Mitochondria! Regulation of the 26S Proteasome

被引：33

作者：

Meul, Thomas ^{[1
]}

Berschneider, Korbinian ^{[1
]}

Schmitt, Sabine ^{[2
,10
]}

Mayr, Christoph H. ^{[1
]}

Mattner, Laura F. ^{[1
]}

Schiller, Herbert B. ^{[1
]}

Yazgili, Ayse S. ^{[1
]}

Wang, Xinyuan ^{[1
]}

Lukas, Christina ^{[1
]}

Schlesser, Camille ^{[1
]}

Prehn, Cornelia ^{[3
]}

Adamski, Jerzy ^{[3
,13
,14
]}

Graf, Elisabeth ^{[4
]}

Schwarzmayr, Thomas ^{[4
]}

Perocchi, Fabiana ^{[5
,12
]}

Kukat, Alexandra ^{[6
]}

Trifunovic, Aleksandra ^{[6
]}

Kremer, Laura ^{[7
]}

Prokisch, Holger ^{[7
,15
]}

Popper, Bastian ^{[8
,9
]}

von Toerne, Christine ^{[10
]}

Hauck, Stefanie M. ^{[10
]}

Zischka, Hans ^{[2
,11
]}

Meiners, Silke ^{[1
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Univ Hosp, German Ctr Lung Res DZL, Comprehens Pneumol Ctr CPC,Helmholtz Zentrum Munc, D-81377 Munich, Germany

[2] Tech Univ Munich, Sch Med, Inst Toxicol & Environm Hyg, D-80802 Munich, Germany

[3] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Endocrinol & Metab, Genome Anal Ctr, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

[4] Helmholtz Zentrum Munchen, Inst Human Genet, Core Facil Next Generat Sequencing, D-85764 Munich, Germany

[5] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Helmholtz Diabet Ctr HDC, D-85764 Neuherberg, Germany

[6] Univ Cologne, Med Fac, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[7] Helmholtz Zentrum Munchen, Inst Neurogen, D-85764 Neuherberg, Germany

[8] Ludwig Maximilian Univ Munich, Biomed Ctr, Core Facil Anim Models, D-82152 Martinsried, Germany

[9] Tech Univ Munich, Sch Med, Inst Pathol, D-81675 Munich, Germany

[10] Helmholtz Zentrum Munchen, Res Unit Prot Sci, D-80939 Munich, Germany

[11] Helmholtz Zentrum Munchen, Inst Mol Toxicol & Pharmacol, D-85764 Neuherberg, Germany

[12] Munich Cluster Syst Neurol, D-81377 Munich, Germany

[13] Tech Univ Munich, Lehrstuhl Expt Genet, D-85350 Freising Weihenstephan, Germany

[14] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, 8 Med Dr, Singapore 117597, Singapore

[15] Tech Univ Munich TUM, Sch Med, Inst Human Genet, D-81675 Munich, Germany

来源：

CELL REPORTS | 2020年 / 32卷 / 08期

关键词：

COMPLEX I DEFICIENCY; PROTEIN-SYNTHESIS; MUTATIONS CAUSE; CULTURED-CELLS; DEGRADATION; PHOSPHORYLATION; DISEASES; SUBUNITS; PATHWAY; SYSTEM;

D O I：

10.1016/j.celrep.2020.108059

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：23

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