CR6 interacting factor 1 deficiency induces premature senescence via SIRT3 inhibition in endothelial cells.

Vascular endothelial cell senescence is an important cause of cardiac-related diseases. Mitochondrial reactive oxygen species (mtROS) have been implicated in cellular senescence and multiple cardiovascular disorders. CR6 interacting factor 1 (CRIF1) deficiency has been shown to increase mtROS via the inhibition of mitochondrial oxidative phosphorylation; however, the mechanisms by which mtROS regulates vascular endothelial senescence have not been thoroughly explored. The goal of this study was to investigate the effects of CRIF1 deficiency on endothelial senescence and to elucidate the underlying mechanisms. CRIF1 deficiency was shown to increase the activity of senescence-associated β-galactosidase along with increased expression of phosphorylated p53, p21, and p16 proteins. Cell cycle arrested in the G0/G1 phase were identified in CRIF1-deficient cells using the flow cytometry. Furthermore, CRIF1 deficiency was also shown to increase cellular senescence by reducing the expression of Sirtuin 3 (SIRT3) via ubiquitin-mediated degradation of transcription factors PGC1α and NRF2. Downregulation of CRIF1 also attenuated the function of mitochondrial antioxidant enzymes including manganese superoxide dismutase (MnSOD), Foxo3a, nicotinamide-adenine dinucleotide phosphate, and glutathione via the suppression of SIRT3. Interestingly, overexpression of SIRT3 in CRIF1-deficient endothelial cells not only reduced mtROS levels by elevating expression of the antioxidant enzyme MnSOD but also decreased the expression of cell senescence markers. Taken together, these results suggest that CRIF1 deficiency induces vascular endothelial cell senescence via ubiquitin-mediated degradation of the transcription coactivators PGC1α and NRF2, resulting in decreased expression of SIRT3.