UCP2 silencing aggravates mitochondrial dysfunction in astrocytes under septic conditions

Abstract

Uncoupling protein 2 (UCP2) plays a positive role in sepsis. However, the role of UCP2 in experimental sepsis in astrocytes remains unknown. The present study was designed to determine whether UCP2 has a protective effect in an experimental sepsis model in astrocytes asnd to clarify the mechanisms responsible for its neuroprotective effects after sepsis. An experimental astrocyte model mimicking sepsis-induced brain injury was established using lipopolysaccharide (LPS) and interferon (IFN)-γ. Additionally, UCP2 knockdown in astrocytes was achieved by adenovirus transfection. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β activity, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels were assessed. The mitochondrial ultrastructure was evaluated, and the expression of UCP2 was determined by western blotting. LPS with IFN-γ co-stimulation increased the mRNA and protein expression levels of UCP2 in astrocytes, damaged the mitochondrial structure, and accelerated the release of TNF-α and IL-1β, resulting in a decrease in the MMP, and the excessive generation of ROS. Moreover, sepsis also caused a reduction in ATP production. The knockdown of UCP2 exacerbated astrocyte injury and mitochondrial impairment. In conclusion, both the function and morphology of mitochondria were damaged in an experimental model of sepsis in astrocytes, and knockdown of UCP2 using shRNA exacerbated this impairment, suggesting that UCP2 has a positive effect on astrocytes as determined in an experimental sepsis model.

Deletion of Mitochondrial Uncoupling Protein 2 Exacerbates Mitochondrial Damage in Mice Subjected to Cerebral Ischemia and Reperfusion Injury under both Normo- and Hyperglycemic Conditions

“…The impact of UCP2 on mitochondrial morphology of the brain tissue after cerebral ischemia and reperfusion has not been reported. Several studies have demonstrated that silencing UCP2 by small interference RNA resulted in more severe mitochondrial swelling, vacuolization and loss of matrix content in cardiomyocytic H9C2 cells and astrocytes compared with control cells challenged with sepsis [47,52,53]. These results support our finding that UCP2 plays an important role in maintaining mitochondrial dynamic and morphological integrity in the brain.…”

“…The slanting of the mitochondrial dynamics to fission may reduce the mitochondrial network and enhance mitochondrial rupture and induce neuronal cell death after cerebral ischemia [46]. UCP2 silencing has been shown to cause mitochondrial dysfunction in astrocytes under septic conditions [47]. However, it is not known whether UCP2 deletion affects the mitochondrial dynamics in astrocytes.…”

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

“…It is clear that more studies are needed to understand what are the differential elements in the response against MPTP intoxication in this species compared to other experimental models. An interesting line to explore could be the neuromelanin, calbindin or UCP2 content of these neurons [ 36 , 37 , 38 , 39 ]. Other emerging questions are the ones related to the catecholaminergic system: are other dopamine-innervated regions altered?…”

A systematic review on nephron protective AYUSH drugs as constituents of NEERI-KFT (A traditional Indian polyherbal formulation) for the management of chronic kidney disease

“…Increased ROS induces accumulation of uncoupling protein-2 (UCP2) interferes with ATP synthase and reduces ATP synthesis in renal tubular epithelial cells. The consequent reduction in ATP, autophagy induced apoptosis or necrosis occur followed by the formation of the apoptosome, activation of cytochrome C , caspase activation, and consequently apoptosis ( Duni et al, 2019 ), ( Granata et al, 2015 ), ( Peng et al, 2019 ).…”