PXD031948

PXD031948 is an original dataset announced via ProteomeXchange.

Title	Orphan precursor proteins and ROS activate the mitochondrial UPR_Interaction proteomics
Description	The mitochondrial unfolded protein response (UPRmt) safeguards mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis. How the mitochondrial protein misfolding information is signalled to the nucleus as part of the human UPRmt remains unclear. Here, we showed that UPRmt signalling is carried out by the co-occurrence of two individual signals – ROS production in mitochondria and accumulation of orphan mitochondrial proteins in the cytosol. Combining proteomics and genetic approaches, we identified that mitochondrial protein misfolding caused the release of ROS into the intermembrane space (IMS), which was essential for UPRmt signalling. ROS released from mitochondria oxidized the cytosolic HSP40 protein DNAJA1 to enhance recruitment of cytosolic HSP70 to orphan mitochondrial proteins that accumulated in parallel in the cytosol due to mitochondrial import defect. This recruitment leads to the release of HSF1 from HSP70 and its subsequent translocation to the nucleus to activate transcription of UPRmt related genes. Strikingly, we found that combining ROS and the accumulation of orphan mitochondrial proteins in the cytosol was sufficient and necessary to activate the UPRmt. Our findings reveal that monitoring of ROS and orphan mitochondrial proteins in cytosol allows an elegant surveillance to control the UPRmt via HSF1 activation in human cells. These observations reveal a novel link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:01:32.887.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD031948
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Reymond Sutandy
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-28 12:18:05	ID requested
1	2023-05-19 05:42:17	announced
⏵ 2	2023-11-14 08:01:33	announced	2023-11-14: Updated project metadata.

10.6019/PXD031948;

submitter keyword: UPRmt, DNAJA1,mitochndria, proteostasis, interactome

Christian Münch
contact affiliation	Institute of Biochemistry II Goethe University Frankfurt – Medical School University Hospital Germany
contact email	ch.muench@em.uni-frankfurt.de
lab head
Reymond Sutandy
contact affiliation	Institute of Biochemistry II, Frankfurt
contact email	sutandy@med.uni-frankfurt.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031948
     1. Label: PRIDE project
     2. Name: Orphan precursor proteins and ROS activate the mitochondrial UPR_Interaction proteomics