Cargando…
Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis
Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus pr...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8817016/ https://www.ncbi.nlm.nih.gov/pubmed/34511600 http://dx.doi.org/10.1038/s41418-021-00868-y |
_version_ | 1784645546953146368 |
---|---|
author | Choi, Chang-Yong Vo, Mai Tram Nicholas, John Choi, Young Bong |
author_facet | Choi, Chang-Yong Vo, Mai Tram Nicholas, John Choi, Young Bong |
author_sort | Choi, Chang-Yong |
collection | PubMed |
description | Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus productive infection. However, the exact molecular mechanisms underlying activation of mitophagy and regulation of apoptosis remain poorly understood despite the identification of various mitophagy-associated proteins. Here, we report that the mitochondrial translation elongation factor Tu, a mitophagy-associated protein encoded by the TUFM gene, locates in part on the outer membrane of mitochondria (OMM) where it acts as an inhibitor of altered mitochondria-induced apoptosis through its autophagic function. Inducible depletion of TUFM potentiated caspase-8-mediated apoptosis in virus-infected cells with accumulation of altered mitochondria. In addition, TUFM depletion promoted caspase-8 activation induced by treatment with TNF-related apoptosis-inducing ligand in cancer cells, potentially via dysregulation of mitochondrial dynamics and mitophagy. Importantly, we revealed the existence of and structural requirements for autophagy-competent TUFM on the OMM; the GxxxG motif within the N-terminal mitochondrial targeting sequences of TUFM was required for self-dimerization and mitophagy. Furthermore, we found that autophagy-competent TUFM was subject to ubiquitin-proteasome-mediated degradation but stabilized upon mitophagy or autophagy activation. Moreover, overexpression of autophagy-competent TUFM could inhibit caspase-8 activation. These studies extend our knowledge of mitophagy regulation of apoptosis and could provide a novel strategic basis for targeted therapy of cancer and viral diseases. |
format | Online Article Text |
id | pubmed-8817016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88170162022-02-16 Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis Choi, Chang-Yong Vo, Mai Tram Nicholas, John Choi, Young Bong Cell Death Differ Article Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus productive infection. However, the exact molecular mechanisms underlying activation of mitophagy and regulation of apoptosis remain poorly understood despite the identification of various mitophagy-associated proteins. Here, we report that the mitochondrial translation elongation factor Tu, a mitophagy-associated protein encoded by the TUFM gene, locates in part on the outer membrane of mitochondria (OMM) where it acts as an inhibitor of altered mitochondria-induced apoptosis through its autophagic function. Inducible depletion of TUFM potentiated caspase-8-mediated apoptosis in virus-infected cells with accumulation of altered mitochondria. In addition, TUFM depletion promoted caspase-8 activation induced by treatment with TNF-related apoptosis-inducing ligand in cancer cells, potentially via dysregulation of mitochondrial dynamics and mitophagy. Importantly, we revealed the existence of and structural requirements for autophagy-competent TUFM on the OMM; the GxxxG motif within the N-terminal mitochondrial targeting sequences of TUFM was required for self-dimerization and mitophagy. Furthermore, we found that autophagy-competent TUFM was subject to ubiquitin-proteasome-mediated degradation but stabilized upon mitophagy or autophagy activation. Moreover, overexpression of autophagy-competent TUFM could inhibit caspase-8 activation. These studies extend our knowledge of mitophagy regulation of apoptosis and could provide a novel strategic basis for targeted therapy of cancer and viral diseases. Nature Publishing Group UK 2021-09-12 2022-02 /pmc/articles/PMC8817016/ /pubmed/34511600 http://dx.doi.org/10.1038/s41418-021-00868-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Choi, Chang-Yong Vo, Mai Tram Nicholas, John Choi, Young Bong Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title | Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title_full | Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title_fullStr | Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title_full_unstemmed | Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title_short | Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis |
title_sort | autophagy-competent mitochondrial translation elongation factor tufm inhibits caspase-8-mediated apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8817016/ https://www.ncbi.nlm.nih.gov/pubmed/34511600 http://dx.doi.org/10.1038/s41418-021-00868-y |
work_keys_str_mv | AT choichangyong autophagycompetentmitochondrialtranslationelongationfactortufminhibitscaspase8mediatedapoptosis AT vomaitram autophagycompetentmitochondrialtranslationelongationfactortufminhibitscaspase8mediatedapoptosis AT nicholasjohn autophagycompetentmitochondrialtranslationelongationfactortufminhibitscaspase8mediatedapoptosis AT choiyoungbong autophagycompetentmitochondrialtranslationelongationfactortufminhibitscaspase8mediatedapoptosis |