The naked mole-rat (NMR, Heterocephalus glaber) is the longest-living known rodent species, with a maximum lifespan of over 30 years. NMRs exhibit negligible senescence, exceptional resistance to cancer, and high basal autophagy activity compared with mouse. The molecular mechanisms and physiological roles underlying the high basal autophagy activity in NMRs remain to be elucidated. We identified that the Atg12-Atg5 conjugate, a critical component of autophagosome formation, was highly expressed in NMR skin fibroblasts (NSFs) compared with that in mouse skin fibroblasts. Phenotypic analysis of Atg5 knockdown NSFs revealed that high basal autophagy activity in NSFs was associated with abundant expression of the Atg12-Atg5 conjugate. Atg5 knockdown in NSFs led to accumulation of dysfunctional mitochondria, and suppressed cell proliferation and cell adhesion ability, promoting apoptosis/anoikis accompanied by upregulation of the apoptosis-related genes, Bax and Noxa. Furthermore, inhibition of the p53/Rb pro-apoptotic pathway with SV40 large T antigen abolished Atg5 knockdown-induced increases in apoptosis/anoikis. Taken together, these findings suggest that high basal autophagy activity in NMR cells, mediated by Atg5, contributes to suppression of p53/Rb-induced apoptosis, which could benefit the longevity of NMR cells.

裸mole鼠（NMR，Heterocephalus glaber）是已知寿命最长的啮齿类动物，最大寿命超过30年。与小鼠相比，NMR的衰老可以忽略不计，对癌症的抵抗力极强，并且具有很高的基础自噬活性。NMR中高基础自噬活性的分子机制和生理学作用尚待阐明。我们确定，Atg12-Atg5缀合物，自噬体形成的关键组成部分，与小鼠皮肤成纤维细胞相比，在NMR皮肤成纤维细胞（NSFs）中高表达。Atg5基因敲除NSFs的表型分析表明，NSFs中高的基础自噬活性与Atg12-Atg5共轭物的大量表达有关。NSF中Atg5的敲低导致线粒体功能障碍，并抑制细胞增殖和细胞粘附能力，Bax和Noxa。此外，用SV40大T抗原抑制p53 / Rb促凋亡途径消除了Atg5敲低诱导的细胞凋亡/凋亡的增加。综上所述，这些发现表明，由Atg5介导的NMR细胞中较高的基础自噬活性有助于抑制p53 / Rb诱导的凋亡，这可能有益于NMR细胞的寿命。