Sui Melissa, Teh Joanne, Fort Kayleigh, Shaw Daniel, Sudmant Peter, Koide Tsuyoshi, Good Jeffrey M, Vazquez Juan M, Brem Rachel B
Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA.
bioRxiv. 2025 Feb 7:2025.02.05.636718. doi: 10.1101/2025.02.05.636718.
Failures of the lysosome-autophagy system are a hallmark of aging and many disease states. As a consequence, interventions that enhance lysosome function are of keen interest in the context of drug development. Throughout the biomedical literature, evolutionary biologists have discovered that challenges faced by humans in clinical settings have been resolved by non-model organisms adapting to wild environments. Here, we used a primary cell culture approach to survey lysosomal characteristics in selected species of the genus . We found that cells from , mice adapted to human environments, had weak lysosomal acidification and high expression and activity of the lysosomal enzyme β-galactosidase, a classic marker of cellular senescence. Cells of wild relatives, especially the Mediterranean mouse , had more robustly performing lysosomes and dampened β-galactosidase levels. We propose that classic laboratory models of lysosome function and senescence may reflect characters that diverge from the phenotypes of wild mice. The phenotype may ultimately provide a blueprint for interventions that ameliorate lysosome breakdown in stress and disease.
溶酶体自噬系统的功能障碍是衰老和许多疾病状态的一个标志。因此，增强溶酶体功能的干预措施在药物开发领域备受关注。在整个生物医学文献中，进化生物学家发现，人类在临床环境中面临的挑战已被非模式生物适应野生环境所解决。在这里，我们采用原代细胞培养方法来研究该属选定物种的溶酶体特征。我们发现，适应人类环境的小鼠的细胞溶酶体酸化能力较弱，溶酶体酶β-半乳糖苷酶（细胞衰老的经典标志物）的表达和活性较高。野生近缘种的细胞，尤其是地中海小鼠的细胞，溶酶体功能更强，β-半乳糖苷酶水平较低。我们认为，溶酶体功能和衰老的经典实验室模型可能反映出与野生小鼠表型不同的特征。该表型最终可能为改善应激和疾病中溶酶体分解的干预措施提供蓝图。
