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

Sci Rep. 2020 Feb 17;10(1):2743. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line, Tumor
  • DNA Fragmentation / drug effects*
  • DNA Fragmentation / radiation effects
  • Doxorubicin / pharmacology
  • Embryo, Nonmammalian
  • Feedback, Physiological
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Linoleic Acid / pharmacology*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • 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
  • RAW 264.7 Cells
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / metabolism*
  • Ultraviolet Rays


  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Guanine Nucleotide Exchange Factors
  • Oleic Acids
  • REI-1 protein, C elegans
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • SH3BP5 protein, human
  • elaidic acid
  • Doxorubicin
  • Linoleic Acid
  • JNK Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6