Deletion of mitochondrial uncoupling protein 2 exacerbates mitophagy and cell apoptosis after cerebral ischemia and reperfusion injury in mice

Abstract

Objective: Uncoupling protein 2 (UCP2) is a member of inner mitochondrial membrane proteins and deletion of UCP2 exacerbates brain damage after cerebral ischemia/reperfusion (I/R). Nevertheless, its functional role during cerebral I/R is not entirely understood. The objective of present study was to explore the influence of UCP2 deletion on mitochondrial autophagy (mitophagy) and mitochondria-mediated cell death pathway after cerebral I/R. Methods: UCP2-/-and wildtype (WT) mice were subjected to 60 min middle cerebral artery occlusion (MCAO) and allowed reperfusion for 24 hours. Infarct volume and histological outcomes were assessed, reactive oxygen species (ROS) and autophagy markers were measured, and mitochondrial ultrastructure was examined. Results: Deletion of UCP2 enlarged infarct volume, increased numbers of necrotic and TUNEL positive cells, and significantly increased pro-apoptotic protein levels in UCP2-/-mice compared with WT mice subjected to the same duration of I/R. Further, deletion of UCP2 increased ROS production, elevated LC3, Beclin1 and PINK1, while it suppressed p62 compared with respective WT ischemic controls. Electron microscopic study demonstrated the number of autophagosomes was higher in the UCP2-/-group, compared with the WT group. Conclusions: It is concluded that deletion of UCP2 exacerbates cerebral I/R injury via reinforcing mitophagy and cellular apoptosis in mice.

Uncoupling Protein 2 Deficiency Enhances NLRP3 Inflammasome Activation Following Hyperglycemia-Induced Exacerbation of Cerebral Ischemia and Reperfusion Damage In Vitro and In Vivo

“…Studies have confirmed that the upregulation of UCP2 can reduce ROS production in cerebral I/R damage [33]. Our previous study showed that UCP2 deficiency increased ROS production after cerebral I/R damage [34]. Taken together, the present study suggests that UCP2 deficiency enhances NLRP3 inflammasome activation by increasing ROS production in the context of hyperglycemia-exacerbated I/R damage.…”

An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation

“…From this perspective, it would be important to broad our knowledge by investigating the fine mechanisms of action of UCP2. In this regard, a link between UCP2 protection and autophagy stimulation has recently emerged with particular regard to cardiomyopathies, including ischemia/reperfusion (I/R) injury and cardiac hypertrophy, acute kidney injury and cerebral ischemia [13][14][15][16][17][18].…”

Connexin 43 in Mitochondria: What Do We Really Know About Its Function?

“…The occurrence of mild mitochondrial uncoupling secondary to changes in Cx43 hemichannels may have consequences on reactive oxygen species (ROS) generation ( Cadenas, 2018 ) and mitophagy ( He et al, 2020 ). Indeed, isolated cardiomyocytes from Cx43-deficient mice become resistant to protection by the ATP-dependent potassium channel opener diazoxide due to impaired mitochondrial ROS production ( Heinzel et al, 2005 ), whereas induction of Cx43 hemichannel permeability by nitric oxide donors increases ROS production in cardiac SSM ( Soetkamp et al, 2014 ).…”