AMPK: The key to ischemia‐reperfusion injury

Cai, Jie; Chen, Xinyue; Liu, Xingyu; Li, Zhangwang; Shi, Ao; Tang, Xiaoyi; Xia, Panpan; Zhang, Jing; Yu, Peng

doi:10.1002/jcp.30875

Cited by 33 publications

(24 citation statements)

References 155 publications

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“…[48] Importantly, AMPK activation could reduce the damage of I/R to the liver. [49] But previous studies pointed out that the AMPKmediated pathway may function primarily in macrophages instead of hepatocytes. [50][51][52] A better understanding of the regulatory network at single-cell level is key for further investigation.…”

Section: Discussionmentioning

confidence: 99%

Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

Fang

Zhang

et al. 2023

Advanced Science

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Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R‐induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+‐dependent malic enzyme 1 (Me1). Mice with hepatocyte‐specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L‐malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R‐induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)‐dependent suppression of the mechanistic target of rapamycin/sterol regulatory element‐binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over‐expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis‐related hepatic conditions.

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Section: Discussionmentioning

confidence: 99%

Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

Fang

Zhang

et al. 2023

Advanced Science

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“…It is known to regulate mitochondrial biogenesis, dynamics and mitophagy [ 75 ]. Its participation in these processes was found to be crucial for its role in the regulation of I/R injury [ 115 , 116 ]. However, the signaling pathways by which it contributes to the amelioration of LIRI are still being uncovered.…”

Section: Mitochondrial Function and Dynamics During Liver I/rmentioning

confidence: 99%

Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury

2023

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Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI.

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“…Neuroinflammation is the main cause of neurodegenerative diseases [29,64]. Activated glial cells release different pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS).…”

Section: Metformin-induced Ampk Activation Modulates Inflammatory Cyt...mentioning

confidence: 99%

Neuroprotective Role of Metformin in a Model of Cerebelar Ataxia

Atella,

Medina,

Atella

et al. 2023

Preprint

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Cerebellar ataxia is a heterogeneous group of neural disorders clinically characterized by cerebellar dysfunction. The diagnosis of patients with progressive cerebellar ataxia is complex due to the direct correlation with other neuron diseases. Although there is still no cure for this pathological condition, some metabolic, hereditary, inflammatory, and immunological factors affecting cerebellar ataxia are being studied and which may become therapeutic targets. Advances in studying the neuroanatomy, pathophysiology, and molecular biology of the cerebellum contributes to better understand the mechanisms behind the development of this disorder. In this study, we analyzed the neuromodulatory role of the AMP-activated protein kinase (AMPK) on cerebellar ataxia induced by the neurotoxin 3-acetylpyridine (3-AP) in brain stem and cerebellum, after pre-treatment with metformin, a pharmacological indirect activator of AMPK. The results shown here suggest that AMPK activation in the brain stem and cerebellum leads to a significant reduction in neuroinflammation in these regions. AMPK was able to restore the changes in fatty acid composition and pro-inflammatory cytokines caused by 3-AP, suggesting that the action of AMPK seems to result in a possible neuroprotection on the cerebellar ataxia model.

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AMPK: The key to ischemia‐reperfusion injury

Cited by 33 publications

References 155 publications

Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury

Neuroprotective Role of Metformin in a Model of Cerebelar Ataxia

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