Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation
Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14826 |
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| author | Ji Hyun Lee Kyu Min Kim Eun Hee Jung Hye Rim Lee Ji Hye Yang Sam Seok Cho Sung Hwan Ki |
| author_facet | Ji Hyun Lee Kyu Min Kim Eun Hee Jung Hye Rim Lee Ji Hye Yang Sam Seok Cho Sung Hwan Ki |
| author_sort | Ji Hyun Lee |
| collection | DOAJ |
| description | Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis. |
| first_indexed | 2024-03-10T21:42:54Z |
| format | Article |
| id | doaj.art-8f8de7356cb94c93aef13d0eb6520f5c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:42:54Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8f8de7356cb94c93aef13d0eb6520f5c2023-11-19T14:31:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191482610.3390/ijms241914826Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell ActivationJi Hyun Lee0Kyu Min Kim1Eun Hee Jung2Hye Rim Lee3Ji Hye Yang4Sam Seok Cho5Sung Hwan Ki6College of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaCollege of Korean Medicine, Dongshin University, Naju 58245, Republic of KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, Republic of KoreaHepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.https://www.mdpi.com/1422-0067/24/19/14826liver fibrosishepatic stellate cellmitophagyparkinSmad2 |
| spellingShingle | Ji Hyun Lee Kyu Min Kim Eun Hee Jung Hye Rim Lee Ji Hye Yang Sam Seok Cho Sung Hwan Ki Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation International Journal of Molecular Sciences liver fibrosis hepatic stellate cell mitophagy parkin Smad2 |
| title | Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation |
| title_full | Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation |
| title_fullStr | Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation |
| title_full_unstemmed | Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation |
| title_short | Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation |
| title_sort | parkin mediated mitophagy by tgf β is connected with hepatic stellate cell activation |
| topic | liver fibrosis hepatic stellate cell mitophagy parkin Smad2 |
| url | https://www.mdpi.com/1422-0067/24/19/14826 |
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