l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells
Abstract We previously reported that perfluorooctanesulfonate (PFOS) causes autophagy-induced apoptosis in renal tubular cells (RTCs) through a mechanism dependent on reactive oxygen species (ROS)/extracellular signal-regulated kinase. This study extended our findings and determined the therapeutic...
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Nature Portfolio
2022-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-08771-3 |
| _version_ | 1818320958006493184 |
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| author | Yuan-Chii Gladys Lee Hsiu-Chu Chou Yen-Ting Chen Szu-Yu Tung Tsui-Ling Ko Batsaikhan Buyandelger Li-Li Wen Shu-Hui Juan |
| author_facet | Yuan-Chii Gladys Lee Hsiu-Chu Chou Yen-Ting Chen Szu-Yu Tung Tsui-Ling Ko Batsaikhan Buyandelger Li-Li Wen Shu-Hui Juan |
| author_sort | Yuan-Chii Gladys Lee |
| collection | DOAJ |
| description | Abstract We previously reported that perfluorooctanesulfonate (PFOS) causes autophagy-induced apoptosis in renal tubular cells (RTCs) through a mechanism dependent on reactive oxygen species (ROS)/extracellular signal-regulated kinase. This study extended our findings and determined the therapeutic potency of l-Carnitine in PFOS-treated RTCs. l-Carnitine (10 mM) reversed the effects of PFOS (100 µM) on autophagy induction and impaired autophagy flux. Furthermore, it downregulated the protein level of p47Phox, which is partly related to PFOS-induced increased cytosolic ROS in RTCs. Moreover, l-Carnitine reduced ROS production in mitochondria and restored PFOS-impeded mitochondrial function, leading to sustained normal adenosine triphosphate synthesis and oxygen consumption and reduced proton leakage in a Seahorse XF stress test. The increased inositol-requiring enzyme 1α expression by PFOS, which indicated endoplasmic reticulum (ER) stress activation, was associated with PFOS-mediated autophagy activation that could be attenuated through 4-phenylbutyrate (5 mM, an ER stress inhibitor) and l-Carnitine pretreatment. Therefore, by reducing the level of IRE1α, l-Carnitine reduced the levels of Beclin and LC3BII, consequently reducing the level of apoptotic biomarkers including Bax and cleaving PARP and caspase 3. Collectively, these results indicate that through the elimination of oxidative stress, extracellular signal–regulated kinase activation, and ER stress, l-Carnitine reduced cell autophagy/apoptosis and concomitantly increased cell viability in RTCs. This study clarified the potential mechanism of PFOS-mediated RTC apoptosis and provided a new strategy for using l-Carnitine to prevent and treat PFOS-induced RTC apoptosis. |
| first_indexed | 2024-12-13T10:33:16Z |
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| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T10:33:16Z |
| publishDate | 2022-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-02fd5ecde73749b7aa8d153d142a60102022-12-21T23:50:47ZengNature PortfolioScientific Reports2045-23222022-03-0112111410.1038/s41598-022-08771-3l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cellsYuan-Chii Gladys Lee0Hsiu-Chu Chou1Yen-Ting Chen2Szu-Yu Tung3Tsui-Ling Ko4Batsaikhan Buyandelger5Li-Li Wen6Shu-Hui Juan7Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical UniversityDepartment of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Physiology, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Physiology, School of Medicine, College of Medicine, Taipei Medical UniversityCollege of Science, National Sun Yat-Sen UniversityDepartment of Physiology, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Clinical Laboratory, En Chu Kong HospitalDepartment of Physiology, School of Medicine, College of Medicine, Taipei Medical UniversityAbstract We previously reported that perfluorooctanesulfonate (PFOS) causes autophagy-induced apoptosis in renal tubular cells (RTCs) through a mechanism dependent on reactive oxygen species (ROS)/extracellular signal-regulated kinase. This study extended our findings and determined the therapeutic potency of l-Carnitine in PFOS-treated RTCs. l-Carnitine (10 mM) reversed the effects of PFOS (100 µM) on autophagy induction and impaired autophagy flux. Furthermore, it downregulated the protein level of p47Phox, which is partly related to PFOS-induced increased cytosolic ROS in RTCs. Moreover, l-Carnitine reduced ROS production in mitochondria and restored PFOS-impeded mitochondrial function, leading to sustained normal adenosine triphosphate synthesis and oxygen consumption and reduced proton leakage in a Seahorse XF stress test. The increased inositol-requiring enzyme 1α expression by PFOS, which indicated endoplasmic reticulum (ER) stress activation, was associated with PFOS-mediated autophagy activation that could be attenuated through 4-phenylbutyrate (5 mM, an ER stress inhibitor) and l-Carnitine pretreatment. Therefore, by reducing the level of IRE1α, l-Carnitine reduced the levels of Beclin and LC3BII, consequently reducing the level of apoptotic biomarkers including Bax and cleaving PARP and caspase 3. Collectively, these results indicate that through the elimination of oxidative stress, extracellular signal–regulated kinase activation, and ER stress, l-Carnitine reduced cell autophagy/apoptosis and concomitantly increased cell viability in RTCs. This study clarified the potential mechanism of PFOS-mediated RTC apoptosis and provided a new strategy for using l-Carnitine to prevent and treat PFOS-induced RTC apoptosis.https://doi.org/10.1038/s41598-022-08771-3 |
| spellingShingle | Yuan-Chii Gladys Lee Hsiu-Chu Chou Yen-Ting Chen Szu-Yu Tung Tsui-Ling Ko Batsaikhan Buyandelger Li-Li Wen Shu-Hui Juan l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells Scientific Reports |
| title | l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells |
| title_full | l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells |
| title_fullStr | l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells |
| title_full_unstemmed | l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells |
| title_short | l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells |
| title_sort | l carnitine reduces reactive oxygen species endoplasmic reticulum stress and maintains mitochondrial function during autophagy mediated cell apoptosis in perfluorooctanesulfonate treated renal tubular cells |
| url | https://doi.org/10.1038/s41598-022-08771-3 |
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