AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria
Abstract Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation f...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07957-7 |
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| _version_ | 1849234213668126720 |
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| author | Lupeng Chen Yue Liu Junzhi Zhang Tongxing Song Jian Wu Zhuqing Ren |
| author_facet | Lupeng Chen Yue Liu Junzhi Zhang Tongxing Song Jian Wu Zhuqing Ren |
| author_sort | Lupeng Chen |
| collection | DOAJ |
| description | Abstract Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation factor 1(ARF1) and perilipin2 (Plin2) regulates LD-mitochondrion contacts under starvation conditions, facilitating the transfer of fatty acids from LDs to mitochondria. In C2C12 cells, starvation increased ARF1’s GTP-binding activity and its localization to mitochondria, enhancing ARF1’s binding to Plin2 and facilitating fatty acid flow from LDs to mitochondria. In contrast, knockdown of ARF1 reduced LD-mitochondrion interactions and blocked fatty acids transfer. Additionally, ARF1-mediated interactions were regulated by AMPK; inhibiting AMPK activity reduced ARF1 localization to LDs and mitochondria, and blocked LD-mitochondrion interactions. In mice, starvation increased ARF1 expression in muscle tissue and LD-mitochondrion contacts. Conversely, inhibiting ARF1 led to lipid accumulation in muscle tissue. In conclusion, our work suggests that ARF1 is a critical regulator of LD-mitochondrion interactions and plays a significant role in energy metabolism regulation in skeletal muscle. |
| format | Article |
| id | doaj-art-0a5e7b666eaf48a8886c12b75a4e2aaa |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0a5e7b666eaf48a8886c12b75a4e2aaa2025-08-20T04:03:13ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111410.1038/s41419-025-07957-7AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondriaLupeng Chen0Yue Liu1Junzhi Zhang2Tongxing Song3Jian Wu4Zhuqing Ren5Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityKey Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural UniversityAbstract Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation factor 1(ARF1) and perilipin2 (Plin2) regulates LD-mitochondrion contacts under starvation conditions, facilitating the transfer of fatty acids from LDs to mitochondria. In C2C12 cells, starvation increased ARF1’s GTP-binding activity and its localization to mitochondria, enhancing ARF1’s binding to Plin2 and facilitating fatty acid flow from LDs to mitochondria. In contrast, knockdown of ARF1 reduced LD-mitochondrion interactions and blocked fatty acids transfer. Additionally, ARF1-mediated interactions were regulated by AMPK; inhibiting AMPK activity reduced ARF1 localization to LDs and mitochondria, and blocked LD-mitochondrion interactions. In mice, starvation increased ARF1 expression in muscle tissue and LD-mitochondrion contacts. Conversely, inhibiting ARF1 led to lipid accumulation in muscle tissue. In conclusion, our work suggests that ARF1 is a critical regulator of LD-mitochondrion interactions and plays a significant role in energy metabolism regulation in skeletal muscle.https://doi.org/10.1038/s41419-025-07957-7 |
| spellingShingle | Lupeng Chen Yue Liu Junzhi Zhang Tongxing Song Jian Wu Zhuqing Ren AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria Cell Death and Disease |
| title | AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| title_full | AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| title_fullStr | AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| title_full_unstemmed | AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| title_short | AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| title_sort | ampk regulates arf1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria |
| url | https://doi.org/10.1038/s41419-025-07957-7 |
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