Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury

Abstract

Objective Cisplatin, an anticancer drug, always lead to nephrotoxicity via causing mitochondrial dysfunction. As a major catabolic pathway, autophagy has been proved that could protect against cisplatin‐induced acute kidney injury (AKI). Base on the activation of autophagy induced by trehalose, we aimed to investigated whether trehalose could alleviate mitochondrial dysfunction and kidney injury in mice though autophagy‐lysosome mediated clearance of damaged mitochondria. Methods Mice were administered a single intraperitoneal (i.p.) injection of cisplatin 16mg/kg to induce AKI, then mice were treated with PBS or trehalose (i.p.). In vitro, HK2 cells were treated with cisplatin 16mg/kg in the presence or absence of trehalose. To evaluate mitochondrial bioenergetic, mitochondrial morphology, membrane potential and ATP content were detected. Results In vivo, comparing with the normal mice, BUN and Crea were significantly increased in AKI mice, while decreased after the treatment with trehalose, indicating that trehalose could alleviate kidney injury in AKI mice. In vitro, along with the activation of autophagy (elevated expression of LC3 II and ATG5), mitochondrial fragmentation, depolarization, and reduced ATP generation induced by cisplatin were markedly inhibited in trehalose‐treated HK2 cells. Moreover, the double immunofluorescence staining results showed that the co‐localization between mitochondria and LC3 was increased, indicating that the mitophagy was induced. In addition, we found that the protective effect of trehalose was largely abolished when the autophagy process was inhibited by HCQ. Conclusion These results indicated that trehalose can ameliorate cisplatin‐induced mitochondrial dysfunction by activating autophagy, and thus it might be a promising therapy to acute kidney injury. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanisms and Functions of Mitophagy and Potential Roles in Renal Disease

“…Hence, pharmacological augmentation of mitophagy represents a promising therapeutic strategy for patients with impaired kidney function. Compounds, including activators of PINK1/Parkin or Nrf2 (e.g., metformin, MitoQ, and CoQ10) and TFEB activator trehalose, have been confirmed to increase mitophagy in experimental DKD or AKI (Song et al, 2016b;Xiao et al, 2017;Sun et al, 2019;Zhu et al, 2020), providing substantial evidence in future clinical research. A recent study reports that dietary supplementation with spermidine conveys cardioprotective effects through activation of mitophagy and ameliorates renal injury via the induction of autophagy in salt-induced hypertension rodent models (Eisenberg et al, 2016).…”

“…Whether antimycin A and myxothiazol induce mitophagy by promoting Parkin activity through p53 downregulation in RTECs remains unclear, and should be investigated further. A recent study by Zhu et al (2020) demonstrated that trehalose administration attenuates mitochondrial dysfunction through activating transcriptional factor EB (TFEB)-mediated autophagy and mitophagy in cisplatin-induced AKI in vitro and in vivo. The study sheds lights on the roles of TFEB on mitophagy and provides a novel promising therapeutic target for AKI.…”

Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance

“…Renal tissues were stained with MitoSOX as previous described 23 , 24 . Briefly, the fresh renal tissues removed from the mice were immediately frozen and cut into 5-µm-thick sections.…”

“…Ultrathin sections prepared from the embedded tissues were stained with 5% uranyl acetate and lead citrate solution and observed by TEM (H-600, Hitachi, Ltd., Tokyo, Japan). Mitochondrial length/width ratio and average area were measured using ImageJ software (NIH, MD, USA) as previously described 24 , 25 . In brief, ~15 mitochondria in each image were randomly selected, and the mitochondrial length and width were traced and measured using the Length parameter; mitochondrial area was measured using the Area parameter.…”

Selective autophagy of intracellular organelles: Recent research advances

“…Interestingly, the role of TFEB in lipid catabolism is evolutionary conserved because the loss-of-function of HLH-30 (worm ortholog of TFEB) also results in impaired lipophagy 309 , 312 . It has been revealed that trehalose treatment alleviates the mitochondrial dysfunction and attenuates cisplatin-induced kidney injury by activation of TFEB-mediated autophagy 313 . Therefore, alternative strategies, such as inducing TFEB activity for only limited periods or enhancing only specific subsets of the TFEB-regulated gene network, should be considered when using TFEB as a therapeutic tool.…”