Abstract
SummaryParadoxical observations have been made regarding the role of caveolin‐1 (Cav‐1) during cellular senescence. For example, caveolin‐1 deficiency prevents reactive oxygen species‐induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re‐addressed the role of caveolin‐1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav‐1−/− mouse embryonic fibroblasts. Cav‐1 deficiency (knockout or knockdown) induced cellular senescence via a p53‐p21‐dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav‐1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD +/NADH ratio. From these results, we concluded that Cav‐1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation.
Highlights
Cellular senescence is defined as an irreversible cellular growth arrest
In mouse embryonic fibroblasts (MEFs) and mouse liver, Cav-1 knockout leads to mitochondrial dysfunction, which is a strong inducer of premature senescence (Bosch et al, 2011; Asterholm et al, 2012)
To address whether Cav-1 is necessary for premature senescence, we first monitored cellular proliferation by counting cell numbers and using a colony-forming assay after Cav-1 knockdown in A549 human lung carcinoma cells, which highly express Cav-1
Summary
Cellular senescence is defined as an irreversible cellular growth arrest. Human fibroblasts have a maximum division number before undergoing senescence (Hayflick & Moorhead, 1961). Cellular senescence is prematurely induced by diverse stresses, such as oxidative stress, oncogene activation, and genomic instability (Campisi & d’Adda di Fagagna, 2007; Lee & Lee, 2014). Senescent cells have various phenotypes, including fried egg-like morphology, b-galactosidase (b-Gal) activation, heterochromatin focus formation, and altered gene expression and protein processing (Shay & Roninson, 2004; Byun et al, 2015). SIRT1 activation prevents cellular senescence, whereas its inactivation increases the transcriptional activity of p53 (Tang et al, 2008; Wang et al, 2012). These findings indicate that the SIRT1-p53 pathway is critical for regulating cellular senescence
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