Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process
Abstract Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-023-00445-y |
| _version_ | 1797377107140018176 |
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| author | Anjila Dongol Xi Chen Peng Zheng Zehra Boz Seyhan Xu-Feng Huang |
| author_facet | Anjila Dongol Xi Chen Peng Zheng Zehra Boz Seyhan Xu-Feng Huang |
| author_sort | Anjila Dongol |
| collection | DOAJ |
| description | Abstract Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases. |
| first_indexed | 2024-03-08T19:48:12Z |
| format | Article |
| id | doaj.art-478887e2409c41e597e257fcf8adc873 |
| institution | Directory Open Access Journal |
| issn | 1745-6150 |
| language | English |
| last_indexed | 2024-03-08T19:48:12Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology Direct |
| spelling | doaj.art-478887e2409c41e597e257fcf8adc8732023-12-24T12:11:42ZengBMCBiology Direct1745-61502023-12-0118111710.1186/s13062-023-00445-yQuinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging processAnjila Dongol0Xi Chen1Peng Zheng2Zehra Boz Seyhan3Xu-Feng Huang4School of Medical, Indigenous and Health Sciences, University of WollongongSchool of Medical, Indigenous and Health Sciences, University of WollongongSchool of Medical, Indigenous and Health Sciences, University of WollongongSchool of Medical, Indigenous and Health Sciences, University of WollongongSchool of Medical, Indigenous and Health Sciences, University of WollongongAbstract Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.https://doi.org/10.1186/s13062-023-00445-yMicrogliaQuinolinic acidNeuroinflammationMitochondriaMitophagyMitolysosome |
| spellingShingle | Anjila Dongol Xi Chen Peng Zheng Zehra Boz Seyhan Xu-Feng Huang Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process Biology Direct Microglia Quinolinic acid Neuroinflammation Mitochondria Mitophagy Mitolysosome |
| title | Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process |
| title_full | Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process |
| title_fullStr | Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process |
| title_full_unstemmed | Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process |
| title_short | Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process |
| title_sort | quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in c elegans a mechanism of impaired aging process |
| topic | Microglia Quinolinic acid Neuroinflammation Mitochondria Mitophagy Mitolysosome |
| url | https://doi.org/10.1186/s13062-023-00445-y |
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