Role of dynamic related protein 1 in mitochondrial dynamic dysfunction in Alzheimer disease

Yilixiati XIAOKAITI,Han-ting ZHANG,James M O′DONNELL,Ying XU

（1.Department of Pharmaceutical Science,School of Pharmacy&Pharmaceutical Science,the State University of New York at Buffalo，Buffalo,NY 14214,USA;2.Department of Behavioral Medicine& Psychiatry,West Virginia University,Morgantown,WV,26505,USA）

Role of dynamic related protein 1 in mitochondrial dynamic dysfunction in Alzheimer disease

Yilixiati XIAOKAITI1,Han-ting ZHANG2,James M O′DONNELL1,Ying XU1

（1.Department of Pharmaceutical Science,School of Pharmacy&Pharmaceutical Science,the State University of New York at Buffalo，Buffalo,NY 14214,USA;2.Department of Behavioral Medicine& Psychiatry,West Virginia University,Morgantown,WV,26505,USA）

Mitochondrial dynamic is very essential biological process in mammalian cells.In healthy cells，mitochondrial dynamic keeps a balance between fission and fusion process.Dynamic related protein 1 (Drp1)plays an essential role in mitochondrial division and is the key point of the distribution and function of mitochondria in axons，dendrites and synapses.Studies in patients with Alzheimer disease suggested that the dysfunction or abnormal expression of Drp1 makes the balance of mitochondrial dynamic fission and fusion in Alzheimer disease moved to the harmful side in hippo⁃campus cells，leading to the imbalance of dynamic changes.Thus，Drp1 may be a valuable and novel target of mitochondrial dynamic changes for treatment of memory loss associated with Alzheimer disease.

dynamic related protein 1;Alzheimer disease;mitochondrial dynamics;fission;fusion

1MECHANISM OF MITOCHONDRIAL DYNAMIC

Mitochondria are dynamic organelles that form filamentous networks or appear as fragmented, rounded structures within cells.Mitochondria play important roles in many cellular activities, such as energy production,metabolism,aging and cell death[1].Neurons have a high demand for mitochondrial metabolism and contain many mitochondria throughout the cytoplasm.In neurons and many other cell types,mitochondria are maintained as short tubular structures,which are highly dynamic and move,divide,and fuse[1-3]. The dynamic interactions among mitochondria by fission and fusion establish organelle size, number and shape and allow for the mixing of mitochondrial contents,including proteins,lipids and DNA.

Mitochondria are organelles essential for neuronal function and survival[4-5].They play an essential role in ATP production,which is vital for maintaining neuronal integrity and function[6-8]. Mitochondria also play a critical role in buffering intracellular Ca2+levels by taking up and releasing Ca2+.At synaptic terminals,mitochondria take up excess intracellular Ca2+and release Ca2+to prolong residual levels,maintaining Ca2+homeostasis[9]. Through this mechanism,synaptic mitochondria are thought to be involved in the regulation of neurotransmission[10-11]or certain types of short-term synaptic plasticity[12-13].Dysfunctional mitochondria not only produce energy and buffer Ca2+less efficiently,butalso release harmful reactive oxygen species(ROS)[14-15].As a result,mitochon⁃drial oxidative stress triggers leakage of mito⁃chondrial inter-membranous contents,such as cytochrome c,into the cytosol,causing caspase activation,DNA damage,and apoptosis[5].The progressive accumulation ofthese damaged mitochondria in axons and synapses over the lifetime of neurons is thought to contribute to the pathogenesis of Alzheimer disease(AD)[16].

1.1 Mechanism of mitochondrial fusion

Mitochondrialfusion is an evolutionarily conserved process,which is mediated by three sorts of GTPases of the dynamin superfamily: mitofusin1(Mfn1),Mfn2,and optic atrophy 1 (OPA1)[17].Because mitochondria have double membranes,mitochondrial fusion is a two-step process requiring outer-membrane fusion followed by inner-membrane fusion.Mfn1 and Mfn2 are integral outer-membrane proteins that mediate outer-membrane fusion,where as OPA1 has multiple isoforms associated with the inner membrane and mediates inner-membrane fusion. OPA1 is expressed as a membrane-integrated long form,which can be cleaved to a soluble shortform bytwo distinctmetalloproteases, the ATP-dependent protease Yme1L and the membrane potential-dependent protease Oma1. It has been well known that the presence of both long and short forms correlates with fusioncompetent mitochondria[18].Proteolytic processing of OPA1 at the Yme1L or Oma1 cleavage site was sufficient to stimulate inner-membrane fusion in mitochondrial fusion which have undergone outer membrane fusion[19].The diverse activating and regulating of OPA1 by two metalloproteases allows differential regulation of inner-membrane fusion. Proteolysis via Yme1L is responsible for OXPHOS-dependent stimulation of inner-membrane fusion. In contrast,under the condition of membrane potential is dissipated,the long isoform of OPA1 would be completely cleaved and inactivated[17]owing to activation of Oma1[20].

1.2 Mechanism of mitochondrial fission

Normal mitochondrial fission is regulated and maintained by highly conserved two GTPase genes:Fis1 and Drp1.As a soluble cytosolic protein thatassembles into spiralfilaments around mitochondrial tubules,Drp1 is trans-located to theoutermembraneofthemitochondria and interacts with multiple proteins,including Fis1,mitochondrial fission factor(Mff)and mito⁃chondrialdynamic proteins of 49 and 51 ku (MiD49 and Mid51)[21],and Mff,Fis1,MiD49 and Mid51 act as receptors for Drp1 and complete mitochondrial division[22].Several different posttranslational modifications,including phosphory⁃lation,ubiquitination and SUMO-ylation,of Drp1 regulate its interactions with mitochondria[23-24]. The Drp1 spiral has been proposed to constrict mitochondrialtubules through conformational changes,driven by GTP hydrolysis,in Drp1 and Dnm1p[25-27].It has been suggested that tubules of the endoplasmic reticulum(ER)wrap around and squeeze mitochondria at the early stage of division,prior to the assembly of Drp1 filaments onto mitochondria[28].This ER-mediated narrowing ofmitochondrialtubulesmaypromoteDrp1 assemble,as the Drp1 spirals diameter is smaller than that of mitochondrial tubules.After the completion of mitochondrial fission,Drp1 spirals likely disassemble from mitochondria for future rounds of mitochondrial fission.

2 ROLE OF DRP1 IN MITOCHONDRIAL DYNAMIC

Drp1 is a multi-functional protein that plays an essential role on mitochondrial division and is the key point of the distribution of mitochondria in axons,dendrites and synapses.The structure of Drp1 contains an N-terminal GTPase domain, a helical domain at the center and a GED domain at the C-terminus.The GTPase domain is highly conserved and reported to have physiological relevance in cellular functioning[29]. Recent research findings suggest that Drp1 is involved in mitochondrial division,mitochondrial distribution, peroxisomal fragmentation, phosphorylation, SUMO-ylation and ubiquitination.Studies focusing on the structure of Drp1 have found that purified human Drp1 self-assembles into multimeric,ringlike structures with dimensions,similar to those of dynamin multimers.These similarities between dynaminandDrp1suggestthatDrp1wrap around the constriction points of dividing mitochondria,analogous to dynamin collars at the necks of budding vesicles[30].Other proteins,including fission 1(Fis1),Mff and MiD49 and MiD51 have been proposed to recruitand assemble Drp1 atthe outer membrane[31]. Researchers have also found significant role of Drp1 and Mfn2 on mitochondrial morphology and cellsurvivalin neuronalcells compared to non-neuronal cells[32].In detail,knockdown or dominant-negative interference ofendogenous Drp1 significantly increased mitochondrial length in both neurons and non-neuronal cells,but caused cell death only in cortical neurons.

3 ALZHEIMER DISEASE AND MITO⁃CHONDRIAL DYNAMIC

Severalrecentmitochondrialstudies of neurodegenerative diseases,such as AD,Parkinson disease(PD),Huntington disease(HD),and amyotrophic lateral sclerosis(ALS),mentioned that excessive mitochondrial fission occurs mainly in neurons that produce high levels of ROS and thatexhibitdefective mitochondrialfunction. Additionally,several biochemical studies on AD revealed that mutant proteins,including Aβ[33], phosphorylated Tau and overexpression of α-synuclein[34]are interacted with mitochondria in affected neurons and that this interaction is primarily responsible for increased levels of free radicals,ultimately causing an imbalance between mitochondrial fission and fusion,and mitochondrial dysfunction and neuronal damage.

It has reached a consensus that mitochondrial dysfunction has been extensively reported in AD pathogenesis:①AD postmortem brains-increased production of free radicals and lipid peroxidation, elevated oxidative DNA protein damagesand decreased ATP production in postmortem AD brains relative to brains from non-demented healthy subjects[35].②AD mouse models-several studies reported increased production of free radicals and lipid peroxidation and reduced levels ATP,cytochrome oxidative enzymatic activity in affected brain regions[36].③AD cells and primary neurons-Increasing studies found that increased levels oflipid peroxidation and free radical production,and reduced levels of mitochondrial ATP,cell viability and cyto-chromeoxidase activity in primary neurons from AD transgenic mice[37]and neuronal cells treated with Aβ peptide[38-39]. These studies strongly suggest that mitochondrial dysfunction associated oxidative stress is important features of AD pathogenesis.

Interestingly,neuronalcells treated with different concentrations of Aβ peptide show a significant decrease in Drp1 expression in a concentration dependentmanner;while itis increased in the mitochondrial fraction instead of cytosolic fraction.In the N2a cells treated with Aβ1-42,the expressions of Drp1 and Fis1 in the mitochondrial fraction are also increased,indicating increased mitochondrial fission; while the expressions of Mfn1,Mfn2,and OPA1 were decreased,and indicating decreased mitochondrial fusion.Thus,these results point to the presence of abnormal mitochondrial dynamics in AD neurons. Transmission electron microscopy of AD neurons treated with Aβ revealed a significant increase in mitochondrial fission,further supporting abnormal mitochondrial dynamics in AD.It was found that significantly decreased neurite outgrowth and decreased mitochondrial function in cells treated with Aβ peptide[40].Drp1-dependent mitochondrial fission is notessentialforthe release of cytochrome c and the subsequent progression of apoptosis,but Drp1 facilitates these processes. In neurons isolated from Nes-Cre Drp1KO mice, the size of mitochondria was increased and the number was decreased.In particular,synapses lacked mitochondria,and synapse formation was defective in these neurons in culture[41].

4 DRP1ANDMITOCHONDRIALDYNAMIC DYSFUNCTION IN ALZHEIMER DISEASE

Abnormal mitochondrial dynamics and synaptic damage have been reported as early cellular changes in AD pathogenesis.Specifi⁃cally,mitochondria exhibited a fragmented struc⁃ture and an abnormal distribution accumulating around the perinuclear area[33].Studies suggestedthat reduced Drp1 and OPA1 and increased levels of Fis1 in APPwt and APPswe M17 cells.Overex⁃pression of APP,through Aβ production,causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution,which contributes to mitochondrial and neuronal dysfunction[33].From a functional perspective, APP overexpression affected mitochondria at multiple levels,including elevating ROS levels,decreasing mitochondrial membrane potential,and reducing ATP production,which result in neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment.

During abnormalmitochondrialdynamics (increased fission and decreased fusion),Aβ interaction with Drp1,increased mitochondrial fragmentation and impaired axonal transport and synaptic degeneration[42-43].Drp1 immunoprecipi⁃tation and immunofluorescence analysis of Aβ antibodies revealed that Drp1 interacts with Aβ monomers and oligomers in AD patients,and these abnormal interactions are increased with disease progression[44].

Reddy group[42]found physical interaction between Drp1 and phosphorylated Tau in their study,which suggests that Drp1 interacts with Aβ and phosphorylated tau,likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies,ultimately possibly leading to neuronaldamage and cognitive decline.The study from Nakanishi and his co-workers[45]also supports the role for hyper⁃phosphorylated Tau in mitochondrial impairment. By overexpression of the postsynaptic protein such as α1-takusan(via interaction with PSD-95, mitigates oligomeric Aβ induced synaptic loss), inhibits Aβ-induced Tau hyperphosphorylation and prevents Aβ-induced mitochondrial fragmen⁃tation in corticaland hippocampalcultured neurons.The interaction between Drp1 and Aβ or between Drp1 and phosphorylated Tau may protect AD neurons against toxic insults of excessive Drp1,Aβ and/or phosphorylated Tau[45].

Nitric oxide(NO)pathway was found to be abnormally regulated in process of AD.Dysregu⁃ lated cyclin dependent kinases 5(Cdk5)causes neurotoxic Aβ processing and cell death,two hallmarks of AD via FOXO3,a transcriptional factor in hippocampal cells,primary neurons and an AD mouse model.Cdk5-mediated phosphoregulation of FOXO3a can activate several genes expression that promote neuronal death and aberrant Aβ processing,thereby contributing to the progression of neurodegenerative pathologies[46]. It is clearly showed that increased levels of NO associated with aberrant formation of s-nitricylation (SNO)-Cdk5 and SNO-Drp1,leading to the dysregulation of downstream pathways,synaptic dysfunction,and finally neuronal damage and neuronal death in AD.Taken together,these findings suggestthatSNO-Drp1 represent a potential therapeutic target for protecting neurons and their synapses in AD.

Mitochondrial dysfunction induced oxidative stress is majorly associated with the pathogenesis of AD[29].This oxidative stress is the generation of DNA damages with subsequent induction of the tumor suppressor protein P53[47].Therefore, induction of the P53 protein in neurons has been associated for a diverse array of neurological diseases including AD.Several studies demon⁃strated that diverse forms of acute neurotoxic stresscommonlycause mitochondrialfission and that enhancing the expression of fusion proteins or suppressing Drp1 activity reduces fission as well as neuronal cell death.Guo and his co-workers[48]found that Drp1 binding to P53 induces mitochondria-related necrosis.In contrast, inhibition of Drp1 by Drp1 small interference RNA (siRNA)reduces necrotic cell death in mouse embryonic fibroblasts exposure to H2O2induced oxidative stress.They confirmed neuronal death is due to the mitochondrial damage,which in turn causes Drp1-P53 interactions through mouse double minute 2 homolog(MDM2).

5 CONCLUSION

Although numerous of studies have elucidated the essentialrole ofDrp1 on mitochondrialdynamic regulation,the panorama ofDrp1 mediated mitochondrial dynamic has not been determined completely.As a hub pointin mitochondrial dynamic regulation network,Drp1 may be a great potential sally spot in novel mitochondrial dynamic based AD therapy strategy.

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线粒体动态相关蛋白1在阿尔茨海默病线粒体动态学中的作用机制研究进展

伊利夏提·肖开提1，张汉霆2，James M O′DONNELL1，徐 英1

（1.Department of Pharmaceutical Science，School of Pharmacy&Pharmaceutical Science，the State University of New York at Buffalo，Buffalo，NY 14214，USA；2.Department of Behavioral Medicine& Psychiatry，West Virginia University，Morgantown，WV，26505，USA）

线粒体动态在哺乳动物细胞内发挥重要作用。在健康细胞内，线粒体保持分裂与融合的动态平衡。线粒体动态相关蛋白1（Drp1）在神经细胞轴突和树突部位线粒体分裂动态调控中发挥枢纽作用。对阿尔茨海默症患者的研究证明，Drp1表达及功能变化会破坏线粒体分裂与融合的动态平衡并导致患者海马细胞的功能损坏或缺失。因此，Drp1具有成为以调节线粒体动态为机制的阿尔茨海默病治疗新方案中的全新药物靶点蛋白。

线粒体动态相关蛋白1；阿尔茨海默病；线粒体动态学；线粒体分裂；线粒体融合

徐 英，E-mail：yxu9@buffalo.edu，Tel：+1（716）829-5116

2016-03-28 接受日期：2016-06-14）

R966

:A

:1000-3002-(2016)06-0667-07

10.3867/j.issn.1000-3002.2016.06.006

Biography:YilixiatiXIAOKAITI(1985-),male,PhD, post-doctoral research assistant，main research field is neuropharmacology.

Ying XU,E-mail：yxu9@buffalo.edu, Tel:+1(716)829-5116

（本文编辑：乔 虹）