Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis

Abstract

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)–treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain–containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β–mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescencein vitroand in the aging human hippocampus

“…The characterization of senescence-associated biomarkers is an important and firststep towards understanding the mechanisms underlying senescence itself and its role in the context of aging and age-related diseases. Emerging evidence shows that the loss of lamin-B1 is an important senescence-associated biomarker in several murine and human cell cultures/lines (Freund et al, 2012) and aging tissues, including in photoaged skin (Wang et al, 2017), thymus (Yue et al, 2019) lung (Saito et al, 2019), kidney and liver (Yousefzadeh et al, 2020). However, relatively less is known about the potential role of lamin-B1 in brain senescence.…”

“…Taken together, these findings strengthen the hypothesis that lamin-B1 loss is a hallmark associated with astrocyte senescence in mouse and human hippocampal aging. Although a direct link between lamin-B1 loss with changes in astrocyte phenotype and function has yet to be investigated, lamin-B1 downregulation has been recognized as a key step for progression of full cellular senescence in other cell types and tissues (Freund et al, 2012; Saito et al, 2019; Shimi et al, 2011), which can, in turn, contribute to tissue degeneration in aging and induce pathological conditions (Saito et al, 2019; Yue et al, 2019). Whether lamin-B1 loss is a consequence of the senescent phenotype or a trigger of astrocyte senescence remains to be investigated.…”

The Regulatory Properties of the Ccr4–Not Complex

“…Lamins provide structure to the nucleus and are also involved in transcriptional regulation [329]. Involvement of lamins in accelerated cellular senescence has been reported by several studies [327,330,331]. Significantly, CNOT1 interacts with LMNA (lamin A) in osteosarcoma cells and depletion of CNOT1 suppresses the cell proliferation through the Hedgehog signaling pathway via its association with LMNA [272].…”

Accelerated aging mechanisms in chronic obstructive pulmonary disease

“…Downregulation of laminin B1 has been recognized as a crucial step for the development of full senescence. A recent study also suggests that laminin B1 reduction is involved in the progression of cellular senescence during COPD pathogenesis through aberrant mammalian target of rapamycin (mTOR) signaling [7].…”