Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway. / Maynard, Scott; Hall, Arnaldur; Galanos, Panagiotis; Rizza, Salvatore; Yamamoto, Tatsuro; Gram, Helena Hagner; Munk, Sebastian H.N.; Shoaib, Muhammad; Sørensen, Claus Storgaard; Bohr, Vilhelm A.; Lerdrup, Mads; Maya-Mendoza, Apolinar; Bartek, Jiri.

In: Nucleic Acids Research, Vol. 50, No. 17, 2022, p. 9948-9965.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Maynard, S, Hall, A, Galanos, P, Rizza, S, Yamamoto, T, Gram, HH, Munk, SHN, Shoaib, M, Sørensen, CS, Bohr, VA, Lerdrup, M, Maya-Mendoza, A & Bartek, J 2022, 'Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway', Nucleic Acids Research, vol. 50, no. 17, pp. 9948-9965. https://doi.org/10.1093/nar/gkac741

APA

Maynard, S., Hall, A., Galanos, P., Rizza, S., Yamamoto, T., Gram, H. H., Munk, S. H. N., Shoaib, M., Sørensen, C. S., Bohr, V. A., Lerdrup, M., Maya-Mendoza, A., & Bartek, J. (2022). Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway. Nucleic Acids Research, 50(17), 9948-9965. https://doi.org/10.1093/nar/gkac741

Vancouver

Maynard S, Hall A, Galanos P, Rizza S, Yamamoto T, Gram HH et al. Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway. Nucleic Acids Research. 2022;50(17):9948-9965. https://doi.org/10.1093/nar/gkac741

Author

Maynard, Scott ; Hall, Arnaldur ; Galanos, Panagiotis ; Rizza, Salvatore ; Yamamoto, Tatsuro ; Gram, Helena Hagner ; Munk, Sebastian H.N. ; Shoaib, Muhammad ; Sørensen, Claus Storgaard ; Bohr, Vilhelm A. ; Lerdrup, Mads ; Maya-Mendoza, Apolinar ; Bartek, Jiri. / Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway. In: Nucleic Acids Research. 2022 ; Vol. 50, No. 17. pp. 9948-9965.

Bibtex

@article{4067796692a54d66b8c00cec60289dc3,
title = "Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway",
abstract = "Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna−/− MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna−/− MEFs) or low levels (HGPS) of PGC1, the key transcription factor for mitochondrial homeostasis. Lmna−/− MEFs showed reduced expression of the NAD+biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATACsequencing revealed a substantially altered chromatin landscape in Lmna−/− MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1 and the NAMPT-NAD+ pathway, with broader implications for the aging process.",
author = "Scott Maynard and Arnaldur Hall and Panagiotis Galanos and Salvatore Rizza and Tatsuro Yamamoto and Gram, {Helena Hagner} and Munk, {Sebastian H.N.} and Muhammad Shoaib and S{\o}rensen, {Claus Storgaard} and Bohr, {Vilhelm A.} and Mads Lerdrup and Apolinar Maya-Mendoza and Jiri Bartek",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2022.",
year = "2022",
doi = "10.1093/nar/gkac741",
language = "English",
volume = "50",
pages = "9948--9965",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "17",

}

RIS

TY - JOUR

T1 - Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway

AU - Maynard, Scott

AU - Hall, Arnaldur

AU - Galanos, Panagiotis

AU - Rizza, Salvatore

AU - Yamamoto, Tatsuro

AU - Gram, Helena Hagner

AU - Munk, Sebastian H.N.

AU - Shoaib, Muhammad

AU - Sørensen, Claus Storgaard

AU - Bohr, Vilhelm A.

AU - Lerdrup, Mads

AU - Maya-Mendoza, Apolinar

AU - Bartek, Jiri

N1 - Publisher Copyright: © The Author(s) 2022.

PY - 2022

Y1 - 2022

N2 - Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna−/− MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna−/− MEFs) or low levels (HGPS) of PGC1, the key transcription factor for mitochondrial homeostasis. Lmna−/− MEFs showed reduced expression of the NAD+biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATACsequencing revealed a substantially altered chromatin landscape in Lmna−/− MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1 and the NAMPT-NAD+ pathway, with broader implications for the aging process.

AB - Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna−/− MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna−/− MEFs) or low levels (HGPS) of PGC1, the key transcription factor for mitochondrial homeostasis. Lmna−/− MEFs showed reduced expression of the NAD+biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATACsequencing revealed a substantially altered chromatin landscape in Lmna−/− MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1 and the NAMPT-NAD+ pathway, with broader implications for the aging process.

U2 - 10.1093/nar/gkac741

DO - 10.1093/nar/gkac741

M3 - Journal article

C2 - 36099415

AN - SCOPUS:85143691701

VL - 50

SP - 9948

EP - 9965

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 17

ER -

ID: 336755317