Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface
Abstract During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria s...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-03-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05723-1 |
| _version_ | 1827982596539154432 |
|---|---|
| author | Ananth Ponneri Babuharisankar Cheng-Liang Kuo Han-Yu Chou Vidhya Tangeda Chi-Chen Fan Chung-Hsing Chen Yung-Hsi Kao Alan Yueh-Luen Lee |
| author_facet | Ananth Ponneri Babuharisankar Cheng-Liang Kuo Han-Yu Chou Vidhya Tangeda Chi-Chen Fan Chung-Hsing Chen Yung-Hsi Kao Alan Yueh-Luen Lee |
| author_sort | Ananth Ponneri Babuharisankar |
| collection | DOAJ |
| description | Abstract During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression. |
| first_indexed | 2024-04-09T22:35:23Z |
| format | Article |
| id | doaj.art-c66c754e9ab74cdfa52468a0bafd12fb |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T22:35:23Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c66c754e9ab74cdfa52468a0bafd12fb2023-03-22T12:32:01ZengNature Publishing GroupCell Death and Disease2041-48892023-03-0114311710.1038/s41419-023-05723-1Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interfaceAnanth Ponneri Babuharisankar0Cheng-Liang Kuo1Han-Yu Chou2Vidhya Tangeda3Chi-Chen Fan4Chung-Hsing Chen5Yung-Hsi Kao6Alan Yueh-Luen Lee7PhD program in molecular medicine, NHRI & NCUNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesPhD program in molecular medicine, NHRI & NCUDepartment of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical TechnologyNational Institute of Cancer Research, National Health Research InstitutesPhD program in molecular medicine, NHRI & NCUPhD program in molecular medicine, NHRI & NCUAbstract During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression.https://doi.org/10.1038/s41419-023-05723-1 |
| spellingShingle | Ananth Ponneri Babuharisankar Cheng-Liang Kuo Han-Yu Chou Vidhya Tangeda Chi-Chen Fan Chung-Hsing Chen Yung-Hsi Kao Alan Yueh-Luen Lee Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface Cell Death and Disease |
| title | Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface |
| title_full | Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface |
| title_fullStr | Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface |
| title_full_unstemmed | Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface |
| title_short | Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface |
| title_sort | mitochondrial lon induced mitophagy benefits hypoxic resistance via ca2 dependent fundc1 phosphorylation at the er mitochondria interface |
| url | https://doi.org/10.1038/s41419-023-05723-1 |
| work_keys_str_mv | AT ananthponneribabuharisankar mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT chengliangkuo mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT hanyuchou mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT vidhyatangeda mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT chichenfan mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT chunghsingchen mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT yunghsikao mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface AT alanyuehluenlee mitochondrialloninducedmitophagybenefitshypoxicresistanceviaca2dependentfundc1phosphorylationattheermitochondriainterface |