PMID- 37627584
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230828
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 12
IP  - 8
DP  - 2023 Aug 9
TI  - Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated 
      Ferroptosis.
LID - 10.3390/antiox12081590 [doi]
LID - 1590
AB  - 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.
FAU - Merkel, Melanie
AU  - Merkel M
AD  - Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, 
      Karl-von-Frisch-Str. 2, 35043 Marburg, Germany.
AD  - Marburg Center of Mind, Brain, and Behavior-CMBB, Hans-Meerwein-Strasse 6, 35032 
      Marburg, Germany.
FAU - Goebel, Bjarne
AU  - Goebel B
AUID- ORCID: 0000-0001-7120-0251
AD  - Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 
      Max-von-Laue-Str. 9, 60439 Frankfurt, Germany.
FAU - Boll, Moritz
AU  - Boll M
AD  - Marburg Center of Mind, Brain, and Behavior-CMBB, Hans-Meerwein-Strasse 6, 35032 
      Marburg, Germany.
FAU - Adhikari, Aasha
AU  - Adhikari A
AD  - Marburg Center of Mind, Brain, and Behavior-CMBB, Hans-Meerwein-Strasse 6, 35032 
      Marburg, Germany.
FAU - Maurer, Viktoria
AU  - Maurer V
AD  - Marburg Center of Mind, Brain, and Behavior-CMBB, Hans-Meerwein-Strasse 6, 35032 
      Marburg, Germany.
FAU - Steinhilber, Dieter
AU  - Steinhilber D
AD  - Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 
      Max-von-Laue-Str. 9, 60439 Frankfurt, Germany.
FAU - Culmsee, Carsten
AU  - Culmsee C
AUID- ORCID: 0000-0002-5121-5015
AD  - Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, 
      Karl-von-Frisch-Str. 2, 35043 Marburg, Germany.
AD  - Marburg Center of Mind, Brain, and Behavior-CMBB, Hans-Meerwein-Strasse 6, 35032 
      Marburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20230809
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC10451816
OTO - NOTNLM
OT  - ACSL4
OT  - GPx4
OT  - HEK293T cells
OT  - LPCAT2
OT  - RSL3
OT  - ferroptosis
OT  - lipid peroxidation
OT  - mitochondria
OT  - mitochondrial ROS
OT  - mitoquinone
COIS- The authors declare no conflict of interest.
EDAT- 2023/08/26 10:46
MHDA- 2023/08/26 10:47
PMCR- 2023/08/09
CRDT- 2023/08/26 01:07
PHST- 2023/07/24 00:00 [received]
PHST- 2023/08/02 00:00 [revised]
PHST- 2023/08/04 00:00 [accepted]
PHST- 2023/08/26 10:47 [medline]
PHST- 2023/08/26 10:46 [pubmed]
PHST- 2023/08/26 01:07 [entrez]
PHST- 2023/08/09 00:00 [pmc-release]
AID - antiox12081590 [pii]
AID - antioxidants-12-01590 [pii]
AID - 10.3390/antiox12081590 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2023 Aug 9;12(8):1590. doi: 10.3390/antiox12081590.