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

Cardioprotection by the mitochondrial unfolded protein response requires ATF5.

Author information

1
Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York.
2
Deaprtment of Medicine, University of Rochester Medical Center, Rochester, New York.
3
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York.
4
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.
5
Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.

Abstract

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

PMID:
31274354
PMCID:
PMC6732477
[Available on 2020-08-01]
DOI:
10.1152/ajpheart.00244.2019

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