Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage.
Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage.
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DOI：
10.1038/s41467-022-34262-0
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发表时间：
2022-11-25
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在西方国家，对乙酰氨基酚过量是导致急性肝衰竭和肝移植的主要原因之一。镁在几个细胞过程中是必不可少的。细胞周期蛋白M家族参与镁的跨细胞膜转运。本文中，我们发现在所有镁转运蛋白中，只有Cyclin M4在对乙酰氨基酚过量患者的肝脏中表达上调，并伴有血清镁水平紊乱。在肝脏中，对乙酰氨基酚通过Cyclin M4干扰线粒体镁库，影响ATP的产生和活性氧的产生，进一步加剧内质网应激。重要的是，Cyclin M4突变体T495I对镁通量没有影响。最后，在肝毒性下显示内质网中Cyclin M4的积累。根据我们对小鼠的研究，在对乙酰氨基酚过量摄入后6至24小时内沉默肝细胞周期蛋白M4可能是对乙酰氨基酚过量引起的肝损伤的治疗靶点。药物性肝损伤（DILI）是急性肝衰竭的重要原因。作者报告说，DILI患者以及对乙酰氨基酚过量治疗的临床前动物模型的血清Mg2+水平下降，并且针对Mg2+转运体Cyclin M4的早期干预可能对临床前模型的对乙酰氨基酚过量有益。
Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury. Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models.
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影响因子：
--
作者：
Borude P;Bhushan B;Apte U
通讯作者：
Apte U
DOI：
10.1016/bs.apha.2018.12.004
发表时间：
2019-01-01
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Fisher, Erik S;Curry, Steven C
通讯作者：
Curry, Steven C
DOI：
10.1016/j.bbamcr.2004.10.013
发表时间：
2005-05-15
影响因子：
5.1
作者：
Kubota, T;Shindo, Y;Oka, K
通讯作者：
Oka, K
影响因子：
16.6
作者：
Barbier-Torres L;Iruzubieta P;Fernández-Ramos D;Delgado TC;Taibo D;Guitiérrez-de-Juan V;Varela-Rey M;Azkargorta M;Navasa N;Fernández-Tussy P;Zubiete-Franco I;Simon J;Lopitz-Otsoa F;Lachiondo-Ortega S;Crespo J;Masson S;McCain MV;Villa E;Reeves H;Elortza F;Lucena MI;Hernández-Alvarez MI;Zorzano A;Andrade RJ;Lu SC;Mato JM;Anguita J;Rincón M;Martínez-Chantar ML
通讯作者：
Martínez-Chantar ML
影响因子：
29.4
作者：
Lee, William M.;Hynan, Linda S.;Robuck, Patricia R.
通讯作者：
Robuck, Patricia R.