Attenuation of mitochondrial and nuclear p38α signaling

A novel mechanism of estrogen neuroprotection in cerebral ischemia

Dong Han, Erin L. Scott, Yan Dong, Limor Raz, Ruimin Wang, Quanguang Zhang

Research output: Contribution to journalReview article

20 Citations (Scopus)

Abstract

P38 mitogen-activated protein kinase (MAPK) is a pro-apoptotic and pro-inflammatory protein that is activated in response to cellular stress. While p38 is known to be activated in response to cerebral ischemia, the precise role of p38 and its isoforms in ischemia-induced neuronal apoptosis remains unclear. In the current study, we examined the differential activation and functional roles of p38α and p38β MAPK isoforms in short-term ovariectomized female rats treated with either the neuroprotective ovarian hormone 17beta-estradiol (E2) or placebo in a model of global cerebral ischemia (GCI). GCI induced biphasic activation of total p38 in the hippocampal CA1, with peaks at 30 min and 1 day after 10-min ischemia-reperfusion. Further study demonstrated that activated p38α, but not p38β, translocated to the nucleus 30 min and 3 h post reperfusion, and that this event coincided with increased phosphorylation of activating transcription factor 2 (ATF2), a p38 target protein. Intriguingly, activated p38α was also enhanced in mitochondrial fractions of CA1 neurons 1 day after GCI, and there was loss of mitochondrial membrane potential, as well as enhanced cytochrome c release and caspase-3 cleavage at 2 days post GCI. Importantly, E2 prevented the biphasic activation of p38, as well as both nuclear and mitochondrial translocation of p38α after GCI, and these findings correlated with attenuation of mitochondrial dysfunction and delayed neuronal cell death in the hippocampal CA1. Furthermore, administration of a p38 inhibitor was able to mimic the neuroprotective effects of E2 in the hippocampal CA1 region by preventing nuclear and mitochondrial translocation of p38α, loss of mitochondrial membrane potential, and neuronal apoptosis. As a whole, this study suggests that changes in subcellular localization of the activated p38α isoform are required for neuronal apoptosis following GCI, and that E2 exerts robust neuroprotection, in part, through dual inhibition of activation and subcellular trafficking of p38α.

Original languageEnglish (US)
Pages (from-to)21-31
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume400
DOIs
StatePublished - Jan 5 2015

Fingerprint

Brain Ischemia
Estrogens
Chemical activation
Protein Isoforms
p38 Mitogen-Activated Protein Kinases
Apoptosis
Activating Transcription Factor 2
Membranes
Mitochondrial Membrane Potential
Phosphorylation
Neuroprotective Agents
Cell death
Reperfusion
Cytochromes c
Caspase 3
Neurons
Ischemia
Rats
Estradiol
Proteins

Keywords

  • Apoptosis
  • Estrogen
  • Global cerebral ischemia
  • Neuroprotection
  • P38

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Attenuation of mitochondrial and nuclear p38α signaling : A novel mechanism of estrogen neuroprotection in cerebral ischemia. / Han, Dong; Scott, Erin L.; Dong, Yan; Raz, Limor; Wang, Ruimin; Zhang, Quanguang.

In: Molecular and Cellular Endocrinology, Vol. 400, 05.01.2015, p. 21-31.

Research output: Contribution to journalReview article

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abstract = "P38 mitogen-activated protein kinase (MAPK) is a pro-apoptotic and pro-inflammatory protein that is activated in response to cellular stress. While p38 is known to be activated in response to cerebral ischemia, the precise role of p38 and its isoforms in ischemia-induced neuronal apoptosis remains unclear. In the current study, we examined the differential activation and functional roles of p38α and p38β MAPK isoforms in short-term ovariectomized female rats treated with either the neuroprotective ovarian hormone 17beta-estradiol (E2) or placebo in a model of global cerebral ischemia (GCI). GCI induced biphasic activation of total p38 in the hippocampal CA1, with peaks at 30 min and 1 day after 10-min ischemia-reperfusion. Further study demonstrated that activated p38α, but not p38β, translocated to the nucleus 30 min and 3 h post reperfusion, and that this event coincided with increased phosphorylation of activating transcription factor 2 (ATF2), a p38 target protein. Intriguingly, activated p38α was also enhanced in mitochondrial fractions of CA1 neurons 1 day after GCI, and there was loss of mitochondrial membrane potential, as well as enhanced cytochrome c release and caspase-3 cleavage at 2 days post GCI. Importantly, E2 prevented the biphasic activation of p38, as well as both nuclear and mitochondrial translocation of p38α after GCI, and these findings correlated with attenuation of mitochondrial dysfunction and delayed neuronal cell death in the hippocampal CA1. Furthermore, administration of a p38 inhibitor was able to mimic the neuroprotective effects of E2 in the hippocampal CA1 region by preventing nuclear and mitochondrial translocation of p38α, loss of mitochondrial membrane potential, and neuronal apoptosis. As a whole, this study suggests that changes in subcellular localization of the activated p38α isoform are required for neuronal apoptosis following GCI, and that E2 exerts robust neuroprotection, in part, through dual inhibition of activation and subcellular trafficking of p38α.",
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