Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis

Melanie Merkel; Bjarne Goebel; Moritz Boll; Aasha Adhikari; Viktoria Maurer; Dieter Steinhilber; Carsten Culmsee

doi:10.3390/antiox12081590

journal article Open Access Aug 09, 2023

Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis

Melanie Merkel Bjarne Goebel

Moritz Boll Aasha Adhikari Viktoria Maurer Dieter Steinhilber Carsten Culmsee

Antioxidants Vol. 12 No. 8 pp. 1590 · MDPI AG

View at Publisher Save 10.3390/antiox12081590

Abstract

Ferroptosis is a form of oxidative cell death that is characterized by enhanced lipid peroxidation and mitochondrial impairment. The enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase (LPCAT) play an essential role in the biosynthesis of polyunsaturated fatty acid (PUFA)-containing phospholipids, thereby providing the substrates for lipid peroxidation and promoting ferroptosis. To examine the impact of mitochondria in ACSL4/LPCAT2-driven ferroptosis, HEK293T cells overexpressing ACSL4 and LPCAT2 (OE) or empty vector controls (LV) were exposed to 1S, 3R-RSL3 (RSL3) for induction of ferroptosis. The ACSL4/LPCAT2 overexpression resulted in higher sensitivity against RSL3-induced cell death compared to LV-transfected controls. Moreover, mitochondrial parameters such as mitochondrial reactive oxygen species (ROS) formation, mitochondrial membrane potential, and mitochondrial respiration deteriorated in the OE cells, supporting the conclusion that mitochondria play a significant role in ACSL4/LPCAT2-driven ferroptosis. This was further confirmed through the protection of OE cells against RSL3-mediated cell death by the mitochondrial ROS scavenger mitoquinone (MitoQ), which exerted protection via antioxidative properties rather than through previously reported metabolic effects. Our findings implicate that mitochondrial ROS production and the accompanying organelle disintegration are essential for mediating oxidative cell death initiated through lipid peroxidation in ferroptosis.

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References

Details

Published: Aug 09, 2023
Vol/Issue: 12(8)
Pages: 1590
License: View

Authors

M

Melanie Merkel

Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany; Marburg Center of Mind, Brain, and Behavior—CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany

B

Bjarne Goebel

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60439 Frankfurt, Germany

M

Moritz Boll

Marburg Center of Mind, Brain, and Behavior—CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany

A

Aasha Adhikari

Marburg Center of Mind, Brain, and Behavior—CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany

V

Viktoria Maurer

Marburg Center of Mind, Brain, and Behavior—CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany

D

Dieter Steinhilber

Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60439 Frankfurt, Germany

C

Carsten Culmsee

Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany; Marburg Center of Mind, Brain, and Behavior—CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany

Funding

Deutsche Forschungsgemeinschaft Award: 2021_3_1_2_Herden

Research Campus Mid-Hessen (FCMH) Award: 2021_3_1_2_Herden

Cite This Article

Melanie Merkel, Bjarne Goebel, Moritz Boll, et al. (2023). Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis. Antioxidants, 12(8), 1590. https://doi.org/10.3390/antiox12081590

Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis

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