Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1 and the NAMPT-NAD+ pathway
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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.
Originalsprog | Engelsk |
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Tidsskrift | Nucleic Acids Research |
Vol/bind | 50 |
Udgave nummer | 17 |
Sider (fra-til) | 9948-9965 |
Antal sider | 18 |
ISSN | 0305-1048 |
DOI | |
Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
J.B. is supported by the Danish Cancer Society [R204-A12617-B153]; Danish Council for Independent Research [DFF-7016-00313]; Novo Nordisk Foundation [NNF20OC0060590]; Swedish Research Council [VR-MH 2014-46602-117891-30]; Danish National Research Foundation [project CARD, DNRF 125]; A.M-M. is supported by the Danish Cancer Society [R302-A17590]; Danish National Research Foundation [project CARD, DNRF 125]; P.G. is supported by the Lundbeck Foundation [R322-2019-2577]; M.L. is supported by the Danish National Research Foundation [CCS, DNRF 115]; Intramural Research Program, National Institute on Aging, National Institute of Health [Z01 AG000723-02 to V.A.B.]. Funding for open access charge: Danish Cancer Society and the Danish National Research Foundation (project CARD). Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2022.
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