Activation of BNIP3-mediated mitophagy protects against renal ischemia–reperfusion injury

Abstract

Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia–reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.

Sulforaphane-cysteine inhibited migration and invasion via enhancing mitophagosome fusion to lysosome in human glioblastoma cells

“…Bnip3 is a proapoptotic atypical BH3-only protein that has been reported to induce apoptosis, necrosis, or autophagy relying on the type of stress and cellular context 43 . As a hallmark of mitophagy, upregulation of Bnip3 was associated with an increase of autophagy flux and mitochondrial protein degradation, as well as mitophagosome formation; loss of Bnip3 led to the accumulation of damaged mitochondria 44 . Bnip3 contributes to ischemia and reperfusion (I/ R) injury which triggers a protective stress response with upregulation of autophagy and removal of damaged mitochondria 45 .…”

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

“…Cardiomyocytes from mice subjected to high fat diet were shown to exhibit elevated levels of mitophagy to prevent cytotoxicity (Tong et al, 2019), although this resulted in reduced mitophagy in liver (Sun et al, 2015). Myocardial ischemia and energy stress (48 h starvation) have been shown to induce mitophagy in cardiomyocytes of mice, whereas ischemic preconditioning as well as ischemiareperfusion injury were shown to induce mitophagy in kidney and brain tissues Livingston et al, 2019;Saito et al, 2019;Tang et al, 2019). Hypoxic conditions also result in mitophagy induction in multiple tissues in mice and in various cell lines in vitro Allen et al, 2013;Sun et al, 2015, Zhang W. et al, 2016.…”

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…Central to OS is the release by impaired mitochondria of excessive reactive oxygen species (ROS) and apoptosisinducing factors, which, in turn, increases telomere consumption, arrests the cell cycle, activates signaling pathways such as protein 53 (P53) and protein 38 mitogen-activated protein kinase (P38MAPK), and leads to cellular-stress-induced apoptosis and senescence [13][14][15] . Mitophagy is the most important way to eliminate damaged mitochondria from cells [16][17][18] , it not only promotes mitochondrial renewal but also reduces excessive ROS and apoptosis-inducing factors released by the damaged mitochondria 19 . Therefore, normal mitophagy is essential for maintaining cell redox homeostasis and promoting cell survival under OS conditions.…”