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NAD+ repletion by the PARP inhibitor PJ34 prevents Sarm1 activation and rotenone-induced cell death

Ankita Sarkar, Malinki Sur, Puja Dey, View ORCID ProfilePiyali Mukherjee
doi: https://doi.org/10.1101/2021.07.30.454548
Ankita Sarkar
1School of Biotechnology, Presidency University Canal Bank Rd, DG Block, Action Area 1D, New Town, Kolkata-700156, West Bengal, India, Tel: +91 8017086495
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Malinki Sur
1School of Biotechnology, Presidency University Canal Bank Rd, DG Block, Action Area 1D, New Town, Kolkata-700156, West Bengal, India, Tel: +91 8017086495
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Puja Dey
1School of Biotechnology, Presidency University Canal Bank Rd, DG Block, Action Area 1D, New Town, Kolkata-700156, West Bengal, India, Tel: +91 8017086495
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Piyali Mukherjee
1School of Biotechnology, Presidency University Canal Bank Rd, DG Block, Action Area 1D, New Town, Kolkata-700156, West Bengal, India, Tel: +91 8017086495
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  • ORCID record for Piyali Mukherjee
  • For correspondence: piyali.dbs@presiuniv.ac.in
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Abstract

The NADase Sarm1 has emerged as an important modulator of programmed axonal degeneration over the past decade but it’s mode of activation within the cell is not clearly understood. Sarm1 is predominantly expressed in the neurons, kidney and liver but the non-neuronal regulation of Sarm1 remains relatively unexplored. Here we demonstrate that treatment of the human embryonic kidney cell line HEK293 cells with the mitochondrial complex I inhibitor rotenone, induced early loss of NAD+ that preceded induction of Sarm1, a primary mediator of rotenone induced cell death. Interestingly, replenishing NAD+ levels by PARP inhibition, a major NAD+ consumer within the cell, not only restored mitochondrial homeostasis but also prevented subsequent Sarm1 induction by rotenone. These early changes were further marked by a distinct subcellular localization pattern of Sarm1 in the nucleus and the mitochondria that was accompanied by significantly reduced cell death. Taken together, our study provides the first preliminary evidence of temporal regulation of endogenous Sarm1 by fluctuating NAD+ levels induced by rotenone that may act as a “biological trigger” of Sarm1 activation. This also points towards an important understanding on how PARP inhibitors like PJ34 could be repurposed in the treatment of Sarm1 mediated mitochondrial deficiency disorders.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 31, 2021.
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NAD+ repletion by the PARP inhibitor PJ34 prevents Sarm1 activation and rotenone-induced cell death
Ankita Sarkar, Malinki Sur, Puja Dey, Piyali Mukherjee
bioRxiv 2021.07.30.454548; doi: https://doi.org/10.1101/2021.07.30.454548
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NAD+ repletion by the PARP inhibitor PJ34 prevents Sarm1 activation and rotenone-induced cell death
Ankita Sarkar, Malinki Sur, Puja Dey, Piyali Mukherjee
bioRxiv 2021.07.30.454548; doi: https://doi.org/10.1101/2021.07.30.454548

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