trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop
trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop
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DOI：
10.1038/s41598-020-59636-6
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发表时间：
2020-02-17
影响因子：
4.6
通讯作者：
Matsuzawa, Atsushi
中科院分区：
文献类型：
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作者：
Hirata, Yusuke;Inoue, Aya;Matsuzawa, Atsushi
反式脂肪酸（TFA）是含有一个或多个反式构型的碳-碳双键的不饱和脂肪酸。流行病学证据表明，反式脂肪酸的消费与各种疾病，包括心血管疾病。然而，潜在的病理机制在很大程度上是未知的。在这里，我们展示了一种新的毒性机制的TFAs引发的DNA损伤。我们发现，在工业食品制造过程中产生的主要TFAs（所谓的工业TFAs），但不是它们相应的顺式异构体，促进阿霉素诱导的细胞凋亡。因此，EA增强了UV诱导的C.蠕虫EA的促凋亡作用通过敲低Sab而被阻断，Sab是一种位于线粒体外膜的c-Jun N-末端激酶（JNK）相互作用蛋白，其介导线粒体活性氧（ROS）产生和JNK活化的相互放大。EA增强阿霉素诱导的线粒体ROS生成和JNK激活，这两者都被抑制的Sab敲低和药理学抑制线粒体ROS生成，JNK，或Src同源2结构域的蛋白酪氨酸磷酸酶1（SHP 1）作为一个Sab-associated蛋白。这些结果表明，响应于DNA损伤，TFA驱动线粒体JNK-Sab-ROS正反馈回路并最终导致细胞凋亡，这可能提供对多种TFA相关疾病的共同发病机制的见解。
trans-Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.