PXD061965

PXD061965 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial surveillance activates the primary UPRmt
Description	The mitochondrial unfolded protein response (UPRmt) is critical for protecting mitochondria against proteotoxic stress. Current UPRmt models propose that mitochondrial defects are detected by cytosolic surveillance mechanisms after release of damage into the cytosol. However, these findings are based on models that induce rapid and severe mitochondrial dysfunction, and thus their mode of toxicity contrasts sharply from physiologically occurring mitochondrial damage, e.g. the gradual accumulation of reactive oxygen species (ROS) during age-related decline or chronic respiratory chain defects. Here, we employed a chemogenetic strategy that induces low levels of H2O2 in the mitochondrial matrix to investigate cellular responses to physiologically relevant levels of mitochondrial dysfunction. We uncover that this mild oxidative stress activates the UPRmt independently of cytosolic signals revealing a so far concealed primary surveillance mechanism within mitochondria. Moreover, we identify the mitochondrial presequence proteases MPP and Oct1 as early molecular targets of ROS: Oxidative stress induces glutathionylation of critical cysteine residues, resulting in diminished proteolytic activity and the accumulation of proteotoxic precursor aggregates in the matrix. These aggregates are detected by intramitochondrial surveillance systems, activating UPRmt signaling. Our findings uncover the primary response to mitochondrial dysfunction, and highlight the organelle's capacity for self-surveillance and its ability to initiate early and rapid protective signaling in the face of mitochondrial dysfunction.
HostingRepository	PRIDE
AnnounceDate	2026-04-07
AnnouncementXML	Submission_2026-04-06_21:06:55.199.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marcin Luzarowski
SpeciesList	scientific name: Saccharomyces cerevisiae (Baker's yeast); NCBI TaxID: NEWT:4932;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-18 01:46:11	ID requested
⏵ 1	2026-04-06 21:06:55	announced

Dataset with its publication pending

submitter keyword: reactive oxygen species, presequence processing, mitochondrial protein biogenesis,Mitochondrial unfolded protein response

Marcin Luzarowski
contact affiliation	Core Facility for Mass Spectrometry and Proteomics, Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
contact email	m.luzarowski@zmbh.uni-heidelberg.de
lab head
Marcin Luzarowski
contact affiliation	University of Heidelberg
contact email	m.luzarowski@zmbh.uni-heidelberg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061965
     1. Label: PRIDE project
     2. Name: Mitochondrial surveillance activates the primary UPRmt