PXD069489

PXD069489 is an original dataset announced via ProteomeXchange.

Title	A Mitochondria-Driven Quality Control Pathway Eliminates Mislocalized Peroxisomal Membrane Proteins
Description	Protein quality control (PQC) systems are essential for maintaining a healthy proteome by removing aberrant proteins, including mislocalized proteins. However, the mechanisms for eliminating mislocalized Peroxisomal Membrane Proteins (PMPs) have remained elusive. Here, using quantitative proteomics in peroxisome biogenesis–deficient cells, we observed widespread downregulation of PMPs without corresponding changes in mRNA levels, indicating selective post-transcriptional turnover. An unbiased CRISPR screen uncovered an inter-organelle PQC axis in which mitochondria act as a surveillance hub to clear mislocalized PMPs, thereby safeguarding cellular proteostasis when peroxisome biogenesis fails. We show that when PMPs fail to reach their native peroxisomal destination, they are rerouted to mitochondria, where the mitochondrial outer membrane resident E3 ligases MUL1 and MARCH5 act redundantly to ubiquitinate them and promote their degradation via the proteasome. Our findings reveal an additional regulatory layer of organelle cross-talk, highlighting a dual role for mitochondrial E3 ligases, previously implicated in de novo peroxisome biogenesis, in actively participating in peroxisomal protein quality control. Notably, simultaneous loss of peroxisomes and mitochondrial E3 ligases markedly impairs cell survival, highlighting the essential role of this pathway. These findings provide critical insights into the pathology of organelle dysfunction, including peroxisome biogenesis disorders, and reveal broader mechanisms of inter-organelle protein quality control.
HostingRepository	PRIDE
AnnounceDate	2026-05-14
AnnouncementXML	Submission_2026-05-14_03:05:49.189.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Keren Bendalak
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-15 10:03:11	ID requested
⏵ 1	2026-05-14 03:05:49	announced

Dataset with its publication pending

submitter keyword: Peroxisome,Protein degradation, MARCH5, E3 ligases, MUL1, Ubiquitin, Protein Quality Control, Peroxisomal membrane proteins (PMPs)

Itay Koren
contact affiliation	Bar-Ilan university, Israel
contact email	itay.koren@biu.ac.il
lab head
Keren Bendalak
contact affiliation	Technion
contact email	kerenb@technion.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069489
     1. Label: PRIDE project
     2. Name: A Mitochondria-Driven Quality Control Pathway Eliminates Mislocalized Peroxisomal Membrane Proteins