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.

中文翻译：

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CR6相互作用因子1缺乏症通过抑制内皮细胞中的SIRT3诱导过早衰老。

血管内皮细胞衰老是与心脏有关的疾病的重要原因。线粒体活性氧（mtROS）与细胞衰老和多种心血管疾病有关。研究表明，CR6相互作用因子1（CRIF1）缺乏会通过抑制线粒体氧化磷酸化而增加mtROS。然而，尚未全面探讨mtROS调节血管内皮衰老的机制。这项研究的目的是调查CRIF1缺乏对内皮细胞衰老的影响并阐明其潜在机制。研究表明，CRIF1缺乏症会增加衰老相关的β-半乳糖苷酶的活性，并增加磷酸化的p53，p21和p16蛋白的表达。使用流式细胞仪在CRIF1缺陷型细胞中鉴定了停滞在G0 / G1期的细胞周期。此外，CRIF1缺乏症还通过泛素介导的转录因子PGC1α和NRF2降解，通过降低Sirtuin 3（SIRT3）的表达来增加细胞衰老。CRIF1的下调还通过抑制SIRT3减弱了线粒体抗氧化酶的功能，包括锰超氧化物歧化酶（MnSOD），Foxo3a，烟酰胺-腺嘌呤二核苷酸磷酸和谷胱甘肽。有趣的是，在缺少CRIF1的内皮细胞中SIRT3的过表达不仅通过提高抗氧化酶MnSOD的表达降低了mtROS水平，还降低了细胞衰老标记的表达。在一起