2022/09/13 by Scott Maynard, Arnaldur Hall, Panagiotis Galanos +10 · 1 citation
Biochemistry, Genetics and Molecular Biology · #Nuclear Structure and Function #Mitochondrial Function and Pathology #RNA Research and Splicing #Biology #Lamin #NAD+ kinase #Mitochondrial DNA #Mitochondrion #Genetics #Cell biology #Molecular biology #Biochemistry #Gene #Enzyme
paper · doi:10.1093/nar/gkac741
openalex publication_date 2022/09/13 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.