Drp1 in Ischemic Neuronal Death: An Unusual Suspect

Abstract

Mitochondria play a crucial role in multitude of cellular processes including energy production, calcium signaling, and apoptosis. This remarkable organelle constantly undergoes a complex cycle of fusion and fission, a crucial quality control system for maintaining homeostasis of the cell. Any impairment in this dynamic behavior is linked to a wide range of cellular abnormalities. Consistent with this concept, neuronal apoptosis often emanates in conjunction with rampant mitochondrial fragmentation. The mitochondrial dynamics are tightly regulated by a master mediator called Dynamin related protein 1 (Drp1), which in normal conditions facilitates mitochondrial fission. However, diverse stress conditions induce intensified translocation of cytosolic Drp1 to the mitochondria, contributing excessive fragmentation and concomitant apoptosis. Despite this knowledge, crucial questions such as how fission of the inner and outer mitochondrial membranes is coordinated and how these processes are linked to apoptosis and necrosis remain to be answered. This review focuses on delineating the mechanism of Drp1 activation and explores the pathophysiological importance of dysregulated mitochondrial fission with a special emphasis on ischemic stroke. Further, it also provides a new mechanistic link between ischemia and Drp1-mediated mitochondrial fission.

Hypothermia-induced ischemic tolerance is associated with Drp1 inhibition in cerebral ischemia-reperfusion injury of mice

“…It is noteworthy that previous studies have indicated that hypothermia and Drp1 inhibition both have similar beneficial effects such as reduction of mitochondrial membrane potential (MMP), calcium mobilization, ROS production, cytochrome c release and caspase activation (Gong et al, 2013;Grohm et al, 2012;Zhao et al, 2005). Some studies have reported that hypothermia reduced expression of p53 (Zhang et al, 2010), which is able to upregulate Drp1 expression at both mRNA and protein levels (Pradeep et al, 2014). In addition, hypothermia reduced Bax expression (Wu and Wang, 2011), which are proapoptotic proteins of Bcl-2 family and triggers for Drp1 activation (Pradeep et al, 2014).…”

“…Some studies have reported that hypothermia reduced expression of p53 (Zhang et al, 2010), which is able to upregulate Drp1 expression at both mRNA and protein levels (Pradeep et al, 2014). In addition, hypothermia reduced Bax expression (Wu and Wang, 2011), which are proapoptotic proteins of Bcl-2 family and triggers for Drp1 activation (Pradeep et al, 2014). So could hypothermia might inhibit Drp1 partially through hypothermia-reduced P53/Bax pathway?…”

“…Notably, growing evidences indicated that mitochondria undergo rapid and extensive mitochondrial fission at an early stage during apoptosis (Bossy-Wetzel et al, 2003;Castanier and Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/brainres Arnoult, 2010;Su et al, 2010). Mitochondrial fission are tightly regulated by a master mediator called Dynamin related protein 1 (Drp1), a certain dynamin-related GTPases, which in normal conditions facilitates mitochondrial fission (Pradeep et al, 2014). Diverse stress induce intensified translocation of cytosolic Drp1 to the mitochondria, contributing mitochondrial fragmentation, ROS generation, Cytochrome C (Cyto C) cytosolic release and activation of caspase-3,-9, culminating in neuronal death.…”

“…Relevant to cerebral ischemia, p-Drp1 S616 has been reported to elevated after transient global ischemia (Chen et al, 2015). Many study groups suggested that Drp1 inhibition provided neuroprotection after IR injury (Disatnik et al, 2013;Grohm et al, 2012;Sharp et al, 2014;Zhang et al, 2013;Pradeep et al, 2014). It was reported that Drp1 siRNA preserved mitochondrial morphology.…”

Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia

“…These findings support the hypothesis that a mitochondrial mechanism may underlie the sex differences in long-term neurobehavioral outcome observed following HI. Mitochondrial fission (or fragmentation) (Pradeep et al, 2014; Zhang et al, 2015; Owens et al, 2015a) and autophagy (Weis et al, 2014; Li et al, 2015; Yu et al, 2015) are known to occur following cerebral ischemia–reperfusion injury. It is hypothesized that mitochondrial fragmentation segregates oxidatively modified mitochondrial proteins for elimination via mitochondrial-specific autophagy (mitophagy) (Twig et al, 2008; Soubannier et al, 2012; Norton et al, 2014).…”