Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway

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 alpha, 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 PGC1 alpha and the NAMPT-NAD(+) pathway, with broader implications for the aging process.

Automated summary

Mutations in the lamin A/C gene can cause various diseases, including premature aging syndrome and malignancies. This study revealed that cells lacking lamin A/C and cells expressing HGPS gene both showed mitochondrial dysfunction, which is associated with impaired gene expression and DNA repair mechanisms related to mitochondria. Furthermore, it was found that the loss of lamin A/C gene can lead to changes in chromatin structure, affecting gene accessibility.