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The ATP/ADP translocase drives mitophagy independent of nucleotide exchange
Mitochondrial homeostasis vitally depends on mitophagy, the programmed degradation of mitochondria. The roster of proteins known to participate in mitophagy remains small. We devised here a multidimensional CRISPR/Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy trigg...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858570/ https://www.ncbi.nlm.nih.gov/pubmed/31618756 http://dx.doi.org/10.1038/s41586-019-1667-4 |
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author | Hoshino, Atsushi Wang, Wei–jia Wada, Shogo McDermott-Roe, Chris Evans, Chantell S. Gosis, Bridget Morley, Michael P. Rathi, Komal S. Li, Jian Li, Kristina Yang, Steven McMannus, Meagen J. Bowman, Caitlyn Potluri, Prasanth Levin, Michael Damrauer, Scott Wallace, Douglas C. Holzbaur, Erika L. F. Arany, Zoltan |
author_facet | Hoshino, Atsushi Wang, Wei–jia Wada, Shogo McDermott-Roe, Chris Evans, Chantell S. Gosis, Bridget Morley, Michael P. Rathi, Komal S. Li, Jian Li, Kristina Yang, Steven McMannus, Meagen J. Bowman, Caitlyn Potluri, Prasanth Levin, Michael Damrauer, Scott Wallace, Douglas C. Holzbaur, Erika L. F. Arany, Zoltan |
author_sort | Hoshino, Atsushi |
collection | PubMed |
description | Mitochondrial homeostasis vitally depends on mitophagy, the programmed degradation of mitochondria. The roster of proteins known to participate in mitophagy remains small. We devised here a multidimensional CRISPR/Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and uncover numerous new components of Parkin-dependent mitophagy(1). Unexpectedly, we identify the adenine nucleotide translocator (ANT) complex as required for mitophagy in multiple cell types. While pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Importantly, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, leading to PINK1 stabilization, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, known to regulate peptide import through TIM23(2). Mice lacking ANT1 reveal blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, these data identify a novel and essential function for ANT as a fundamental mediator of mitophagy in health and disease. |
format | Online Article Text |
id | pubmed-6858570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-68585702020-04-16 The ATP/ADP translocase drives mitophagy independent of nucleotide exchange Hoshino, Atsushi Wang, Wei–jia Wada, Shogo McDermott-Roe, Chris Evans, Chantell S. Gosis, Bridget Morley, Michael P. Rathi, Komal S. Li, Jian Li, Kristina Yang, Steven McMannus, Meagen J. Bowman, Caitlyn Potluri, Prasanth Levin, Michael Damrauer, Scott Wallace, Douglas C. Holzbaur, Erika L. F. Arany, Zoltan Nature Article Mitochondrial homeostasis vitally depends on mitophagy, the programmed degradation of mitochondria. The roster of proteins known to participate in mitophagy remains small. We devised here a multidimensional CRISPR/Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and uncover numerous new components of Parkin-dependent mitophagy(1). Unexpectedly, we identify the adenine nucleotide translocator (ANT) complex as required for mitophagy in multiple cell types. While pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Importantly, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, leading to PINK1 stabilization, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, known to regulate peptide import through TIM23(2). Mice lacking ANT1 reveal blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, these data identify a novel and essential function for ANT as a fundamental mediator of mitophagy in health and disease. 2019-10-16 2019-11 /pmc/articles/PMC6858570/ /pubmed/31618756 http://dx.doi.org/10.1038/s41586-019-1667-4 Text en Reprints and permissions information is available at www.nature.com/reprints (http://www.nature.com/reprints) . Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hoshino, Atsushi Wang, Wei–jia Wada, Shogo McDermott-Roe, Chris Evans, Chantell S. Gosis, Bridget Morley, Michael P. Rathi, Komal S. Li, Jian Li, Kristina Yang, Steven McMannus, Meagen J. Bowman, Caitlyn Potluri, Prasanth Levin, Michael Damrauer, Scott Wallace, Douglas C. Holzbaur, Erika L. F. Arany, Zoltan The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title | The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title_full | The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title_fullStr | The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title_full_unstemmed | The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title_short | The ATP/ADP translocase drives mitophagy independent of nucleotide exchange |
title_sort | atp/adp translocase drives mitophagy independent of nucleotide exchange |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858570/ https://www.ncbi.nlm.nih.gov/pubmed/31618756 http://dx.doi.org/10.1038/s41586-019-1667-4 |
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