MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis

Shi, Lang; Song, Zhixia; Li, Yuzhen; Huang, Jing; Zhao, Fan; Luo, Yanwen; Wang, Juan; Deng, Fangjing; Shadekejiang, Halinuer; Zhang, Mingjiao; Dong, Shengyu; Wu, Xiongfei; Zhu, Jiefu

doi:10.1016/j.ajt.2022.09.003

Cited by 28 publications

(12 citation statements)

References 47 publications

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“…An important downstream event of mitochondrial dysfunction is the activation of innate immune response, which is associated with the pathogenesis of IRI [ 28 , 44 , 45 ]. Mitochondrial damage and mtDNA leakage are frequently detected in various human diseases, particularly in cases of acute tissue injury [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury

Song,

Xia,

Shi

et al. 2024

Cell Mol Biol Lett

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Background Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. Methods We induced ischemia–reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. Results Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. Conclusions Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury

Song,

Xia,

Shi

et al. 2024

Cell Mol Biol Lett

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“…lncRNA TUG1 carried by human urine-derived stem cell (USC)-derived exosomes (USC-Exo) regulates ASCL4-mediated ferroptosis by interacting with SRSF1 and then protects against IRI-induced AKI [ 71 ]. In addition, Shi et al indicated that miR-20a-5p negatively regulated ACSL4 by targeting the 3’ UTR of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis and alleviating kidney IRI [ 72 ].…”

Section: Programmed Cell Death In Iri-akimentioning

confidence: 99%

The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives

Li,

Yu,

Zhu

et al. 2024

Cell Death Discov.

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Renal ischemia‒reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), which is a potentially life-threatening condition with a high mortality rate. IRI is a complex process involving multiple underlying mechanisms and pathways of cell injury and dysfunction. Additionally, various types of cell death have been linked to IRI, including necroptosis, apoptosis, pyroptosis, and ferroptosis. These processes operate differently and to varying degrees in different patients, but each plays a role in the various pathological conditions of AKI. Advances in understanding the underlying pathophysiology will lead to the development of new therapeutic approaches that hold promise for improving outcomes for patients with AKI. This review provides an overview of the recent research on the molecular mechanisms and pathways underlying IRI-AKI, with a focus on regulated cell death (RCD) forms such as necroptosis, pyroptosis, and ferroptosis. Overall, targeting RCD shows promise as a potential approach to treating IRI-AKI.

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“…Accumulating studies have shown that ferroptosis plays a role in the genesis of kidney diseases. 35 Accumulating evidence has shown epigenetic regulation of ferroptosis in kidney diseases, including acute kidney injury (AKI), 484 , 485 diabetic nephropathy (DN), 486 renal fibrosis, 487 renal IRI (RIRI), 488 – 492 sepsis-induced acute kidney injury (SAKI), 493 toxin-mediated kidney toxicity, 494 and crystal nephropathies. 495 Below, we summarize the epigenetic regulation of ferroptosis by phosphorylation, ncRNAs, deacetylation, and ubiquitination in kidney diseases (Table 12 and Fig.…”

Section: Epigenetic and Posttranslational Modifications Regulating Fe...mentioning

confidence: 99%

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Wang,

Hu,

et al. 2023

Sig Transduct Target Ther

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Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

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MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis

Cited by 28 publications

References 47 publications

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury

The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

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