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

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.Unlabelled Image