Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: The role of inhibition of Drp1 in ischemic brain damage

Zuo, Wei; Zhang, Shuai; Xia, Changfa; Guo, Xiaofeng; He, Wen‐Bin; Chen, Nai‐Hong

doi:10.1016/j.neuropharm.2014.07.002

Cited by 143 publications

(127 citation statements)

References 58 publications

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“…Besides, downregulation of DLP1 has been reported to prevent mitochondrial autophagy in mouse heart (Ikeda et al ., 2015; Shirakabe et al ., 2016). DLP1 has also been described to modulate mitophagy, possibly involving the interaction of DLP1 with the mitophagy receptor FUN14 domain‐containing 1 Pan troglodytes (FUNDC1) (Zuo et al ., 2014; Wu et al ., 2016). In yeast, the autophagic scaffold protein atg11p binds to and recruits Dnm1p/DLP1 to promote mitochondrial fission that occurs upon mitophagy (Mao et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Wang

et al. 2017

Aging Cell

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SummaryMitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPS c‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.

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Section: Discussionmentioning

confidence: 99%

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Wang

et al. 2017

Aging Cell

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“…5,8,40 Once recruited to mitochondria, Drp1 forms spiral tubules at the OMM and constrict the mitochondria using its intrinsic GTPase activity. 4,29 Mdivi-1 is a BBB permeable inhibitor of Drp1 that when injected systemically achieves maximum concentration in the brain by 4 h, and has a half-life of about 12 h. 41,18,20,30,[41][42][43][44][45][46][47] Blocking Drp1 by Mdivi-1 could restore mitochondrial dynamics, improve mitochondrial function by preserving mitochondrial structural integrity, and mÉ and ATP levels. 41 Treatment with Mdivi was shown to significantly decrease the infarct volume, apoptotic neuronal death and neurological deficits following transient middle cerebral artery occlusion (MCAO) in adult mice and rats.…”

mentioning

confidence: 99%

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Balog

Mehta

Vemuganti

2016

J Cereb Blood Flow Metab

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Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults.

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“…ROS is produced by both molecular oxygen entered to cell during reperfusion [73] and released by mitochondria in the case of stress [74].…”

Section: Autophagy and Ischemia/ Reperfusionmentioning

confidence: 99%

“…One of the important factors affects autophagic response is duration of I and R. Zuo et al [74] shown that activity of autophagy increases as long as period of ischemia and reperfusion strings out. Atg10 is activated form of Atg12, beside of this, is another ubiquitin-conjugating enzyme and provides conjugation of Atg12 and Atg5 [82,83].…”

Section: Autophagy and Ischemia/ Reperfusionmentioning

confidence: 99%

The Role of Autophagy in Stress and Cancer

Bostancıklıoğlu¹

2015

Single Cell Biol

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Programmed cell death plays an important role in development and disease. There are three main types of programmed cell death: apoptosis, autophagy, and necrosis. Apoptosis works on the two basic pathways called extrinsic and intrinsic; when there is a stress factor in a cell, apoptosis starts. Autophagy is critical for the continuation of normal human physiology such as the cellular homeostasis, energy balance, development and cellular defense. In addition to these, it may play a role in the pathogenesis of cancer, neurodegenerative diseases, aging, muscular diseases, infectious diseases, and immune system diseases.While some autophagy genes showed tumor suppressive effect during the development of cancer, some other genes contributes to the survival of cancer cells during cancer progression. Therefore, the relationship between autophagy and cancer is quite complex. The role of autophagy in cancer varies depending on the stage of the cancer, the metabolic status of cell and the presence of stress. Also, it was reported that the expression of certain molecules associated with autophagy vary in different types of cancer. Autophagy is activated and allows the continuation of the viability of tumor cells in hypoxia. In case of nutrient deficiency, autophagy allows tumor tissue to gain time until nutrient, oxygen and growth factors become eligible again. Therefore, autophagy is seen as a necessary mechanism for tumor continuity. Autophagy increases both in cancer cells and normal cells during the cancer treatment. But, due to cancer cells use autophagy to survive more than normal cells; this case may generate new therapeutic opportunities. The studies needed to conduct to find new ways for using the genes play role in autophagy in cancer treatment.In the present study, we aimed to throw light on the interaction of autophagy mechanism and some stresses such as ischemia and reperfusion and cancer development.

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Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: The role of inhibition of Drp1 in ischemic brain damage

Cited by 143 publications

References 58 publications

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Mitochondrial fission and fusion in secondary brain damage after CNS insults

The Role of Autophagy in Stress and Cancer

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