Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis
Abstract Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD,...
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| Format: | Article |
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Nature Portfolio
2023-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-34710-x |
| _version_ | 1827948141672923136 |
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| author | R. Undamatla O. G. Fagunloye J. Chen L. R. Edmunds A. Murali A. Mills B. Xie M. M. Pangburn I. Sipula G. Gibson C. St. Croix M. J. Jurczak |
| author_facet | R. Undamatla O. G. Fagunloye J. Chen L. R. Edmunds A. Murali A. Mills B. Xie M. M. Pangburn I. Sipula G. Gibson C. St. Croix M. J. Jurczak |
| author_sort | R. Undamatla |
| collection | DOAJ |
| description | Abstract Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN accelerates the onset of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD. |
| first_indexed | 2024-04-09T12:49:43Z |
| format | Article |
| id | doaj.art-aa7fe506c5da4b44ab0be9759318a6ae |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T12:49:43Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-aa7fe506c5da4b44ab0be9759318a6ae2023-05-14T11:16:38ZengNature PortfolioScientific Reports2045-23222023-05-0113111310.1038/s41598-023-34710-xReduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosisR. Undamatla0O. G. Fagunloye1J. Chen2L. R. Edmunds3A. Murali4A. Mills5B. Xie6M. M. Pangburn7I. Sipula8G. Gibson9C. St. Croix10M. J. Jurczak11Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghDepartment of Cell Biology, Center for Biologic Imaging, University of PittsburghDepartment of Cell Biology, Center for Biologic Imaging, University of PittsburghDivision of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of PittsburghAbstract Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN accelerates the onset of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD.https://doi.org/10.1038/s41598-023-34710-x |
| spellingShingle | R. Undamatla O. G. Fagunloye J. Chen L. R. Edmunds A. Murali A. Mills B. Xie M. M. Pangburn I. Sipula G. Gibson C. St. Croix M. J. Jurczak Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis Scientific Reports |
| title | Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis |
| title_full | Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis |
| title_fullStr | Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis |
| title_full_unstemmed | Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis |
| title_short | Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis |
| title_sort | reduced mitophagy is an early feature of nafld and liver specific parkin knockout hastens the onset of steatosis inflammation and fibrosis |
| url | https://doi.org/10.1038/s41598-023-34710-x |
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