Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions
Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell...
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/4027 |
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| author | Alibek Abdrakhmanov Maria A. Yapryntseva Vitaliy O. Kaminskyy Boris Zhivotovsky Vladimir Gogvadze |
| author_facet | Alibek Abdrakhmanov Maria A. Yapryntseva Vitaliy O. Kaminskyy Boris Zhivotovsky Vladimir Gogvadze |
| author_sort | Alibek Abdrakhmanov |
| collection | DOAJ |
| description | Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA alone or in combination with cisplatin did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L (also known as NIX), key participants in receptor-mediated mitophagy. Under hypoxic conditions, stimulation of autophagy, as assessed by the accumulation of lipidated form of LC3 (LC3II), was observed. To exclude the contribution of canonical macroautophagy in LC3II accumulation, experiments were performed using U1810 cells lacking ATG13, a key enzyme of macroautophagy. Despite the absence of ATG13, hypoxia-mediated accumulation of LC3II was not affected, underlying the importance of the receptor-mediated pathway. In order to prove the protective role of BNIP3 against cisplatin-induced apoptosis, BNIP3-deficient A549 cells were used. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, in cells lacking BNIP3, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L and lead to cell death suppression due to the elimination of proapoptotic mitochondria. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions. |
| first_indexed | 2024-03-10T08:57:24Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:24Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4fbfb07dec9b4a0abf0b171b945c419b2023-11-22T07:02:44ZengMDPI AGCancers2072-66942021-08-011316402710.3390/cancers13164027Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic ConditionsAlibek Abdrakhmanov0Maria A. Yapryntseva1Vitaliy O. Kaminskyy2Boris Zhivotovsky3Vladimir Gogvadze4Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, RussiaFaculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, RussiaInstitute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, SwedenFaculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, RussiaFaculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, RussiaTargeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA alone or in combination with cisplatin did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L (also known as NIX), key participants in receptor-mediated mitophagy. Under hypoxic conditions, stimulation of autophagy, as assessed by the accumulation of lipidated form of LC3 (LC3II), was observed. To exclude the contribution of canonical macroautophagy in LC3II accumulation, experiments were performed using U1810 cells lacking ATG13, a key enzyme of macroautophagy. Despite the absence of ATG13, hypoxia-mediated accumulation of LC3II was not affected, underlying the importance of the receptor-mediated pathway. In order to prove the protective role of BNIP3 against cisplatin-induced apoptosis, BNIP3-deficient A549 cells were used. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, in cells lacking BNIP3, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L and lead to cell death suppression due to the elimination of proapoptotic mitochondria. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions.https://www.mdpi.com/2072-6694/13/16/4027cancerhypoxiacell deathautophagymitophagymitochondria |
| spellingShingle | Alibek Abdrakhmanov Maria A. Yapryntseva Vitaliy O. Kaminskyy Boris Zhivotovsky Vladimir Gogvadze Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions Cancers cancer hypoxia cell death autophagy mitophagy mitochondria |
| title | Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions |
| title_full | Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions |
| title_fullStr | Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions |
| title_full_unstemmed | Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions |
| title_short | Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions |
| title_sort | receptor mediated mitophagy rescues cancer cells under hypoxic conditions |
| topic | cancer hypoxia cell death autophagy mitophagy mitochondria |
| url | https://www.mdpi.com/2072-6694/13/16/4027 |
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