Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
Myeloid cell leukemia-1 (<i>Mcl-1</i>) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that <i>Mcl-1</i>′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, da...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/9/1469 |
| _version_ | 1827672920235704320 |
|---|---|
| author | Alexandra G. Moyzis Navraj S. Lally Wenjing Liang Rita H. Najor Åsa B. Gustafsson |
| author_facet | Alexandra G. Moyzis Navraj S. Lally Wenjing Liang Rita H. Najor Åsa B. Gustafsson |
| author_sort | Alexandra G. Moyzis |
| collection | DOAJ |
| description | Myeloid cell leukemia-1 (<i>Mcl-1</i>) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that <i>Mcl-1</i>′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that <i>Mcl-1</i> plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether <i>Mcl-1</i> regulates autophagy in the heart. We found that cardiac-specific overexpression of <i>Mcl-1</i> had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, <i>Mcl-1</i> did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of <i>Mcl-1</i> increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via <i>Mcl-1</i>′s LC3-interacting regions and mutation of these sites significantly reduced <i>Mcl-1</i>-mediated mitochondrial clearance. We also found that <i>Mcl-1</i> interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that <i>Mcl-1</i> suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor. |
| first_indexed | 2024-03-10T04:16:02Z |
| format | Article |
| id | doaj.art-7374be493b0a4ebab23b2257751eb359 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:16:02Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-7374be493b0a4ebab23b2257751eb3592023-11-23T07:59:39ZengMDPI AGCells2073-44092022-04-01119146910.3390/cells11091469Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial DamageAlexandra G. Moyzis0Navraj S. Lally1Wenjing Liang2Rita H. Najor3Åsa B. Gustafsson4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92130, USAMyeloid cell leukemia-1 (<i>Mcl-1</i>) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that <i>Mcl-1</i>′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that <i>Mcl-1</i> plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether <i>Mcl-1</i> regulates autophagy in the heart. We found that cardiac-specific overexpression of <i>Mcl-1</i> had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, <i>Mcl-1</i> did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of <i>Mcl-1</i> increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via <i>Mcl-1</i>′s LC3-interacting regions and mutation of these sites significantly reduced <i>Mcl-1</i>-mediated mitochondrial clearance. We also found that <i>Mcl-1</i> interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that <i>Mcl-1</i> suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor.https://www.mdpi.com/2073-4409/11/9/1469<i>Mcl-1</i>Bnip3mitochondriaautophagymitophagyheart |
| spellingShingle | Alexandra G. Moyzis Navraj S. Lally Wenjing Liang Rita H. Najor Åsa B. Gustafsson Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage Cells <i>Mcl-1</i> Bnip3 mitochondria autophagy mitophagy heart |
| title | Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage |
| title_full | Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage |
| title_fullStr | Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage |
| title_full_unstemmed | Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage |
| title_short | Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage |
| title_sort | mcl 1 differentially regulates autophagy in response to changes in energy status and mitochondrial damage |
| topic | <i>Mcl-1</i> Bnip3 mitochondria autophagy mitophagy heart |
| url | https://www.mdpi.com/2073-4409/11/9/1469 |
| work_keys_str_mv | AT alexandragmoyzis mcl1differentiallyregulatesautophagyinresponsetochangesinenergystatusandmitochondrialdamage AT navrajslally mcl1differentiallyregulatesautophagyinresponsetochangesinenergystatusandmitochondrialdamage AT wenjingliang mcl1differentiallyregulatesautophagyinresponsetochangesinenergystatusandmitochondrialdamage AT ritahnajor mcl1differentiallyregulatesautophagyinresponsetochangesinenergystatusandmitochondrialdamage AT asabgustafsson mcl1differentiallyregulatesautophagyinresponsetochangesinenergystatusandmitochondrialdamage |