Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury
Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury
复制标题
通过抑制 VDAC1 寡聚化保护线粒体可减轻对乙酰氨基酚诱导的急性肝损伤中的铁死亡
DOI：
10.1007/s10565-021-09624-x
复制
发表时间：
2021-08-17
影响因子：
6.1
通讯作者：
Li, Xiaobo
中科院分区：
文献类型：
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作者：
Niu, Baolin;Lei, Xiaohong;Li, Xiaobo
对乙酰氨基酚（APAP）过量是药物性肝损伤（DILI）的常见原因。最近发现APAP诱导的肝损伤（AILI）与铁凋亡有关。然而，线粒体在APAP诱导的铁凋亡中的功能作用和潜在机制尚不清楚。在这项研究中，通过尾静脉向APAP损伤的小鼠注射电压依赖性阴离子通道（VDAC）寡聚化抑制剂VBIT-12和铁凋亡抑制剂。利用靶向代谢组学和非靶向脂质组学分析来探索APAP诱导的线粒体功能障碍和随后的铁凋亡的潜在机制。因此，APAP过量导致通常在铁凋亡中观察到的特征性变化。铁凋亡抑制剂ferrostatin-1（或UAMC 3203）和铁螯合剂去铁胺的使用进一步证实了铁凋亡是AILI的原因。与三羧酸循环和脂肪酸β-氧化抑制相关的线粒体功能障碍可能驱动APAP诱导的肝细胞铁凋亡。APAP过量诱导肝细胞中VDAC 1寡聚化，并且通过VBIT-12保护线粒体减轻APAP诱导的铁凋亡。在APAP诱导的肝细胞铁凋亡中，神经酰胺和心磷脂水平通过UAMC 3203或VBIT-12增加。分别负责神经酰胺和心磷脂合成的Smpd 1和Taz表达的敲低，加重了APAP诱导的肝细胞线粒体功能障碍和铁凋亡，而Tazo过表达则保护了这些过程。通过免疫组化染色，我们发现与自身免疫性肝病、慢性病毒性肝炎B和非酒精性脂肪性肝病（NAFLD）患者相比，DILI患者肝活检样本中4-羟基壬烯醛（4-HNE）蛋白加合物水平升高。总之，通过抑制VDAC 1寡聚化来保护线粒体，通过恢复AILI中的神经酰胺和心磷脂含量来减轻肝细胞铁凋亡。
Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid β-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown ofSmpd1andTazexpression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereasTazoverexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.Graphical abstract