LAUSR

It has been suggested that mitochondrial dysfunction underlies the myocardial injury seen following cardiorenal syndrome type 3 (CRS-3). Both mitophagy and the mitochondrial unfolded protein response (UPRmt) are protective programs that preserve mitochondrial homeostasis. Here, we explored whether Bax inhibitor-1 (BI-1) overexpression attenuates CRS-3-related myocardial injury through activation of mitophagy and the UPRmt in cardiomyocytes. Following CRS-3 induction via renal ischemia-reperfusion injury, BI-1 transgenic (BI1TG) mice showed greater preservation of myocardial integrity and relaxation function and less cardiomyocyte apoptosis than wild-type (WT) mice. Moreover, BI-1 overexpression attenuated CRS-3-mediated myocardial inflammation, as indicated by decreased MCP-1 and IL-6 expression and normalized ATP production in cardiomyocytes. After CRS-3 induction, mitophagy was inhibited in cardiomyocytes from WT mice, as indicated by both decreased Fundc1 transcription and mt-Keima fluorescence, and modest activation of the UPRmt, denoted by a slight increase in Atf6 mRNA levels. By contrast, activation of mitophagy and marked UPRmt upregulation were observed in cardiac tissue from BI1TG mice. shRNA-mediated silencing of Fundc1 or Atf6 greatly impaired mitochondrial metabolism and survival in cultured cardiomyocytes overexpressing BI-1. Thus, upregulation of BI-1 expression aimed at activating mitophagy and the UPRmt may represent a useful therapeutic approach for the treatment of CRS-3.