PXD019697

PXD019697 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial regulation of the 26S proteasome
Description	The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Inhibition of the respiratory chain impairs proteasome activity, regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome. Defects in respiratory chain caused metabolic reprogramming of the Krebs cycle and deficiency in the amino acid aspartate resulting in reduced 26S proteasome function. Aspartate supplementation fully restored assembly and activity of 26S proteasome complexes. This metabolic reprogramming involved sensing of aspartate via the mTORC1 pathway and the mTORC1-dependent transcriptional activation of defined proteasome assembly factors. Metabolic regulation of 26S function was confirmed in patient-derived skin fibroblasts with respiratory dysfunction containing a single mitochondrial mutation. Importantly, treatment of primary human lung fibroblasts with the respiratory chain inhibitor and anti-diabetic drug metformin similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.
HostingRepository	PRIDE
AnnounceDate	2020-09-18
AnnouncementXML	Submission_2020-09-18_01:21:45.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christoph Mayr
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-10 07:22:28	ID requested
⏵ 1	2020-09-18 01:21:45	announced

Dataset with its publication pending

submitter keyword: 26S proteasome, mitochondria, respiratory complex I, aspartate, metabolic reprogramming, proteasome assembly factors, pyruvate

Silke Meiners
contact affiliation	Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany
contact email	silke.meiners@helmholtz-muenchen.de
lab head
Christoph Mayr
contact affiliation	CPC/ILBD HemholtzZentrum München
contact email	Christoph.Mayr@helmholtz-muenchen.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019697
     1. Label: PRIDE project
     2. Name: Mitochondrial regulation of the 26S proteasome