trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop

• Published in: Scientific reports Vol. 10; no. 1; p. 2743
• Main Authors: Hirata, Yusuke, Inoue, Aya, Suzuki, Saki, Takahashi, Miki, Matsui, Ryosuke, Kono, Nozomu, Noguchi, Takuya, Matsuzawa, Atsushi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.02.2020; Nature Publishing Group
• Subjects: 631/337/1427/2566; 631/45/275; 631/80/86/2366; 692/499; 82/29; 96/109; 96/2; 96/95; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - radiation effects; c-Jun protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins - antagonists & inhibitors; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cardiovascular diseases; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA damage; DNA Fragmentation - drug effects; DNA Fragmentation - radiation effects; Doxorubicin; Doxorubicin - pharmacology; Embryo, Nonmammalian; Embryos; Epidemiology; Fatty acids; Feedback; Feedback, Physiological; Food industry; Gene Expression Regulation; Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; HEK293 Cells; HeLa Cells; Homology; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Isomers; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Lethality; Linoleic Acid - pharmacology; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; Oleic Acids - pharmacology; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Protein-tyrosine-phosphatase; Proteins; RAW 264.7 Cells; Reactive oxygen species; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); SHP-1 protein; Transcription factors; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59636-6

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.