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Parkin in cancer:mitophagy-related/unrelated tasks

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World Journal of Hepatology 2017年第7期9卷 349-351页

作者： Nabil Eid Yoichi Kondo Division of Life Sciences Department of Anatomy and Cell BiologyOsaka Medical CollegeTakatsukiOsaka 569-8686Japan

Dysfunctional mitochondria may produce excessive reactive oxygen species, thus inducing DNA damage, which may be oncogenic if not repaired. As a major role of the PINK1-Parkin pathway involves selective autophagic clearance of damaged mitochondria via a process termed mitophagy, Parkin-mediated mitophagy may be a tumorsuppressive mechanism. As an alternative mechanism for tumor inhibition beyond mitophagy, Parkin has been reported to have other oncosuppressive functions such as DNA repair, negative regulation of cell proliferation and stimulation of p53 tumor suppressor function. The authors recently reported that acute ethanol-induced mitophagy in hepatocytes was associated with Parkin mitochondrial translocation and colocalization with accumulated 8-OHd G(a marker of DNA damage and mutagenicity). This finding suggests:(1) the possibility of Parkin-mediated repair of damaged mitochondrial DNA in hepatocytes of ethanol-treated rats(ETRs) as an oncosuppressive mechanism; and(2) potential induction of cytoprotective mitophagy in ETR hepatocytes if mitochondrial damage is too severe to be repaired. Below is a summary of the various roles Parkin plays in tumor suppression, which may or may not be related to mitophagy. A proper understanding of the various tasks performed by Parkin in tumorigenesis may help in cancer therapy by allowing the PINK1-Parkin pathway to be targeted.

关键词： Cancer Ethanol Liver mitophagy Parkin PINK1 8-OHdG

Miro2 supplies a platform for Parkin translocation to damaged mitochondria

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Science Bulletin 2019年第11期64卷 730-747页

作者： Jiu-Qiang Wang Shu Zhu Yihan Wang Fengli Wang Chaoqiang An Dongfang Jiang Lijie Gao Yingfeng Tu Xuefei Zhu Yun Wang Hongmei Liu Juanjuan Gong Zhongshuai Sun Xi Wang Leimei Liu Keyan Yang Caixia Guo Tie-Shan Tang State Key Laboratory of Membrane Biology Institute of ZoologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Key Laboratory of Genomics and Precision Medicine Beijing Institute of GenomicsUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China Department of Foresight and Evaluation Research Chinese Academy of Science and Technology for DevelopmentBeijing 100038China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

PINK1/Parkin-mediated mitophagy is an important process in selective removal of damaged mitochondria, in which translocation of Parkin to damaged mitochondria is recognized as an initiation step. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Here we show that Miro2, an outer mitochondrial membrane protein, undergoes demultimerization from a tetramer to a monomer and alteration in mitochondrial localization upon CCCP treatment, suggesting a CCCP-induced realignment of Miro2. The realignment of Miro2 is tightly regulated by PINK1-mediated phosphorylation at Ser325/Ser430 and by Ca^2+binding to EF2 domain, which are both essential for the subsequent Parkin translocation. Interestingly, ablation of Miro2 in mouse causes delayed reticulocyte maturation, lactic acidosis and cardiac disorders. Furthermore, several Miro2 mutations found in the congenital lactic acidosis patients also disable its realignment and Parkin translocation. These findings reveal an important role of Miro2 to mediate Parkin translocation by sensing both depolarization and Ca^2+release from damaged mitochondria to ensure the accuracy of mitophagy.

关键词： Miro2 Parkin Mitochondria Ca^2+ mitophagy PINK1

Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer

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Acta Pharmaceutica Sinica B 2019年第5期9卷 1061-1077页

作者： Dong Mei Binlong Chen Bing He Haibin Liu Zhiqiang Lin Jialiang Lin Xiaoyan Zhang Ning Sun Libo Zhao Xiaoling Wang Qiang Zhang Clinical Research Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijing100045China Key Laboratory of Molecular Pharmaceutics New Drug Delivery SystemsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China Department of General Surgery China-Japan Friendship HospitalBeijing100029China Institute of Systems Biomedicine School of Basic Medical SciencesPeking University Health Science CenterBeijing100191China

Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin(RAP) into 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.

关键词： Autophagic cell death Combination therapy Targeted delivery Rapamycin Breast cancer Transferrin receptor mitophagy Nanomedicines 7pep

Mitochondrial dysfunction in Parkinson’s disease

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Translational Neurodegeneration 2016年第1期5卷 118-125页

作者： Qingsong Hu Guanghui Wang Laboratory of Molecular Neuropathology Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu 215021China The Second Affiliated Hospital of Soochow University Soochow UniversitySuzhouJiangsu 215021China

Parkinson’s disease(PD)is the second most common neurodegenerative disease,which is characterized by loss of dopaminergic(DA)neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases.Although the cause of PD is still unclear,the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis.Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss.Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis.The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD.Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin-or genetic factorinduced PD cellular and animal models.Moreover,PINK1 and parkin,two autosomal recessive PD gene products,have important roles in mitophagy,a cellular process to clear damaged mitochondria.PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy.In this review,we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.

关键词： Parkinson’s disease Neurodegeneration Mitochondrial deficiency MPTP Mitochondrial complex I inhibitor mitophagy

Neuroprotective mechanisms ofε-viniferin in a rotenone-induced cell model of Parkinson's disease:significance of SIRT3-mediated FOXO3 deacetylation

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Neural Regeneration Research 2020年第11期15卷 2143-2153页

作者： Shuo Zhang Yan Ma Juan Feng Department of Neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of Ultrasound Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

Trans-(-)-ε-viniferin(ε-viniferin)has antioxidative and anti-inflammatory effects.It also has neuroprotective effects in Huntington's disease by activating the SIRT3/LKB1/AMPK signaling pathway;however,it remains unknown whetherε-viniferin also has a neuroprotective role in Parkinson's disease.A Parkinson's disease cell model was induced by exposing SH-SY5 Y cells to 3.0μM rotenone for 24 hours,and cells were then treated with 1.0μMε-viniferin for 24 hours.Treatment withε-viniferin upregulated SIRT3 expression,which promoted FOXO3 deacetylation and nuclear localization.ε-Viniferin also increased ATP production and decreased reactive oxygen species production.Furthermore,ε-viniferin treatment alleviated rotenone-induced mitochondrial depolarization and reduced cell apoptosis,and restored the expression of mitochondrial homeostasis-related proteins.However,when cells were transfected with SIRT3 or FOXO3 shRNA prior to rotenone andε-viniferin treatment,these changes were reversed.The results from the present study indicate thatε-viniferin enhances SIRT3-mediated FOXO3 deacetylation,reduces oxidative stress,and maintains mitochondrial homeostasis,thus inhibiting rotenone-induced cell apoptosis.ε-Viniferin may therefore be a promising treatment strategy for Parkinson's disease.

关键词： deacetylation FOXO3 mitochondrial homeostasis mitophagy oxidative stress Parkinson's disease SIRT3 ε-viniferin

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

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Translational Neurodegeneration 2016年第1期5卷 152-160页

作者： Bao Wang Neeta Abraham Guodong Gao Qian Yang Department of Neurosurgery Tangdu HospitalThe Fourth Military Medical UniversityNo.569 Xinsi RoadBaqiao DistrictXi’an 710038Shaanxi ProvinceChina Department of Neurology Beth Isreal Deaconess Medical CenterHarvard Medical School330 Brookline AveBoston 02215MAUSA

Parkinson’s disease(PD)is the second most common neurodegenerative disease.Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis.In this review,we briefly summarized autophagy pathway,which consists of macroautophagy,microautophagy and chaperone-mediated autophagy(CMA).Then,we discussed the involvement of mitochondrial dysfunction in PD pathogenesis.We specifically reviewed the recent developments in the relationship among several PD related genes,autophagy and mitochondrial dysfunction,followed by the therapeutic implications of these pathways.In conclusion,we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD.Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.

关键词： Parkinson’s disease Autophagy Macroautophagy mitophagy Chaperone-mediated autophagy Mitochondria α-synuclein PINK/Parkin LRRK2 DJ-1

Faulty homocysteine recycling in diabetic retinopathy

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Eye and Vision 2020年第1期7卷 36-46页

作者： Renu A.Kowluru Ghulam Mohammad Nikhil Sahajpal Department of Ophthalmology Visual Sciences and Anatomical SciencesWayne State University4717 St.AntoineDetroitMI 48201USA

Background:Although hyperglycemia is the main instigator in the development of diabetic retinopathy,elevated circulating levels of a non-protein amino acid,homocysteine,are also associated with an increased risk of retinopathy.Homocysteine is recycled back to methionine by methylenetetrahydrofolate reductase(MTHFR)and/or transsulfurated by cystathionineβ-synthase(CBS)to form cysteine.CBS and other transsulfuration enzyme cystathionine-γ-lyase(CSE),through desulfuration,generates H_(2)S.Methionine cycle also regulates DNA methylation,an epigenetic modification associated with the gene suppression.The aim of this study was to investigate homocysteine and its metabolism in diabetic retinopathy.Methods:Homocysteine and H_(2)S levels were analyzed in the retina,and CBS,CSE and MTHFR in the retinal microvasculature from human donors with established diabetic retinopathy.Mitochondrial damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics(fission-fusionmitophagy).DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation technique.The direct effect of homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells(HRECs)incubated with 100μM L-homocysteine.Results:Compared to age-matched nondiabetic control human donors,retina from donors with established diabetic retinopathy had~3-fold higher homocysteine levels and~50%lower H_(2)S levels.The enzymes important for both transsulfuration and remethylation of homocysteine including CBS,CSE and MTHFR,were 40–60%lower in the retinal microvasculature from diabetic retinopathy donors.While the mitochondrial fission protein,dynamin related protein 1,and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3(LC3),were upregulated,the fusion protein mitofusin 2 was downregulated.In the same retinal microvessel preparations from donors with diabetic retinopathy,DNA at the promoters of CBS and MTHFR were hypermethylated.Incu

关键词： Diabetic retinopathy DNA methylation Homocysteine Hydrogen sulfide mitophagy Epigenetics Mitochondria Oxidative stress Retina

Deciphering the dual role and prognostic potential of PINK1 across cancer types

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Neural Regeneration Research 2021年第4期16卷 659-665页

作者： Katherine Dai Daniel P.Radin Donna Leonardi Department of Molecular Cellularand Developmental BiologyYale UniversityNew HavenCTUSA Department of Pharmacology Stony Brook University School of MedicineStony BrookNYUSA Bergen County Academies HackensackNJUSA

Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many cancers.Concerted mutations in key tumor suppressor genes,such as PTEN,and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic resistance.Mounting research has demonstrated that PTEN-induced putative kinase 1(PINK1)acts as a pivotal regulator of mitochondrial homeostasis in several cancer types,a function that also extends to the regulation of tumor cell proliferative capacity.In addition,involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies,further expounding PINK1’s multifunctional nature.This review discusses the oncogenic roles of PINK1 in multiple tumor cell types,with an emphasis on maintenance of mitochondrial homeostasis,while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the Warburg effect.From a clinical standpoint,its expression may also dictate the response to genotoxic stressors commonly used to treat multiple malignancies.By detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner,we present avenues for future studies of this dynamic protein.

关键词： apoptosis cancer cell cycle inflammation metabolic stress mitochondral quality control mitophagy PINK1 tumor Warburg effect

Mitochonic acid 5 regulates mitofusin 2 to protect microglia

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Neural Regeneration Research 2021年第9期16卷 1813-1820页

作者： Jian Tan Shuang-Xi Chen Qing-Yun Lei Shan-Qing Yi Na Wu Yi-Lin Wang Zi-Jian Xiao Heng Wu Department of Neurology The First Affiliated Hospital of University of South ChinaHengyangHunan ProvinceChina

Microglial apoptosis is associated with neuroinflammation and no effective strategies are currently available to protect microglia against inflammation-induced apoptosis. Mouse microglial BV-2 cells(5 × 10^6) were incubated with 10 μg/mL lipopolysaccharides for 12 hours to mimic an inflammatory environment. Then the cells were co-cultured with mitochonic acid 5(MA-5) for another 12 hours. MA-5 improved the survival of lipopolysaccharide-exposed cells. MA-5 decreased the activity of caspase-3, which is associated with apoptosis. MA-5 reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells, and increased adenosine triphosphate levels in cells. MA-5 decreased the open state of the mitochondrial permeability transition pore and reduced calcium overload and diffusion of second mitochondria-derived activator of caspase(Smac). MA-5 decreased the expression of apoptosis-related proteins(mitochondrial Smac, cytoplasmic Smac, pro-caspase-3, cleaved-caspase-3, and caspase-9), and increased the levels of anti-apoptotic proteins(Bcl2 and X-linked inhibitor of apoptosis protein), mitochondria-related proteins(mitochondrial fusion protein 2, mitochondrial microtubule-associated proteins 1 A/1 B light chain 3 B II), and autophagy-related proteins(Beclin1, p62 and autophagy related 5). However, MA-5 did not promote mitochondrial homeostasis or decrease microglial apoptosis when Mitofusin 2 expression was silenced. This shows that MA-5 increased Mitofusin 2-related mitophagy, reversed cellular energy production and maintained energy metabolism in BV-2 cells in response to lipopolysaccharide-induced inflammation. These findings indicate that MA-5 may promote the survival of microglial cells via Mitofusin 2-related mitophagy in response to lipopolysaccharide-induced inflammation.

关键词： apoptosis autophagy related 5 Beclin1 BV-2 cells caspase-3 inflammation lipopolysaccharide mitophagy Smac survival