Proteomics

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Lack of the mitochondrial NAD transporter SLC25A51 redistributes NAD+ compartmentalization and cellular ADP-ribosylation

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte

SUBMITTER: Deena Leslie Pedrioli  

LAB HEAD: Michael O. Hottiger

PROVIDER: PXD031373 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels.

Güldenpfennig Anka A   Hopp Ann-Katrin AK   Muskalla Lukas L   Manetsch Patrick P   Raith Fabio F   Hellweg Lars L   Dördelmann Cyril C   Leslie Pedrioli Deena M DM   Johnsson Kai K   Superti-Furga Giulio G   Hottiger Michael O MO  

Nucleic acids research 20230901 17

Though the effect of the recently identified mitochondrial NAD+ transporter SLC25A51 on glucose metabolism has been described, its contribution to other NAD+-dependent processes throughout the cell such as ADP-ribosylation remains elusive. Here, we report that absence of SLC25A51 leads to increased NAD+ concentration not only in the cytoplasm and but also in the nucleus. The increase is not associated with upregulation of the salvage pathway, implying an accumulation of constitutively synthesize  ...[more]

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