{"doi":"10.1093/nar/gkac741","title":"Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α 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 PGC1α, 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, ATAC-sequencing 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 PGC1α and the NAMPT-NAD+ pathway, with broader implications for the aging process.","journal":"Nucleic Acids Research","year":2022,"id":238715,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":863173,"name":"Arnaldur Hall","orcid":"0000-0001-6847-4438","position":1,"is_corresponding":false},{"id":628832,"name":"Panagiotis Galanos","orcid":"0000-0003-1403-4685","position":2,"is_corresponding":false},{"id":652234,"name":"Salvatore Rizza","orcid":"0000-0001-7335-4684","position":3,"is_corresponding":false},{"id":863174,"name":"Tatsuro Yamamoto","orcid":"0000-0002-9178-4837","position":4,"is_corresponding":false},{"id":863905,"name":"Helena Hagner Gram","orcid":null,"position":5,"is_corresponding":false},{"id":863175,"name":"Sebastian Howen Nesgaard Munk","orcid":"0000-0002-4601-4833","position":6,"is_corresponding":false},{"id":863176,"name":"Muhammad Shoaib","orcid":"0000-0003-1296-5005","position":7,"is_corresponding":false},{"id":863177,"name":"Claus Storgaard Sørensen","orcid":"0000-0001-6022-9710","position":8,"is_corresponding":false},{"id":234869,"name":"Vilhelm A. Bohr","orcid":"0000-0003-4823-6429","position":9,"is_corresponding":false},{"id":266707,"name":"Mads Lerdrup","orcid":"0000-0002-7730-8973","position":10,"is_corresponding":false},{"id":628841,"name":"Apolinar Maya‐Mendoza","orcid":"0000-0001-7452-9896","position":11,"is_corresponding":false},{"id":628843,"name":"Jiří Bártek","orcid":"0000-0003-2013-7525","position":12,"is_corresponding":false},{"id":863172,"name":"Scott Maynard","orcid":"0000-0001-5625-936X","position":0,"is_corresponding":true}],"reference_count":110,"raw_metadata":null,"created_at":"2026-07-19T00:22:31.741535Z","pmid":"36099415","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}