PARP1/2-linked ADP-ribosylation impairs trophoblast mitochondrial respiration in a TNF-α model of inflammation-mediated preeclampsia.
- 1University of Ottawa
Abstract
Inflammation-mediated preeclampsia (I-PE) is associated with increased placental NAD+-dependent ADP-ribosylation and NAD+ depletion. We investigated whether PARP1/2- or tankyrase-sensitive ADP-ribosylation contributes to inflammation-associated trophoblast dysfunction and whether pharmacological inhibition improves trophoblast function under inflammatory stress. We profiled mRNA expression of genes encoding enzymes that catalyze poly-ADP-ribosylation (PARP1, PARP2, TNKS1, TNKS2) and selected enzymes that catalyze mono-ADP-ribosylation (PARP7, PARP10, PARP12, and PARP14), in human I-PE placentas (control n=23; I-PE n=10) and an LPS-induced rat model of I-PE (control n=8, LPS n=8). HTR-8/SVneo cells were treated with TNF- alone or with olaparib, (PARP1/2 inhibitor) or XAV939 (TNKS1/2 inhibitor). Global mono- and poly-ADP-ribosylation (MAR/PAR), including a PARP1-associated ~120-kDa ADP-ribosylation signal and pathway enrichment of proteins identified from this region, were assessed alongside mitochondrial respiration, OXPHOS protein abundance, 4-hydroxynonenal, migration, and viability. In human I-PE placentas, mRNA abundance of poly-ADP-ribosylating enzymes did not differ significantly from controls, whereas mono-ADP-ribosylating enzymes were increased in LPS-exposed rat placentas. In HTR-8/SVneo cells, TNF- induced a prominent PARP1 associated ~120-kDa MAR/PAR signal that was suppressed by olaparib, but not XAV939. Proteins identified from this ~120-kDa region were enriched for known PARP1 targets and immune/stress-response pathways. Olaparib, but not XAV939, improved basal and maximal respiration, ATP production, and spare respiratory capacity. TNF- did not significantly alter oxidative phosphorylation (OXPHOS) subunits, 4-HNE abundance, viability, or migration at 24 h. These data support PARP1/2-sensitive ADP-ribosylation, most consistent with PARP1-linked activity, as a contributor to inflammation-mediated trophoblast bioenergetic dysfunction. The PARP1/2-NAD+ axis may therefore represent a mechanism-directed target for future studies of I-PE.
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BibTeX
@misc{nikakhtar2026parp12linked,
title = {{PARP1/2-linked ADP-ribosylation impairs trophoblast mitochondrial respiration in a TNF-α model of inflammation-mediated preeclampsia.}},
author = {A. Nik-Akhtar and S. Vanegas Pineda and J. Ouellet and Y. Cariaco and F. Jahan and K. J. Menzies and S. A. Bainbridge},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.758860},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.758860v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - PARP1/2-linked ADP-ribosylation impairs trophoblast mitochondrial respiration in a TNF-α model of inflammation-mediated preeclampsia.
AU - A. Nik-Akhtar
AU - S. Vanegas Pineda
AU - J. Ouellet
AU - Y. Cariaco
AU - F. Jahan
AU - K. J. Menzies
AU - S. A. Bainbridge
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.758860
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.758860v1
AB - Inflammation-mediated preeclampsia (I-PE) is associated with increased placental NAD+-dependent ADP-ribosylation and NAD+ depletion. We investigated whether PARP1/2- or tankyrase-sensitive ADP-ribosylation contributes to inflammation-associated trophoblast dysfunction and whether pharmacological inhibition improves trophoblast function under inflammatory stress. We profiled mRNA expression of genes encoding enzymes that catalyze poly-ADP-ribosylation (PARP1, PARP2, TNKS1, TNKS2) and selected enzymes that catalyze mono-ADP-ribosylation (PARP7, PARP10, PARP12, and PARP14), in human I-PE placentas (control n=23; I-PE n=10) and an LPS-induced rat model of I-PE (control n=8, LPS n=8). HTR-8/SVneo cells were treated with TNF- alone or with olaparib, (PARP1/2 inhibitor) or XAV939 (TNKS1/2 inhibitor). Global mono- and poly-ADP-ribosylation (MAR/PAR), including a PARP1-associated ~120-kDa ADP-ribosylation signal and pathway enrichment of proteins identified from this region, were assessed alongside mitochondrial respiration, OXPHOS protein abundance, 4-hydroxynonenal, migration, and viability. In human I-PE placentas, mRNA abundance of poly-ADP-ribosylating enzymes did not differ significantly from controls, whereas mono-ADP-ribosylating enzymes were increased in LPS-exposed rat placentas. In HTR-8/SVneo cells, TNF- induced a prominent PARP1 associated ~120-kDa MAR/PAR signal that was suppressed by olaparib, but not XAV939. Proteins identified from this ~120-kDa region were enriched for known PARP1 targets and immune/stress-response pathways. Olaparib, but not XAV939, improved basal and maximal respiration, ATP production, and spare respiratory capacity. TNF- did not significantly alter oxidative phosphorylation (OXPHOS) subunits, 4-HNE abundance, viability, or migration at 24 h. These data support PARP1/2-sensitive ADP-ribosylation, most consistent with PARP1-linked activity, as a contributor to inflammation-mediated trophoblast bioenergetic dysfunction. The PARP1/2-NAD+ axis may therefore represent a mechanism-directed target for future studies of I-PE.
ER -