Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA.
Department of Genetics, Genomics and Bioinformatics, University at Buffalo, Buffalo, NY 14263, USA.
Cell Rep. 2024 Feb 27;43(2):113738. doi: 10.1016/j.celrep.2024.113738. Epub 2024 Feb 12.
Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
线粒体功能障碍是细胞衰老的一个标志，线粒体功能的丧失被认为是导致与衰老相关的细胞功能下降的一个潜在因果因素。我们最近的研究结果表明，多能转录因子 NANOG 的异位表达通过重新布线代谢途径，使衰老细胞的功能失调线粒体恢复活力。在这项研究中，我们报告 NANOG 恢复了脯氨酸生物合成途径中关键酶 PYCR1 和 PYCR2 的表达。此外，衰老的间充质干细胞表现出严重的线粒体呼吸功能障碍，通过补充脯氨酸可以得到缓解。脯氨酸通过激活 AMP 激活的蛋白激酶α和上调 Parkin 的表达来诱导线粒体自噬，增强线粒体清除，最终恢复细胞代谢。值得注意的是，脯氨酸处理还减轻了几种衰老特征，包括 DNA 损伤、衰老相关的β-半乳糖苷酶、炎症细胞因子表达和受损的成肌分化能力。总的来说，这项研究强调了脯氨酸在自噬中的作用及其逆转与衰老相关的线粒体功能障碍和衰老特征的潜力。
