Thioredoxin 1 promotes autophagy through transnitrosylation of Atg7 during myocardial ischemia

J Clin Invest. 2023 Feb 1;133(3):e162326. doi: 10.1172/JCI162326.


Modification of cysteine residues by oxidative and nitrosative stress affects structure and function of proteins, thereby contributing to the pathogenesis of cardiovascular disease. Although the major function of thioredoxin 1 (Trx1) is to reduce disulfide bonds, it can also act as either a denitrosylase or transnitrosylase in a context-dependent manner. Here we show that Trx1 transnitrosylates Atg7, an E1-like enzyme, thereby stimulating autophagy. During ischemia, Trx1 was oxidized at Cys32-Cys35 of the oxidoreductase catalytic center and S-nitrosylated at Cys73. Unexpectedly, Atg7 Cys545-Cys548 reduced the disulfide bond in Trx1 at Cys32-Cys35 through thiol-disulfide exchange and this then allowed NO to be released from Cys73 in Trx1 and transferred to Atg7 at Cys402. Experiments conducted with Atg7 C402S-knockin mice showed that S-nitrosylation of Atg7 at Cys402 promotes autophagy by stimulating E1-like activity, thereby protecting the heart against ischemia. These results suggest that the thiol-disulfide exchange and the NO transfer are functionally coupled, allowing oxidized Trx1 to mediate a salutary effect during myocardial ischemia through transnitrosylation of Atg7 and stimulation of autophagy.

Keywords: Autophagy; Cardiology; Cell Biology; Hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Cysteine / metabolism
  • Disulfides
  • Mice
  • Myocardial Ischemia* / genetics
  • Oxidation-Reduction
  • Thioredoxins* / genetics
  • Thioredoxins* / metabolism


  • Atg7 protein, mouse
  • Autophagy-Related Protein 7
  • Cysteine
  • Disulfides
  • Thioredoxins
  • Txn1 protein, mouse