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

Selective brain hypothermia ameliorates focal cerebral ischemia-reperfusion injury via inhibiting Fis1 in rats

“…Furthermore, mitochondrial ultrastructural analysis revealed that at 24 h after reperfusion, the level of mitochondrial fission was lower in the HT group than in the I/R group and NT group. Combined with our present research and a previous report [17], we hypothesized that SBH could down-regulate the expression of Fis1 in the mitochondrial outer membrane, inhibiting excessive mitochondrial fission induced by the binding of Drp1 to Fis1, reducing the cytosolic release of Cyto c and eventually ameliorating cellular apoptosis.…”

“…General hypothermia can attenuate mitochondrial oxidative stress and reduce mitochondrial membrane permeability [39,40]. In addition, in our previous study, general hypothermia reduced mitochondrial fission by inhibiting the translation of Drp1 from the cytoplasm to the mitochondrial outer membrane [17]. Drp1 is mainly localized to the cytoplasm, and mitochondrial fission is inhibited in cells with Fis1 deletion mutations [16].…”

“…Hypothermia may be the most potent neuroprotective strategy that can affect multiple pathways at various stages of ischemic stroke, such as calcium overload, oxidative stress, mitochondrial dysfunction, and apoptosis. According to our previous study, general hypothermia-induced neuroprotective effects against cerebral I/R injury are associated with suppressing mitochondrial fission by inhibiting the translocation of Drp1 from the cytoplasm to mitochondria in mice [17]. However, compared with general hypothermia, selective brain hypothermia (SBH) is strongly expected to become a novel attractive treatment for ischemic stroke due to its rapid cooling action and fewer systemic side effects [18,19].…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In neurons, protein kinase A (PKA)-mediated Drp1 phosphorylation of a highly conserved serine residue (S637 in human Drp1 isoform 1), inhibits Drp1 function and mitochondrial fission, whereas dephosphorylation of this residue has the opposite effect (Cribbs and Strack, 2007;Chang and Blackstone, 2007;Cereghetti et al, 2008). By contrast, phosphorylation of Drp1 at S616 by cyclin dependent kinases, protein kinase C (PKC) or extracellular signal regulated kinases (ERKs) (Lee and Yoon, 2014), has been shown to promote Drp1 activity and mitochondrial fragmentation in mitotic cells, as well as in neurons Tang et al, 2016). In addition to phosphorylation of Drp1, nitrosylation of its cysteine residue 644 triggered by nitric oxide (NO), has been suggested to facilitate Drp1-mediated mitochondrial fission and neuronal death in Alzheimer's disease (AD) Cho et al, 2009) and Huntington's disease (HD) (Haun et al, 2013).…”

Phosphoregulation of DRP1 at the mitochondria in vivo regulates ischemic sensitivity in the brain and memory

“…Phosphorylation of a highly conserved serine residue (S637 in human isoform 1, S656 in rat isoform 1), targeted by protein kinase A (PKA) in neurons, inhibits Drp1's GTPase function and mitochondrial fission, while dephosphorylation of this residue has the opposite effect promoting Drp1 localization to mitochondria and fission (Chang and Blackstone 2007, Cribbs and Strack 2007, Cereghetti, Stangherlin et al 2008. Conversely, phosphorylation of S616 (human isoform 1) by cyclin dependent kinases, as well as protein kinase C (PKC) and extracellular signal regulated kinase (ERK) (Lee and Yoon 2014), has been shown to promote Drp1 activity and mitochondrial fragmentation in mitotic cells, as well as in neurons (Cho, Cho et al 2014, Tang, Liu et al 2016. In addition to phosphorylation, nitrosylation of cysteine 644 on Drp1, triggered by nitric oxide (NO), has been suggested to facilitate Drp1-mediated mitochondrial fission and neuron death in Alzheimer's Disease (AD) (Cho, Nakamura et al 2009, Nakamura, Cieplak et al 2010) and…”