Cardioprotection by the mitochondrial unfolded protein response requires ATF5

摘要

The mitochondrial unfolded protein response (UPR~mt) is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. UPR~mt 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 UPR~mt. Herein, we hypothesized pharmacological UPR~mt activation may protect against cardiac ischemia-reperfusion (I/R) injury in an ATF5-dependent manner. Accordingly, in vivo administration of the UPR~mt 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 UPR~mt activation was not cardioprotective, and loss of ATF5 did not impact baseline 1/R injury without UPR~mt induction. In vivo UPR~mt induction significantly upregulated many known UPR~mt-linked genes (cardiac quantitative PCR and Western blot analysis), and RNA-Seq revealed an UPR~mt-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 UPR~mt and the first demonstration that UPR~mt is a cardioprotective drug target.