The release of Cyt C from damaged mitochondria no doubt plays a central role in mediating caspase activation during apoptosis [
58]. The common view is that the influence of Bcl-2 family members on apoptosis is also based on their ability to regulate the permeability of mitochondrial membranes to ions and proteins [
59]. The Bcl-2 family includes anti-apoptotic proteins such as Bcl-xl and Bcl-2 and pro-apoptotic proteins such as Bax, Bak, and Bad. [
60]. The activation of Bax or Bak can induce Cyt C release, while the inhibition of Cyt C release by Bcl-2 and Bcl-xl is also well recognized. MSCs are able to secrete a series of cytokines and trophic growth factors, including hepatocyte growth factor (HGF) [
61], vascular endothelial growth factor (vEGF) [
62], and insulin-like growth factor-1 (IGF-1) [
63], which may upregulate anti-apoptotic proteins, downregulate pro-apoptotic proteins, reduce Cyt C release and finally minimize mitochondrial injury during AKI. In a glycerol-induced AKI model, treatment with MSCs increased ATP production, decreased ROS levels, decreased the expression of mitochondrial apoptosis-related proteins and reduced tubular epithelial cell apoptosis, revealing the beneficial effects of MSCs in attenuating mitochondrial respiratory function and relieving renal injury [
64]. Peng et al. transplanted MSCs into cisplatin-induced AKI rats. They found that the mechanism underlying the renal protective effects of infused MSCs might come from the reduced release of Cyt C from the mitochondria into the cytoplasm and the reduced level of malondialdehyde (MDA), indicating that MSCs can protect renal cells from mitochondrial-related apoptosis and oxidative damage [
65]. Similarly, after injection with bone marrow MSCs-derived conditioned medium, cisplatin-induced AKI rats had reduced mitochondrial ROS levels and improved tubular cell morphology. The authors also confirmed that the beneficial effects were mediated by the activation of the wnt4/β-catenin pathway [
66].
As mentioned above, mitochondrial fission is an important pathophysiological change during AKI and results in the leakage of apoptosis-related substances. Thus, the inhibition of mitochondrial fission could be another therapeutic target in AKI. Previous studies have demonstrated the beneficial role of mdivi-1, which is a pharmacologic DRP1 inhibitor, in blocking mitochondrial fragmentation and protecting kidneys against AKI [
12,
43]. In addition to mdivi-1, miR-30 is also involved in the process of mitochondrial homeostasis by blocking DRP1 activation. Alleviation of mitochondrial fission through the miR-30/DRP1 pathway has been observed in myocardial tissues [
67]. Based on this fact, Gu et al. conducted a series of studies to test the role of MSCs in the regulation of mitochondrial fission via the miR-30/DRP1 pathway. They applied extracellular vesicles derived from human Wharton Jelly MSCs (hWJMSCs) in a rat model of unilateral I/R AKI. Enhanced expression of miR-30, deactivation of DRP1, alleviation of mitochondrial fragmentation and reduction of cell apoptosis were observed, suggesting that MSCs might be involved in the modulation of mitochondrial fission via miR-30, thereby protecting the kidney from injury [
68].