Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene
Abstract Background MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson’s disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast inte...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Biological Procedures Online |
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| Online Access: | https://doi.org/10.1186/s12575-024-00236-3 |
| _version_ | 1797209525223161856 |
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| author | Hongzhi Li Jing Zhang Yuqi Shen Yifan Ye Qingyou Jiang Lan Chen Bohao Sun Zhuo Chen Luxi Shen Hezhi Fang Jifeng Yang Haihua Gu |
| author_facet | Hongzhi Li Jing Zhang Yuqi Shen Yifan Ye Qingyou Jiang Lan Chen Bohao Sun Zhuo Chen Luxi Shen Hezhi Fang Jifeng Yang Haihua Gu |
| author_sort | Hongzhi Li |
| collection | DOAJ |
| description | Abstract Background MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson’s disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP+-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice. Results The study in vitro showed NDI1 prevented MPP+-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra. Conclusions NDI1 compensates for the defective complex I in MPP+/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance. |
| first_indexed | 2024-04-24T09:56:05Z |
| format | Article |
| id | doaj.art-15cc9dfaf1134b84a5d90d9c1059b105 |
| institution | Directory Open Access Journal |
| issn | 1480-9222 |
| language | English |
| last_indexed | 2024-04-24T09:56:05Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Biological Procedures Online |
| spelling | doaj.art-15cc9dfaf1134b84a5d90d9c1059b1052024-04-14T11:08:04ZengBMCBiological Procedures Online1480-92222024-04-0126111510.1186/s12575-024-00236-3Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 GeneHongzhi Li0Jing Zhang1Yuqi Shen2Yifan Ye3Qingyou Jiang4Lan Chen5Bohao Sun6Zhuo Chen7Luxi Shen8Hezhi Fang9Jifeng Yang10Haihua Gu11Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Internal Neurology, Beijing Friendship Hospital, Capital Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityAbstract Background MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson’s disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP+-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice. Results The study in vitro showed NDI1 prevented MPP+-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra. Conclusions NDI1 compensates for the defective complex I in MPP+/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance.https://doi.org/10.1186/s12575-024-00236-3Parkinson’s diseaseMPTPRespiratory chain complexYeast NDI1 geneViral vectorTherapy |
| spellingShingle | Hongzhi Li Jing Zhang Yuqi Shen Yifan Ye Qingyou Jiang Lan Chen Bohao Sun Zhuo Chen Luxi Shen Hezhi Fang Jifeng Yang Haihua Gu Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene Biological Procedures Online Parkinson’s disease MPTP Respiratory chain complex Yeast NDI1 gene Viral vector Therapy |
| title | Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene |
| title_full | Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene |
| title_fullStr | Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene |
| title_full_unstemmed | Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene |
| title_short | Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene |
| title_sort | targeting mitochondrial complex i deficiency in mpp mptp induced parkinson s disease cell culture and mouse models by transducing yeast ndi1 gene |
| topic | Parkinson’s disease MPTP Respiratory chain complex Yeast NDI1 gene Viral vector Therapy |
| url | https://doi.org/10.1186/s12575-024-00236-3 |
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