Cardioprotection by the mitochondrial unfolded protein response requires ATF5

Am J Physiol Heart Circ Physiol. 2019 Aug 1;317(2):H472-H478. doi: 10.1152/ajpheart.00244.2019. Epub 2019 Jul 5.


The mitochondrial unfolded protein response (UPRmt) is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. UPRmt activation upregulates chaperones, proteases, antioxidants, and glycolysis at the gene level to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5) is a proposed mediator of the mammalian UPRmt. Herein, we hypothesized pharmacological UPRmt activation may protect against cardiac ischemia-reperfusion (I/R) injury in an ATF5-dependent manner. Accordingly, in vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h before ex vivo I/R injury (perfused heart) was cardioprotective in wild-type but not global Atf5-/- mice. Acute ex vivo UPRmt activation was not cardioprotective, and loss of ATF5 did not impact baseline I/R injury without UPRmt induction. In vivo UPRmt induction significantly upregulated many known UPRmt-linked genes (cardiac quantitative PCR and Western blot analysis), and RNA-Seq revealed an UPRmt-induced ATF5-dependent gene set, which may contribute to cardioprotection. This is the first in vivo proof of a role for ATF5 in the mammalian UPRmt and the first demonstration that UPRmt is a cardioprotective drug target.NEW & NOTEWORTHY Cardioprotection can be induced by drugs that activate the mitochondrial unfolded protein response (UPRmt). UPRmt protection is dependent on activating transcription factor 5 (ATF5). This is the first in vivo evidence for a role of ATF5 in the mammalian UPRmt.

Keywords: cardioprotection; chaperone; ischemia; metabolism; mitochondria; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factors / deficiency
  • Activating Transcription Factors / genetics
  • Activating Transcription Factors / metabolism*
  • Animals
  • Disease Models, Animal
  • Doxycycline / pharmacology*
  • Female
  • Gene Expression Regulation
  • Isolated Heart Preparation
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oligomycins / pharmacology*
  • Unfolded Protein Response / drug effects*


  • Activating Transcription Factors
  • Atf5 protein, mouse
  • Oligomycins
  • Doxycycline