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PXD023939-1

PXD023939 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
DescriptionIntegrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria and mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here, we show that mtDNA damage after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, leads to an exacerbated mtDNA turnover. mtDNA removal depends on lysosomal function and requires the autophagy protein Atg5 but is independent of canonical mitophagy or autophagy. Using proximity labelling, we demonstrated that the area of influence of mitochondrial nucleoids differs upon mtDNA damage, which induces mitochondrial membrane remodelling and endosomal recruitment in close proximity to mitochondrial nucleoid sub compartments. Targeting of nucleoids is controlled by the mitochondrial transmembrane proteins ATAD3 and SAMM50, which together with the endosomal trafficking protein VPS35, orchestrate endosomal nucleoid engulfment. SAMM50 acts as a gatekeeper to avoid mtDNA release to the cytoplasm and facilitating mtDNA transfer to VPS35. Lastly, we show that stimulation of lysosomal activity by rapamycin selectively removes mtDNA deletions in vivo, without affecting mtDNA copy number. With these results, we unveil the molecular players of a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network, a process with multiple potential benefits to understand human mtDNA related diseases, either inherited, acquired or due to normal ageing.
HostingRepositoryPRIDE
AnnounceDate2022-11-07
AnnouncementXMLSubmission_2022-11-07_05:30:38.501.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSebastianKallabis
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListacetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Eclipse; Q Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-02-02 01:55:09ID requested
12022-11-07 05:30:38announced
22023-11-14 08:56:09announced2023-11-14: Updated project metadata.
Publication List
Keyword List
submitter keyword: mitophagy, Twinkle, autophagy, mitochondrial nucleoid,mtDNA
Contact List
DavidPla-Martin
contact affiliationCenter for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Köln, Köln, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany (lab head)
contact emaildplamart@uni-koeln.de
lab head
SebastianKallabis
contact affiliationDepartment for Systems Immunology & Proteomics Institute of Innate Immunity University Hospital Bonn Venusberg - Campus 1 53127 Bonn Germany
contact emailkallabis@uni-bonn.de
dataset submitter
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