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Aging and disease    2018, Vol. 9 Issue (5) : 924-937     DOI: 10.14336/AD.2017.1126
Review |
Mitochondria in Ischemic Stroke: New Insight and Implications
Liu Fan Liu1, Jianfei Lu1, Anatol Manaenko2, Junjia Tang3, Qin Hu1,*
1Discipline of Neuroscience, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Departments of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
3Department of neurosurgery, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
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Abstract  

Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction has been regarded as one of the hallmarks of ischemia/reperfusion (I/R) induced neuronal death. Maintaining the function of mitochondria is crucial in promoting neuron survival and neurological improvement. In this article, we review current progress regarding the roles of mitochondria in the pathological process of cerebral I/R injury. In particular, we emphasize on the most critical mechanisms responsible for mitochondrial quality control, as well as the recent findings on mitochondrial transfer in acute stroke. We highlight the potential of mitochondria as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.

Keywords Ischemic stroke      mitochondrial quality control      mitophagy      mitochondrial transfer      neuroprotection     
Corresponding Authors: Qin Hu   
About author: These authors contributed equally to this work.
Issue Date: 10 October 2017
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Liu Fan
Lu Jianfei
Manaenko Anatol
Tang Junjia
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Cite this article:   
Liu Fan,Lu Jianfei,Manaenko Anatol, et al. Mitochondria in Ischemic Stroke: New Insight and Implications[J]. Aging and disease, 2018, 9(5): 924-937.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1126     OR     http://www.aginganddisease.org/EN/Y2018/V9/I5/924
Figure 1.  Mechanisms underlying neuronal death in ischemic stroke

(1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. (2) Excitotoxicity. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. (3) Acidotoxity. Extracellular acidification leads to ischemic neuronal death by activating acid-sensing ion channel 1a (ASIC1a). (4) Protein misfolding. Protein misfolding and aggregation are observed after brain ischemia. (5) Inflammatory reaction. Microglia are activated and release cytokines and chemokines to induce inflammation reaction. All the factors mentioned above work synergistically to trigger cell death pathways such as apoptosis, necroptosis and autophagy. ROS: reactive oxygen species; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; NMDAR: N-methyl-D-aspartate receptor; KAR: kainite receptor; DAPK1: death associated protein kinase 1; PSD95: postsynaptic density protein 95; ASIC1a: acid-sensing ion channel 1a; RIPK1: receptor interacting protein kinase 1; TNF-α: tumor necrosis factor-α; IL-6: Interleukin 6; IL-1: Interleukin 1.

MammalsYeastRole in mitochondria dynamicsLocation
Drp1Dnm1pFissoncytosolic, and recruited to outer membrane during fission
Fis1Fis1pFissonOuter mitochondrial membrane
Endophilin B1-Fissoncytosolic, and recruited to outer membrane during fission
Mfn1/2F201pFusionOuter mitochondrial membrane
Opa1Mgm1pFusionInner mitochondrial membrane
KIFs_TransportCytosolic
Cytoplasmic dyneinDynclilTransportCytosolic
Table 1  Mitochondrial dynamic-related proteins.
Figure 2.  Mitochondria play a central role in ischemic neuronal death

Ischemia triggers the depolarization of mitochondrial membrane potential (ΔΨm), reduction of ATP production, accumulation of PINK1, recruitment of Parkin, overproduction of reactive oxygen species (ROS), overloading of matrix calcium, and opening of mitochondrial permeability transition pore (mPTP), eventually leading to neuronal death.

Figure 3.  Mitochondrial fusion, fission or transport in neurons

Damaged mitochondria can be repaired through fusion with healthy mitochondria, and mitochondrial fission enables the segregation of damaged mitochondria and subsequent elimination via mitophagy. Mitochondria are transported and packed at axonal synapses, and are essential for neuronal transmission and plasticity.

AgentsProposed mechanismsRefs.
Drp1 siRNAInhibition of fission via DRP1 down-regulation[55-57, 61]
Drp1 cysteine mutationInhibition of fission by preventing S-nitrosylation induced Drp1 activation[59]
Ginkgolide KInhibition of fission by increasing Drp1 phosphorylation and inhibiting Drp1 recruitment[60]
mdivi-1Inhibition of fission by inhibiting the GTPase activity of Drp1[55, 61]
P110Inhibition of fission by inhibiting Drp1 enzyme activity and blocking Drp1/Fis1 interaction[62, 63]
Mfn2 overexpressionPromotion of fusion[49, 50]
Table 2  Chemical agents targeting mitochondrial dynamics in ischemic stroke
Figure 4.  Intercellular mitochondrial transfer

Mitochondria can be released by donate cells and uptake by recipient cells. Stressed or dying cells release mitochondria through tunneling nanotubes (TNTs) or microvesicles. Mitochondrial transfer can occur between same or different cell types.

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