Cell Reports (Aug 2020)
Mitochondrial Regulation of the 26S Proteasome
- Thomas Meul,
- Korbinian Berschneider,
- Sabine Schmitt,
- Christoph H. Mayr,
- Laura F. Mattner,
- Herbert B. Schiller,
- Ayse S. Yazgili,
- Xinyuan Wang,
- Christina Lukas,
- Camille Schlesser,
- Cornelia Prehn,
- Jerzy Adamski,
- Elisabeth Graf,
- Thomas Schwarzmayr,
- Fabiana Perocchi,
- Alexandra Kukat,
- Aleksandra Trifunovic,
- Laura Kremer,
- Holger Prokisch,
- Bastian Popper,
- Christine von Toerne,
- Stefanie M. Hauck,
- Hans Zischka,
- Silke Meiners
Affiliations
- Thomas Meul
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Korbinian Berschneider
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Sabine Schmitt
- Institute of Toxicology and Environmental Hygiene, Technical University of Munich, School of Medicine, 80802 Munich, Germany; Research Unit Protein Science, Helmholtz Zentrum München, 80939 Munich, Germany
- Christoph H. Mayr
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Laura F. Mattner
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Herbert B. Schiller
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Ayse S. Yazgili
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Xinyuan Wang
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Christina Lukas
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Camille Schlesser
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany
- Cornelia Prehn
- Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
- Jerzy Adamski
- Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85350 Freising-Weihenstephan, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
- Elisabeth Graf
- Institute of Human Genetics, Core Facility Next-Generation-Sequencing, Helmholtz Zentrum München, 85764 Munich, Germany
- Thomas Schwarzmayr
- Institute of Human Genetics, Core Facility Next-Generation-Sequencing, Helmholtz Zentrum München, 85764 Munich, Germany
- Fabiana Perocchi
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, 85764, Neuherberg, Germany; Munich Cluster for Systems Neurology, 81377, Munich, Germany
- Alexandra Kukat
- Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Medical Faculty, University of Cologne, D-50931 Cologne, Germany
- Aleksandra Trifunovic
- Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Medical Faculty, University of Cologne, D-50931 Cologne, Germany
- Laura Kremer
- Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Holger Prokisch
- Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany
- Bastian Popper
- Biomedical Center, Core facility animal models, Ludwig-Maximilian-University Munich, 82152 Martinsried, Germany; Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Christine von Toerne
- Research Unit Protein Science, Helmholtz Zentrum München, 80939 Munich, Germany
- Stefanie M. Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, 80939 Munich, Germany
- Hans Zischka
- Institute of Toxicology and Environmental Hygiene, Technical University of Munich, School of Medicine, 80802 Munich, Germany; Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Silke Meiners
- Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany; Corresponding author
- Journal volume & issue
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Vol. 32,
no. 8
p. 108059
Abstract
Summary: The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications.
