang,

Fuß

et al. 2024

Preprint

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Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.

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Section: Discussionsupporting

confidence: 62%

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis

Culmsee,

Tang,

Fuß

et al. 2024

Preprint

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“…27,28 Indeed, synthetic antioxidant pharmaceutical agents such as Fer-1 (ferrostatin-1) and MitoQ can inhibit LIPOX propagation and block ferroptosis. [29][30][31][32] Inhibition of ferroptosis by Fer-1 or MitoQ has been shown to significantly reduce infarct size in murine hearts. [32][33][34][35][36] In this article, we explored the relationship between the triggers of I/R injury, Ca 2+ , and ROS, and how they independently or synergistically regulate mitochondrial damage through mPTP opening or LIPOX.…”

Section: Novelty and Significancementioning

confidence: 99%

“…27,28 Indeed, synthetic antioxidant pharmaceutical agents such as Fer-1 (ferrostatin-1) and MitoQ can inhibit LIPOX propagation and block ferroptosis. 29–32 Inhibition of ferroptosis by Fer-1 or MitoQ has been shown to significantly reduce infarct size in murine hearts. 32–36…”

mentioning

confidence: 99%

Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury

Mendoza,

Patel,

Robichaux

et al. 2024

Circulation Research

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BACKGROUND: During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca 2+ and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultimately necrotic death. However, the mechanisms of how these triggers individually or cooperatively open the pore have yet to be determined. METHODS: Here, we use a combination of isolated mitochondrial assays and in vivo I/R surgery in mice. We challenged isolated liver and heart mitochondria with Ca 2+ , ROS, and Fe 2+ to induce mitochondrial swelling. Using inhibitors of the mPTP (cyclosporine A or ADP) lipid peroxidation (Fer-1 [ferrostatin-1], mitoquinone), we determined how the triggers elicit mitochondrial damage. Additionally, we used the combination of inhibitors during I/R injury in mice to determine if dual inhibition of these pathways is additivity protective. RESULTS: In the absence of Ca 2+ , we determined that ROS fails to trigger mPTP opening. Instead, high levels of ROS induce mitochondrial dysfunction and rupture independently of the mPTP through lipid peroxidation. As expected, Ca 2+ in the absence of ROS induces mPTP-dependent mitochondrial swelling. Subtoxic levels of ROS and Ca 2+ synergize to induce mPTP opening. Furthermore, this synergistic form of Ca 2+ - and ROS-induced mPTP opening persists in the absence of CypD (cyclophilin D), suggesting the existence of a CypD-independent mechanism for ROS sensitization of the mPTP. These ex vivo findings suggest that mitochondrial dysfunction may be achieved by multiple means during I/R injury. We determined that dual inhibition of the mPTP and lipid peroxidation is significantly more protective against I/R injury than individually targeting either pathway alone. CONCLUSIONS: In the present study, we have investigated the relationship between Ca 2+ and ROS, and how they individually or synergistically induce mitochondrial swelling. Our findings suggest that Ca 2+ mediates mitochondrial damage through the opening of the mPTP, although ROS mediates its damaging effects through lipid peroxidation. However, subtoxic levels both Ca 2+ and ROS can induce mPTP-mediated mitochondrial damage. Targeting both of these triggers to preserve mitochondria viability unveils a highly effective therapeutic approach for mitigating I/R injury.

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“…Mitochondrial dysfunction with excessive ROS production, autophagy disruption, lipofuscin accumulation, and lipid peroxidation are common pathomechanisms in these disorders. 34,55,115,116,118,119 Indirect evidence of ferroptosis include abnormal levels of iron import, storage, and export proteins indicating iron dyshomeostasis, reduced expression of GSH and other antioxidants, upregulation of the NRF2, and accumulation of products from lipid peroxidation, such as malonyldialdehyde and 4-hydroxynonenal. [16][17][18][19][20][21] A set of iron-responsive elements in 59untranslated regions of mRNA can bind excessive iron and fold mRNA into loops that affect transcription of proteins such as amyloid precursor protein (APP), α-synuclein, and prion protein; many of these proteins interact with iron, which may initiate a potential feedback to accelerate ferroptosis.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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Ferroptosis is a unique form of programmed cell death pathway that is mechanistically different from necrosis, apoptosis, or autophagy.1 Ferroptosis is induced by reactive oxygen species (ROS) originating from multiple sources, especially accumulation of free intracellular divalent iron (Fe2+), leading to peroxidation of polyunsaturated fatty acids (PUFAs) and resulting in membrane damage (Figure). One major trigger of ferroptosis is decreased availability of intracellular antioxidant enzymes, particularly glutathione peroxidases (GPXs).1-7 Because of its high lipid concentration and oxygen consumption rate, the nervous tissue is extremely vulnerable to oxidative damage and ferroptosis. With aging, iron accumulates in the brain, which predisposes to and exacerbates these processes.8 Iron promotes ferroptosis both directly and as a cofactor required for the activity of enzymes mediating redox reactions and lipid peroxidation.9,10 Epigenetic regulation can determine cell sensitivity to ferroptosis by affecting intracellular iron levels, oxidative stress, and lipid metabolism.11 Ferroptosis affects all cell types in the nervous system, including neurons, glial cells, and pericytes.12 Microglia are the primary iron-accumulating cells in disease.13,14 Recent evidence indicates that iron-laden microglia have a critical role in ferroptosis associated with neurodegeneration.15 Studies in vitro, in experimental disease models, and in human brain tissue indicate that iron accumulation, oxidative stress, and lipid peroxidation are major disease mechanisms in a wide range of neurologic disorders. These studies also suggest that the different components of the ferroptosis pathway are potential targets for therapeutic intervention. The mechanisms of ferroptosis and its role in neurologic disorders have been the subject of several recent comprehensive reviews.7,8,16-21 Some of these concepts pertinent to neurodegeneration will be emphasized in this study.

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Mitochondrial Lipid Peroxidation Is Responsible for Ferroptosis

Cited by 31 publications

References 46 publications

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis

Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury

What Is the Role of Ferroptosis in Neurodegeneration?

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