Parkin coordinates mitochondrial lipid remodeling to execute mitophagy

Report18 October 2022 Transparent process Parkin coordinates mitochondrial lipid remodeling to execute mitophagy Chao-Chieh Lin Chao-Chieh Lin orcid.org/0000-0001-5890-9004 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Jin Yan Jin Yan orcid.org/0000-0002-0116-7705 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Meghan D Kapur Meghan D Kapur Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, ​Investigation, Writing - original draft Search for more papers by this author Kristi L Norris Kristi L Norris Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Cheng-Wei Hsieh Cheng-Wei Hsieh orcid.org/0000-0003-2453-2071 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan Contribution: Methodology Search for more papers by this author De Huang De Huang Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Methodology Search for more papers by this author Nicolas Vitale Nicolas Vitale orcid.org/0000-0002-4752-4907 Institut des Neurosciences Cellulaires et IntégrativesUPR-3212 CNRS - Université de Strasbourg, Strasbourg, France Contribution: Methodology Search for more papers by this author Kah-Leong Lim Kah-Leong Lim orcid.org/0000-0002-5440-2588 Lee Kong Chian School of Medicine, Singapore City, Singapore Contribution: Conceptualization Search for more papers by this author Ziqiang Guan Ziqiang Guan Department of Biochemistry, Duke University Medical Center, Durham, NC, USA Contribution: Methodology Search for more papers by this author Xiao-Fan Wang Xiao-Fan Wang Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Funding acquisition Search for more papers by this author Jen-Tsan Chi Jen-Tsan Chi orcid.org/0000-0003-3433-903X Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Funding acquisition Search for more papers by this author Wei-Yuan Yang Wei-Yuan Yang orcid.org/0000-0002-8939-651X Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan Contribution: Conceptualization, Methodology Search for more papers by this author Tso-Pang Yao Corresponding Author Tso-Pang Yao [email protected] orcid.org/0000-0001-8914-3224 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Writing - review & editing Search for more papers by this author Chao-Chieh Lin Chao-Chieh Lin orcid.org/0000-0001-5890-9004 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Jin Yan Jin Yan orcid.org/0000-0002-0116-7705 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Meghan D Kapur Meghan D Kapur Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, ​Investigation, Writing - original draft Search for more papers by this author Kristi L Norris Kristi L Norris Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Data curation, Formal analysis, ​Investigation, Methodology, Writing - original draft Search for more papers by this author Cheng-Wei Hsieh Cheng-Wei Hsieh orcid.org/0000-0003-2453-2071 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan Contribution: Methodology Search for more papers by this author De Huang De Huang Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Methodology Search for more papers by this author Nicolas Vitale Nicolas Vitale orcid.org/0000-0002-4752-4907 Institut des Neurosciences Cellulaires et IntégrativesUPR-3212 CNRS - Université de Strasbourg, Strasbourg, France Contribution: Methodology Search for more papers by this author Kah-Leong Lim Kah-Leong Lim orcid.org/0000-0002-5440-2588 Lee Kong Chian School of Medicine, Singapore City, Singapore Contribution: Conceptualization Search for more papers by this author Ziqiang Guan Ziqiang Guan Department of Biochemistry, Duke University Medical Center, Durham, NC, USA Contribution: Methodology Search for more papers by this author Xiao-Fan Wang Xiao-Fan Wang Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Funding acquisition Search for more papers by this author Jen-Tsan Chi Jen-Tsan Chi orcid.org/0000-0003-3433-903X Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Funding acquisition Search for more papers by this author Wei-Yuan Yang Wei-Yuan Yang orcid.org/0000-0002-8939-651X Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan Contribution: Conceptualization, Methodology Search for more papers by this author Tso-Pang Yao Corresponding Author Tso-Pang Yao [email protected] orcid.org/0000-0001-8914-3224 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Writing - review & editing Search for more papers by this author Author Information Chao-Chieh Lin1,2,†, Jin Yan1,†, Meghan D Kapur1,†, Kristi L Norris1,†, Cheng-Wei Hsieh3, De Huang1, Nicolas Vitale4, Kah-Leong Lim5, Ziqiang Guan6, Xiao-Fan Wang1, Jen-Tsan Chi2, Wei-Yuan Yang3 and Tso-Pang Yao *,1 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA 2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA 3Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 4Institut des Neurosciences Cellulaires et IntégrativesUPR-3212 CNRS - Université de Strasbourg, Strasbourg, France 5Lee Kong Chian School of Medicine, Singapore City, Singapore 6Department of Biochemistry, Duke University Medical Center, Durham, NC, USA † These authors contributed equally to this work *Corresponding author. Tel: +1 919 613 8654; E-mail: [email protected] EMBO Reports (2022)23:e55191https://doi.org/10.15252/embr.202255191 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria. Synopsis Parkin orchestrates mitophagy by coordinating mitochondrial lipid remodeling and sequential production of mitochondrial phosphatic acid and diacylglycerol. Parkin engages phospholipase D2 (PLD2) to generate mitochondrial phosphatidic acid. Parkin-mediated mitochondrial ubiquitination recruits the ubiquitin-binding autophagic receptors, optineurin and NDP52, which promote mitochondrial diacylglycerol production via Lipin-1. Mitochondrial diacylglycerol production stimulates autophagosome assembly and mitophagy. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 23,Issue 12,06 December 2022This month's cover highlights the article Cryo–EM structure of the octameric pore of Clostridium perfringens β–toxin by Julia Bruggisser, Ioan Iacovache, Horst Posthaus, Benoît Zuber and colleagues. The cover shows two octameric pores of C. Perfringens β–toxin in a lipid bilayer. One pore is shown bound to its receptor CD31 while the second is shown as cut through at the edge of the membrane. Alternating protomers in the oligomer are shown in different shades of blue while for the receptor, which was model based on an AlphaFold prediction, alternating Ig domains are shown in different shades of yellow. (Scientific image by Ioan Iacovache and Julia Bruggisser. Illustration created in Blender (http://www.blender.org) using a phospholipid bilayer template by Dr. Joseph G. Manion (https://cgfigures.gumroad.com/l/eJzxj. Copyright (author or institute): Institute of Anatomy, University of Bern) Volume 23Issue 126 December 2022In this issue ReferencesRelatedDetailsLoading ...