Cardioprotection by the mitochondrial unfolded protein response requires ATF5

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 I/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. NEW & NOTEWORTHY Cardioprotection can be induced by drugs that activate the mitochondrial unfolded protein response (UPR mt ). UPR mt protection is dependent on activating transcription factor 5 (ATF5). This is the first in vivo evidence for a role of ATF5 in the mammalian UPR mt .