FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury

Abstract

The mitochondrial unfolded protein response (UPR^mt) is an adaptive transcriptional response involving the activation of proteases, chaperones, and antioxidant enzymes and serves to degrade abnormal or unfolded proteins and restore mitochondrial function. Although the cardioprotective action of the UPR^mt has been verified in myocardial ischemia/reperfusion (I/R) injuries, the upstream signals involved remain unclear. Here, we explored the regulatory mechanisms underlying UPR^mt in the reperfused mouse heart. UPR^mt was slightly activated by I/R injury. UPR^mt activation (using oligomycin) and inhibition (with the protease inhibitor AEBSF) respectively alleviated and augmented the reperfusion-mediated myocardial damage. Gene expression analysis demonstrated that oxidative stress was partly inhibited by UPR^mt through upregulation of mitochondria-localized, not cytoplasmic, antioxidant enzymes. Contributing to cardiomyocyte survival under I/R, the transcription of pro-apoptotic proteins Bcl2 and c-IAP was also stimulated by UPR^mt. Moreover, UPR^mt upregulated mitochondrial fusion-related, but not fission-related, genes and stimulated the expression of mitochondrial biogenesis markers in reperfused hearts. Finally, we found that FUN14 domain containing 1 (FUNDC1)-mediated mitophagy induces the mitochondrial DNA decrease, triggering UPR^mt. These results demonstrate that FUNDC1 functions upstream of the UPR^mt to maintain mitochondrial quality control during myocardial I/R injury.

Keywords: Cardiomyocyte; FUNDC1; Mitochondrial unfolded protein response; Mitophagy; Myocardial I/R injury.