PXD058150

PXD058150 is an original dataset announced via ProteomeXchange.

Title	Putative PINK1/Parkin activators cause mitochondrial stress and lower the threshold for mitophagy
Description	The PINK1/Parkin pathway is responsible for targeting damaged mitochondria for degradation via mitophagy. Because genetic evidence links impaired mitophagy to Parkinson’s disease, pharmacologic enhancement of mitophagy represents a promising disease-modifying strategy. Here, we characterize two pharmacological mitophagy activators: a new Parkin activator, FB231, described here and the reported PINK1 activator MTK458. We demonstrate that both compounds activate their targets and lower the threshold for PINK1/Parkin-mediated mitophagy induced by mitochondrial stressors. Using global proteomics, however, we also find that FB231 and MTK458 exert mild mitochondrial stress that leads to cleavage of OPA1 and activation of the integrated stress response, in a PINK1/Parkin-independent manner. Both compounds cause mitochondrial stress and thereby sensitizes cells to mitophagy induction by classical mitochondria toxins. We provide a model that rationalizes this hitherto unknown mechanism for mitophagy activators, whereby normally “silent” mitochondrial toxins can act as potent PINK1/Parkin potentiators in the context of mitochondrial stress.
HostingRepository	PRIDE
AnnounceDate	2025-06-03
AnnouncementXML	Submission_2025-06-02_18:20:42.959.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ting-Yu Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-21 12:21:03	ID requested
⏵ 1	2025-06-02 18:20:43	announced

Dataset with its publication pending

submitter keyword: mitochondria

mitophagy, autophagy

PINK1/Parkin pathway

mitochondrial stress

neurodegeneration

Parkinson’s disease

integrated stress response (ISR)

drug discovery

off-target toxicity.

Tsui-Fen Chou
contact affiliation	Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
contact email	tfchou@caltech.edu
lab head
Ting-Yu Wang
contact affiliation	Caltech
contact email	tywang@caltech.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058150
     1. Label: PRIDE project
     2. Name: Putative PINK1/Parkin activators cause mitochondrial stress and lower the threshold for mitophagy