ABSTRACT
Rationale The mitochondrial unfolded protein response (UPRmt) is a conserved signaling pathway triggered by mitochondrial dysfunction. The transcription factor ATF5 is proposed to be central to mammalian UPRmt signaling. We hypothesized that UPRmt activation may be cardioprotective against ischemia-reperfusion (IR) injury, and that this protection would require ATF5.
Objective To determine whether pharmacologic UPRmt activation protects mouse hearts from acute IR injury in an ATF5-dependent manner.
Methods and Results Loss of ATF5 did not affect baseline IR injury in an ex-vivo perfused heart model. However, in-vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h prior to ex-vivo IR injury was cardioprotective. Such protection was absent in hearts from Atf5-/- mice, as well as in hearts given doxycycline only during ex-vivo perfusion. Genes encoding known UPRmtlinked chaperones exhibited modest but significant cardiac induction by oligomycin after 6 h. In addition, cardiac gene expression analysis by RNA-Seq revealed mild induction of numerous genes in an ATF5-dependent manner, which may be important for cardioprotection.
Conclusion ATF5 is required for cardioprotection induced by drugs that activate the UPRmt.
