PXD031373-1

PXD031373 is an original dataset announced via ProteomeXchange.

Title	Lack of the mitochondrial NAD transporter SLC25A51 redistributes NAD+ compartmentalization and cellular ADP-ribosylation
Description	Nicotinamide adenine dinucleotide (NAD+) is a vital small molecule with important redox capacity in oxidative phosphorylation (OXPHOS) and a key co-factor in various enzymatic reactions. The recent identification of the mitochondrial NAD+ transporter SLC25A51 provides strong evidence for a direct regulation of the mitochondrial NAD+ pool. Though the effect of this transporter on glucose metabolism has been described, its contribution to other NAD+-dependent processes such as ADP-ribosylation remains elusive. Here, we report that knockdown of SLC25A51 decreased the NAD+ concentration in mitochondria but increased the NAD+ concentration in the cytoplasm and nucleus. The increase in nuclear and cytoplasmic NAD+ was not due to the upregulation of the salvage pathway, thus pointing towards an overall redistribution of NAD+ from the mitochondria towards the cyto/nuclear compartment. Furthermore, the NAD+ redistribution induced by knockdown or knockout of SLC25A51 resulted, as quantified by immunofluorescence or analyzed by mass-spectrometry, in a loss of mitochondrial ADP-ribosylation and an increase of PARP1-mediated nuclear ADP-ribosylation under basal conditions. Further, MMS/Olaparib induced PARP1 chromatin retention and the sensitivity of triple-negative MDA-MB-436 breast cancer cells to PARP inhibition were both reduced upon knockdown of SLC25A51. In addition, H2O2-induced PARP1-dependent nuclear ADP-ribosylation was prolonged while phosphorylation of H2AX was unexpectedly reduced. Together these results provide evidence that lack of SCL25A51 and subsequently altered NAD+ compartmentalization affects not only mitochondrial and nuclear ADP-ribosylation but also other chromatin associated events.
HostingRepository	PRIDE
AnnounceDate	2023-10-24
AnnouncementXML	Submission_2023-10-24_10:59:51.179.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DeenaLeslie Pedrioli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	adenosine diphosphoribosyl (ADP-ribosyl) modified residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-01 01:25:32	ID requested
⏵ 1	2023-10-24 10:59:52	announced
2	2023-11-14 09:07:04	announced	2023-11-14: Updated project metadata.

G, ü, ldenpfennig A, Hopp AK, Muskalla L, Manetsch P, Raith F, Hellweg L, D, ö, rdelmann C, Leslie Pedrioli DM, Johnsson K, Superti-Furga G, Hottiger MO, Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels. Nucleic Acids Res, 51(17):9248-9265(2023) [pubmed]

submitter keyword: SL25A51, ADP-ribosylation,Mitochondia

Michael O.Hottiger
contact affiliation	Head of Department Department of Molecular Mechanisms of Disease University of Zurich Winterthurerstr. 190 8057 Zurich, Switzerland
contact email	michael.hottiger@dmmd.uzh.ch
lab head
DeenaLeslie Pedrioli
contact affiliation	University of Zürich
contact email	deena.lesliepedrioli@dmmd.uzh.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031373
     1. Label: PRIDE project
     2. Name: Lack of the mitochondrial NAD transporter SLC25A51 redistributes NAD+ compartmentalization and cellular ADP-ribosylation