Jian-Xing Liu1, Chen Yang1, Wei-Huang Zhang1, Hong-Yong Su1, Ze-Jian Liu1, Qingjun Pan2, Hua-Feng Liu3. 1. Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China. 2. Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China. Electronic address: pqj@gdmu.edu.cn. 3. Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China. Electronic address: hf-liu@263.net.
Abstract
AIMS: The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI). MAIN METHODS: In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point. KEY FINDINGS: The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly. SIGNIFICANCE: It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.
AIMS: The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI). MAIN METHODS: In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point. KEY FINDINGS: The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly. SIGNIFICANCE: It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.
Authors: Sebastien Preau; Dominique Vodovar; Boris Jung; Steve Lancel; Lara Zafrani; Aurelien Flatres; Mehdi Oualha; Guillaume Voiriot; Youenn Jouan; Jeremie Joffre; Fabrice Uhel; Nicolas De Prost; Stein Silva; Eric Azabou; Peter Radermacher Journal: Ann Intensive Care Date: 2021-07-03 Impact factor: 6.925