Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired
Abstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40680-5 |
| _version_ | 1797558117300436992 |
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| author | Wenjing Liang Shakti Sagar Rishith Ravindran Rita H. Najor Justin M. Quiles Liguo Chi Rachel Y. Diao Benjamin P. Woodall Leonardo J. Leon Erika Zumaya Jason Duran David M. Cauvi Antonio De Maio Eric D. Adler Åsa B. Gustafsson |
| author_facet | Wenjing Liang Shakti Sagar Rishith Ravindran Rita H. Najor Justin M. Quiles Liguo Chi Rachel Y. Diao Benjamin P. Woodall Leonardo J. Leon Erika Zumaya Jason Duran David M. Cauvi Antonio De Maio Eric D. Adler Åsa B. Gustafsson |
| author_sort | Wenjing Liang |
| collection | DOAJ |
| description | Abstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited. |
| first_indexed | 2024-03-10T17:26:59Z |
| format | Article |
| id | doaj.art-02588d67bd4f4beeb14563fa5e5e84d7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:26:59Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-02588d67bd4f4beeb14563fa5e5e84d72023-11-20T10:08:42ZengNature PortfolioNature Communications2041-17232023-08-0114111810.1038/s41467-023-40680-5Mitochondria are secreted in extracellular vesicles when lysosomal function is impairedWenjing Liang0Shakti Sagar1Rishith Ravindran2Rita H. Najor3Justin M. Quiles4Liguo Chi5Rachel Y. Diao6Benjamin P. Woodall7Leonardo J. Leon8Erika Zumaya9Jason Duran10David M. Cauvi11Antonio De Maio12Eric D. Adler13Åsa B. Gustafsson14Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoDepartment of Medicine, University of California San DiegoDepartment of Surgery, University of California San DiegoDepartment of Surgery, University of California San DiegoDepartment of Medicine, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoAbstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.https://doi.org/10.1038/s41467-023-40680-5 |
| spellingShingle | Wenjing Liang Shakti Sagar Rishith Ravindran Rita H. Najor Justin M. Quiles Liguo Chi Rachel Y. Diao Benjamin P. Woodall Leonardo J. Leon Erika Zumaya Jason Duran David M. Cauvi Antonio De Maio Eric D. Adler Åsa B. Gustafsson Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired Nature Communications |
| title | Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| title_full | Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| title_fullStr | Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| title_full_unstemmed | Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| title_short | Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| title_sort | mitochondria are secreted in extracellular vesicles when lysosomal function is impaired |
| url | https://doi.org/10.1038/s41467-023-40680-5 |
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