ArticleNeurochemical research2018
NR4A1 Promotes Cerebral Ischemia Reperfusion Injury by Repressing Mfn2-Mediated Mitophagy and Inactivating the MAPK-ERK-CREB Signaling Pathway.
Article in Neurochemical research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 83 citations in OpenAlex.
- HPC restores mitochondrial homeostasis and ameliorates hypoxic stress through the GSK-3β/β-catenin signaling pathway.Cell death & disease · 2026Article
- Protein Phosphatase 1 Regulatory Subunit 17 (PPP1R17) Regulates Cerebral Ischemia and Ischemia-Reperfusion Brain Injury by Suppressing YAP1-Mediated Mitophagy.Molecular neurobiology · 2025Article
- Controversy and multiple roles of the solitary nucleus receptor Nur77 in disease and physiology.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of osteosarcoma cells.European journal of medical research · 2025Article
- Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) Promotes the Adipogenesis of Intramuscular Preadipocytes through PI3K/AKT Pathway in Goats.Animals : an open access journal from MDPI · 2024Article
- Analysis of the mechanism ofThe Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2024Article
- The mitochondria as a potential therapeutic target in cerebral I/R injury.Frontiers in neuroscience · 2024Review
- MAM-mediated mitophagy and endoplasmic reticulum stress: the hidden regulators of ischemic stroke.Frontiers in cellular neuroscience · 2024Review
- Enhancing mitophagy by ligustilide through BNIP3-LC3 interaction attenuates oxidative stress-induced neuronal apoptosis in spinal cord injury.International journal of biological sciences · 2024Article
- Protective mechanisms of quercetin in neonatal rat brain injury induced by hypoxic-ischemic brain damage (HIBD).Food science & nutrition · 2023Article
- NR4A1 Aggravates Myocardial Ischaemia-Reperfusion Injury by Inhibiting OPA1-Mediated Mitochondrial Fusion.Journal of cardiovascular translational research · 2023Article
- Z-ligustilide preferentially caused mitochondrial dysfunction in AML HL-60 cells by activating nuclear receptors NUR77 and NOR1.Chinese medicine · 2023Article
- lncRNA and circRNA expression profiles in the hippocampus of AβExperimental and therapeutic medicine · 2023Article
- The critical role of the endolysosomal system in cerebral ischemia.Neural regeneration research · 2023Review
- Oridonin ameliorates caspase-9-mediated brain neuronal apoptosis in mouse with ischemic stroke by inhibiting RIPK3-mediated mitophagy.Acta pharmacologica Sinica · 2023Article
- Targeting neuronal mitophagy in ischemic stroke: an update.Burns & trauma · 2023Review
- Inhibition of Prostaglandin E2 Receptor EP3 Attenuates Oxidative Stress and Neuronal Apoptosis Partially by Modulating p38MAPK/FOXO3/Mul1/Mfn2 Pathway after Subarachnoid Hemorrhage in Rats.Oxidative medicine and cellular longevity · 2022Article
- Quercetin Mitigates Methamphetamine-Induced Anxiety-Like Behavior Through Ameliorating Mitochondrial Dysfunction and Neuroinflammation.Frontiers in molecular neuroscience · 2022Article
- Mitochondria-associated endoplasmic reticulum membranes and cardiac hypertrophy: Molecular mechanisms and therapeutic targets.Frontiers in cardiovascular medicine · 2022Review
- Mitochondrial Quality Control in Cardiac-Conditioning Strategies against Ischemia-Reperfusion Injury.Life (Basel, Switzerland) · 2021Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial dysfunction has been acknowledged as the key pathogenic mechanism in cerebral ischemia-reperfusion (IR) injury. Mitophagy is the protective system used to sustain mitochondrial homeostasis. However, the upstream regulator of mitophagy in response to brain IR injury is not completely understood. Nuclear receptor subfamily 4 group A member 1 (NR4A1) has been found to be associated with mitochondrial protection in a number of diseases. The aim of our study is to explore the functional role of NR4A1 in cerebral IR injury, with a particular focus on its influence on mitophagy. Wild-type mice and NR4A1-knockout mice were used to generate cerebral IR injury in vivo. Mitochondrial function and mitophagy were detected via immunofluorescence assays and western blotting. Cellular apoptosis was determined via MTT assays, caspase-3 activity and western blotting. Our data revealed that NR4A1 was significantly increased in the reperfused brain tissues. Genetic ablation of NR4A1 reduced the cerebral infarction area and repressed neuronal apoptosis. The functional study demonstrated that NR4A1 modulated cerebral IR injury by inducing mitochondrial damage. Higher NR4A1 promoted mitochondrial potential reduction, evoked cellular oxidative stress, interrupted ATP generation, and initiated caspase-9-dependent apoptosis. Mechanistically, NR4A1 induced mitochondrial damage by disrupting Mfn2-mediated mitophagy. Knockdown of NR4A1 elevated Mfn2 expression and therefore reversed mitophagic activity, sending a prosurvival signal for mitochondria in the setting of cerebral IR injury. Further, we demonstrated that NR4A1 modulated Mfn2 expression via the MAPK-ERK-CREB signaling pathway. Blockade of the ERK pathway could abrogate the permissive effect of NR4A1 deletion on mitophagic activation, contributing to neuronal mitochondrial apoptosis. Overall, our results demonstrate that the pathogenesis of cerebral IR injury is closely associated with a drop in protective mitophagy due to increased NR4A1 through the MAPK-ERK-CREB signaling pathway.
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