Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury

• Published in: Life sciences (1973) Vol. 235; p. 116828
• Main Authors: Liu, Jian-xing, Yang, Chen, Zhang, Wei-huang, Su, Hong-yong, Liu, Ze-jian, Pan, Qingjun, Liu, Hua-feng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.10.2019; Elsevier BV
• Subjects: acute kidney injury; adenosine triphosphate; Apoptosis; caspases; Cecum; Cell death; Damage accumulation; Diabetes mellitus; diabetic nephropathy; Dynamics; Energy demand; Fission; Fission and fusion; Injuries; Kidneys; mice; Mitochondria; Mitophagy; Nephropathy; Organic chemistry; Oxidative stress; Pathogenesis; Quality control; Reabsorption; renal tubules; resorption; Secretion; Sepsis; Septic acute kidney injury; therapeutics; Septic acute kidney injury; Mitochondria; Mitophagy; Apoptosis; Fission and fusion
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2019.116828

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). 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. 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. 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. Diagram of mitochondrial dynamics and mitophagy. Mitochondria are dynamic organelles that constantly undergo fusion and fission in healthy cells. Mitochondrial fusion is mediated by mitofusin1, mitofusion2, and OPA1, whereas fission mainly involves Drp1 and Fis1. Upon cellular stress, such as inflammation and ROS, mitochondria morphology and functions are altered, characterized by membrane disruption, increased permeability, reduced membrane potential, mitochondrial-associated pro-apoptotic protein activation, and ROS accumulation, increasing fission levels following activation of Drp1 and inhibition of OPA1. Activated fission or arrest fusion of mitochondria resulted in mitochondrial fragmentation. Fragmented mitochondria are sensitized to Bax insertion and oligomerization to induce the formation of pathological pores, i.e., mitochondrial outer membrane permeabilization, to trigger cell death. The fragmented mitochondria may be degraded by mitophagy to suppress cell death as a cytoprotective mechanism. Under physiological conditions, Pink1 is constitutively degraded and maintained at low levels in healthy mitochondria. When mitochondria damage results in depolarization of the membrane potential, the degradation of Pink1 is prevented, and the E3 ligase Parkin is recruited from the cytosol via Pink1 kinase activity. Finally, Parkin conjugates ubiquitin to various proteins on the outer mitochondrial membrane and mediates autophagic elimination of dysfunctional mitochondria. However, this cytoprotective mechanism may be overwhelmed in the presence of persistently high levels of pro-apoptotic proteins and accumulation of ROS. The increased expression of mitochondria-associated pro-apoptotic proteins, such as Bak and Bax activate the expression of caspase-3 to cleave Parkin, and ROS accumulation promotes the cleavage of Parkin by NLRP3-dependent caspase-1 and caspase-8, which together result in insufficient mitophagy. [Display omitted]