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SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria

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Virologica Sinica 2023年第4期38卷 520-530页

作者： Shan Zong Yan Wu Weiling Li Qiang You Qian Peng Chenghai Wang Pin Wan Tao Bai Yanling Ma Binlian Sun Jialu Qiao Wuhan Institute of Biomedical Sciences School of MedicineJianghan UniversityWuhan430056China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China Hubei Key Laboratory of Wudang Local Chinese Medicine Research Hubei University of MedicineShiyan442000China Division of Gastroenterology Tongji Medical CollegeHua Zhong University of Science and TechnologyWuhan430030China Department of Respiratory and Critical Care Medicine Hubei Province Clinical Research Center for Major Respiratory DiseasesNHC Key Laboratory of Pulmonary DiseasesUnion HospitalTongji Medical CollegeHua Zhong University of Science and TechnologyWuhan430030China

Autophagy plays an important role in the interaction between viruses and host cells.SARS-CoV-2 infection can disrupt the autophagy process in target cells.However,the precise molecular mechanism is still unknown.In this study,we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes.From further investigation,we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy.The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy.Moreover,both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy,in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy.This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy,which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.

关键词： SARS-CoV-2 Nsp8 Autophagy mitophagy Mitochondrial damage

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylationmediated mitophagy

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Acta Pharmaceutica Sinica B 2022年第2期12卷 838-852页

作者： Xin Sun Yuhan Shu Guiqin Ye Caixia Wu Mengting Xu Ruilan Gao Dongsheng Huang Jianbin Zhang Department of Oncology Cancer Center of Zhejiang Provincial People’s HospitalAffiliated People’s HospitalHangzhou Medical CollegeHangzhou 310014China Clinical Research Institute Zhejiang Provincial People’s HospitalAffiliated People’s HospitalHangzhou Medical CollegeHangzhou 310014China Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province Hangzhou Medical CollegeHangzhou 310014China College of Biomedical Engineering&Instrument Science Zhejiang UniversityHangzhou 310028China Department of Hematology the First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310006China

Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly understood.Here,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell proliferation.Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of Parkin.Using mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase HDAC2.Under treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin protein.In in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor suppression.In tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA.Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.

关键词： Parkin mitophagy ACAT1 HDAC2 Acetylation Ubiquitination Tumor suppression Cervical cancer

Miriplatin-loaded liposome,as a novel mitophagy inducer,suppresses pancreatic cancer proliferation through blocking POLG and TFAM-mediated mtDNA replication

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4477-4501页

作者： Xiaowei Wang Mengyan Wang Meilian Cai Rongguang Shao Guimin Xia Wuli Zhao State Key Laboratory of Respiratory Health and Multimorbidity Key Laboratory of Antibiotic BioengineeringMinistry of HealthLaboratory of OncologyInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Pharmaceutics Department Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.

关键词： Miriplatin-loaded liposome Pancreatic cancer Caveolae-mediated endocytosis Caveolin-1 mitophagy Mitochondria DNA POLG TFAM

ROS-mediated BNIP3-dependent mitophagy promotes coelomocyte survival in Apostichopus japonicus in response to Vibrio splendidus infection

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Zoological Research 2022年第2期43卷 285-300页

作者： Lian-Lian Sun Yi-Na Shao Mei-Xiang You Cheng-Hua Li State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China Laboratory for Marine Fisheries Science and Food Production Processes Qingdao National Laboratory for Marine Science and TechnologyQingdaoShandong 266071China State-Province Joint Laboratory of Marine Biotechnology and Engineering Ningbo UniversityNingboZhejiang 315211China

Organisms produce high levels of reactive oxygen species(ROS)to kill pathogens or act as signaling molecules to induce immune responses;however,excessive ROS can result in cell death.To maintain ROS balance and cell survival,mitophagy selectively eliminates damaged mitochondria via mitophagy receptors in vertebrates.In marine invertebrates,however,mitophagy and its functions remain largely unknown.In the current study,Vibrio splendidus infection damaged mitochondrial morphology in coelomocytes and reduced mitochondrial membrane potential(ΔΨm)and mitophagosome formation.The colocalization of mitochondria and lysosomes further confirmed that lipopolysaccharide(LPS)treatment increased mitophagy flux.To explore the regulatory mechanism of mitophagy,we cloned Bcl2/adenovirus E1 B 19 kDa protein-interacting protein 3(BNIP3),a common mitophagy receptor,from sea cucumber Apostichopus japonicus(Aj BNIP3)and confirmed that Aj BNIP3 was significantly induced and accumulated in mitochondria after V.splendidus infection and LPS exposure.At the mitochondrial membrane,Aj BNIP3 interacts with microtubule-associated protein 1 light chain 3(LC3)on phagophore membranes to mediate mitophagy.After Aj BNIP3 interference,mitophagy flux decreased significantly.Furthermore,Aj BNIP3-mediated mitophagy was activated by ROS following the addition of exogenous hydrogen peroxide(H2 O2),ROS scavengers,and ROS inhibitors.Finally,inhibition of BNIP3-mediated mitophagy by Aj BNIP3 small interfering RNA(si RNA)or high concentrations of lactate increased apoptosis and decreased coelomocyte survival.These findings highlight the essential role of Aj BNIP3 in damaged mitochondrial degradation during mitophagy.This mitophagy activity is required for coelomocyte survival in A.japonicus against V.splendidus infection.

关键词： Apostichopus japonicus mitophagy Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 Reactive oxygen species Microtubule-associated protein 1 light chain 3

Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

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Translational Neurodegeneration 2022年第1期11卷 461-473页

作者： Kuan Zeng Xuan Yu Yacoubou Abdoul Razak Mahaman Jian-Zhi Wang Rong Liu Yi Li Xiaochuan Wang Department of Psychiatry Wuhan Mental Health CenterWuhan 430012China Co-Innovation Center of Neurodegeneration Nantong UniversityNantong 226001China Department of Pathophysiology School of Basic MedicineKey Laboratory of Education Ministry/Hubei Province of China for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Wuhan Hospital for Psychotherapy Wuhan 430012China Shenzhen Huazhong University of Science and Technology Research Institute Shenzhen 518000China.

Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration,including Alzheimer’s disease(AD).A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development.The interaction between mitophagy deficits and Aβor Tau pathology may form a vicious cycle and cause neuronal damage and death.Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD.Defective mitophagy is a potential target for AD prevention and treatment.

关键词： mitophagy Alzheimer’s disease PINK1 Tau Aβ

Insight into Crosstalk Between mitophagy and Apoptosis/Necroptosis:Mechanisms and Clinical Applications in Ischemic Stroke

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Current Medical Science 2022年第2期42卷 237-248页

作者： Yan-di YANG Zi-xin LI Xi-min HU Hao WAN Qi ZHANG Rui XIAO Kun XIONG Department of Anatomy and Neurobiology School of Basic Medical ScienceCentral South UniversityChangsha 410013China Clinical Medicine Eight-year Program 03 Class18 GradeXiangya School of MedicineCentral South UniversityChangsha 410013China Clinical Medicine Eight-Year Program 02 Class17 GradeXiangya School of MedicineCentral South UniversityChangsha 410013China Administrative Office the Third Xiangya HospitalCentral South UniversityChangsha 410013China Hunan Key Laboratory of Ophthalmology Changsha 410008China Key Laboratory of Emergency and Trauma Ministry of EducationCollege of Emergency and TraumaHainan Medical UniversityHaikou 571199China

Ischemic stroke is a serious cerebrovascular disease with high morbidity and mortality.As a result of ischemia-reperfusion,a cascade of pathophysiological responses is triggered by the imbalance in metabolic supply and demand,resulting in cell loss.These cellular injuries follow various molecular mechanisms solely or in combination with this disorder.Mitochondria play a driving role in the pathophysiological processes of ischemic stroke.Once ischemic stroke occurs,damaged cells would respond to such stress through mitophagy.mitophagy is known as a conservatively selective autophagy,contributing to the removal of excessive protein aggregates and damaged intracellular components,as well as aging mitochondria.Moderate mitophagy may exert neuroprotection against stroke.Several pathways associated with the mitochondrial network collectively contribute to recovering the homeostasis of the neurovascular unit.However,excessive mitophagy would also promote ischemia-reperfusion injury.Therefore,mitophagy is a double-edged sword,which suggests that maximizing the benefits of mitophagy is one of the direction of future efforts.This review emphasized the role of mitophagy in ischemic stroke,and highlighted the crosstalk between mitophagy and apoptosis/necroptosis.

关键词： mitophagy ischemic stroke apoptosis necroptosis clinical application crosstalk

Single-wavelength-excited fluorogenic nanoprobe for accurate realtime ratiometric analysis of broad pH fluctuations in mitophagy

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Nano Research 2022年第7期15卷 6515-6521页

作者： Xin Zhang Juan Chen Jiwen Hu Anna du Rietz Xiongyu Wu Ruilong Zhang Zhongping Zhang Kajsa Uvdal Zhangjun Hu Department of Physics Chemistryand Biology(IFM)Linköping UniversityLinköping SE 58183Sweden School of Chemistry and Chemical Engineering Anhui UniversityHefei 230601China

mitophagy has a critical role in maintaining cellular homeostasis through acidic lysosomes engulfing excess or impaired mitochondria,thereby pH fluctuation is one of the most significant indicators for tracking mitophagy.Then such precise pH tracking demands the fluorogenic probe that has tailored contemporaneous features,including mitochondrial-specificity,excellent biocompatibility,wide pH-sensitive range of 8.0–4.0,and especially quantitative ability.However,available molecular probes cannot simultaneously meet all the requirements since it is extremely difficult to integrate multiple functionalities into a single molecule.To fully address this issue,we herein integrate two fluorogenic pH sensitive units,a mitochondria-specific block,cellpenetrating facilitator,and biocompatible segments into an elegant silica nano scaffold,which greatly ensures the applicability for real-time tracking of pH fluctuations in mitophagy.Most significantly,at a single wavelength excitation,the integrated pHsensitive units have spectra-distinguishable fluorescence towards alkaline and acidic pH in a broad range that covers mitochondrial and lysosomal pH,thus enabling a ratiometric analysis of pH variations during the whole mitophagy.This work also provides constructive insights into the fabrication of advanced fluorescent nanoprobes for diverse biomedical applications.

关键词： mitochondrial pH mitophagy ratiometric fluorescence nanoprobe cell imaging

Role of mitophagy in the hallmarks of aging

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The Journal of Biomedical Research 2023年第1期37卷 1-14页

作者： Jie Wen Tingyu Pan Hongyan Li Haixia Fan Jinhua Liu Zhiyou Cai Bin Zhao Department and Institute of Neurology Guangdong Medical UniversityZhanjiangGuangdong 524001China Guangdong Key Laboratory of Aging-related Cardiac and Cerebral Diseases ZhanjiangGuangdong 524001China Chongqing Key Laboratory of Neurodegenerative Diseases Chongqing 400013China Department of Neurology Chongqing General HospitalChongqing 400013China Department of Neurology the Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan 646000China Chongqing Medical University Chongqing 400042China

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance.The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

关键词： mitophagy aging dietary restriction telomere shortening epigenetic alterations protein imbalance

Choline dehydrogenase interacts with SQSTM1 to activate mitophagy and promote coelomocyte survival in Apostichopus japonicus following Vibrio splendidus infection

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动物学研究(英文) 2023年第5期44卷 905-918页

作者： Lian-Lian Sun Ying-Fen Dai Mei-Xiang You Cheng-Hua Li State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China Laboratory for Marine Fisheries Science and Food Production Processes Qingdao National Laboratory for Marine Science and TechnologyQingdaoShandong 266071China

Previous studies have shown that Vibrio splendidus infection causes mitochondrial damage in Apostichopus japonicus coelomocytes,leading to the production of excessive reactive oxygen species(ROS)and irreversible apoptotic cell death.Emerging evidence suggests that mitochondrial autophagy(mitophagy)is the most effective method for eliminating damaged mitochondria and ROS,with choline dehydrogenase(CHDH)identified as a novel mitophagy receptor that can recognize non-ubiquitin damage signals and microtubule-associated protein 1 light chain 3(LC3)in vertebrates.However,the functional role of CHDH in invertebrates is largely unknown.In this study,we observed a significant increase in the mRNA and protein expression levels of A.japonicus CHDH(AjCHDH)in response to V.splendidus infection and lipopolysaccharide(LPS)challenge,consistent with changes in mitophagy under the same conditions.Notably,AjCHDH was localized to the mitochondria rather than the cytosol following V.splendidus infection.Moreover,AjCHDH knockdown using si RNA transfection significantly reduced mitophagy levels,as observed through transmission electron microscopy and confocal microscopy.Further investigation into the molecular mechanisms underlying CHDH-regulated mitophagy showed that AjCHDH lacked an LC3-interacting region(LIR)for direct binding to LC3 but possessed a FB1 structural domain that binds to SQSTM1.The interaction between AjCHDH and SQSTM1 was further confirmed by immunoprecipitation analysis.Furthermore,laser confocal microscopy indicated that SQSTM1 and LC3 were recruited by AjCHDH in coelomocytes and HEK293T cells.In contrast,AjCHDH interference hindered SQSTM1 and LC3 recruitment to the mitochondria,a critical step in damaged mitochondrial degradation.Thus,AjCHDH interference led to a significant increase in both mitochondrial and intracellular ROS,followed by increased apoptosis and decreased coelomocyte survival.Collectively,these findings indicate that AjCHDH-mediated mitophagy plays a crucial role in coelomocyte survival in A.japon

关键词： Choline dehydrogenase mitophagy SQSTM1 Microtubule-associated protein 1 light chain 3 Apostichopus japonicus