PXD013469

PXD013469 is an original dataset announced via ProteomeXchange.

Title	Role of ATR in mitochondrial functions and metabolism
Description	The PIKK superfamily member ATR is a key factor in DNA damage response (DDR) and is vital for the maintenance of genomic stability. DNA single strand breaks (SSBs) and replication stress activate ATR to phosphorylate a wide range of downstream substrates, which activates cell cycle checkpoint, senescence induction, cell death, and R-loop disintegration. ATR mutation causes the human ATR-Seckel syndrome, characterized by dwarfism, microcephaly and intellectual disabilities. Recent studies have implied ATR in non-nuclear functions; however, ATR's function in mitochondrial metabolism and a link to human diseases remains largely unknown. Here we show that ATR is located in mitochondria and its deletion alters mitochondrial dynamics prior to the DDR. ATR deletion disturbs the electron transfer chain (ETC) resulting in ROS overproduction and switches energy production from OXPHOS to the TCA cycle. Multi-omics analyses together with biochemical studies showed an imbalance of ETC proteins and membrane lipids accompanied with a dysregulation of key metabolic signaling pathways, including AMPK, mTOR and PGC1α. Pharmacological intervention of AMPK signaling or ETC functions delineates the metabolic pathways affected in ATR deleted cells. Mitochondrial metabolic dysfunction is more pronounced in ATR deleted neural cells and brain tissues, implicating a connection with neuropathological processes. Thus, ATR plays, beyond its well-known DDR function, an important role for cell metabolism and mitochondrial functionality, which contributes to the manifestation of neuronal deficit of ATR-Seckel.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_08:13:37.538.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joanna Kirkpatrick
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-12 00:38:49	ID requested
⏵ 1	2025-05-06 08:13:38	announced

Marx C, Qing X, Gong Y, Kirkpatrick J, Siniuk K, Beznoussenko GV, Kidiyoor GR, Kirtay M, Buder K, Koch P, Westermann M, Bruhn C, Brown EJ, Xu X, Foiani M, Wang ZQ, DNA damage response regulator ATR licenses PINK1-mediated mitophagy. Nucleic Acids Res, 53(5):(2025) [pubmed]

10.1093/nar/gkaf178;

curator keyword: Biological

submitter keyword: metabolism,ATR, mitochondrial function

Zhao-Qi Wang
contact affiliation	Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) Beutenbergstrasse 11 07745 Jena, Germany
contact email	Zhao-Qi.Wang@leibniz-fli.de
lab head
Joanna Kirkpatrick
contact affiliation	The Francis Crick Institute
contact email	joanna.kirkpatrick@leibniz-fli.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD013469

PRIDE project URI

• PRIDE
  1. PXD013469
     1. Label: PRIDE project
     2. Name: Role of ATR in mitochondrial functions and metabolism