TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions
Abstract Background Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01524-x |
| _version_ | 1827326740433731584 |
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| author | Laxman Manandhar Raghbendra Kumar Dutta Pradeep Devkota Arun Chhetri Xiaofan Wei Channy Park Hyug Moo Kwon Raekil Park |
| author_facet | Laxman Manandhar Raghbendra Kumar Dutta Pradeep Devkota Arun Chhetri Xiaofan Wei Channy Park Hyug Moo Kwon Raekil Park |
| author_sort | Laxman Manandhar |
| collection | DOAJ |
| description | Abstract Background Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown. Methods To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion. Results This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation. Conclusions Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger’s syndrome and ageing. |
| first_indexed | 2024-03-07T14:49:51Z |
| format | Article |
| id | doaj.art-b32217acb2234f5ab512c12ab4492cfa |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-07T14:49:51Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-b32217acb2234f5ab512c12ab4492cfa2024-03-05T19:46:51ZengBMCCell Communication and Signaling1478-811X2024-02-0122111310.1186/s12964-024-01524-xTFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditionsLaxman Manandhar0Raghbendra Kumar Dutta1Pradeep Devkota2Arun Chhetri3Xiaofan Wei4Channy Park5Hyug Moo Kwon6Raekil Park7Department of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologySchool of Life Sciences, Ulsan National Institute of Science and TechnologyDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and TechnologyAbstract Background Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown. Methods To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion. Results This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation. Conclusions Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger’s syndrome and ageing.https://doi.org/10.1186/s12964-024-01524-xCalciumPeroxisomeAutophagyCatalaseROSTFEB |
| spellingShingle | Laxman Manandhar Raghbendra Kumar Dutta Pradeep Devkota Arun Chhetri Xiaofan Wei Channy Park Hyug Moo Kwon Raekil Park TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions Cell Communication and Signaling Calcium Peroxisome Autophagy Catalase ROS TFEB |
| title | TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions |
| title_full | TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions |
| title_fullStr | TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions |
| title_full_unstemmed | TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions |
| title_short | TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions |
| title_sort | tfeb activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient conditions |
| topic | Calcium Peroxisome Autophagy Catalase ROS TFEB |
| url | https://doi.org/10.1186/s12964-024-01524-x |
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