Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have distinct features from normal fibroblasts (NFs). However, the discriminative nature of heterogeneous CAFs under glucose starvation remains unknown. In this study, we investigated the changes in the mitochondrial calcium concentration and relevant intracellular machinery in CAFs under glucose-deficient conditions. Xenografted tumor masses were dissected into multiple pieces and subjected to the CAF isolation using magnetically activated cell sorting (MACS). NFs were separated from the normal lung and skin. Under glucose starvation, CAFs from the tumor mass exhibited heterogeneity in cell proliferation, ATP production and calcium concentration. Compared to NFs, mitochondrial calcium concentration was significantly higher in glucose-starved CAFs with upregulation of mitochondrial calcium uniporter (MCU) that led to enhancement of ATP production and cell growth. Intriguingly, treatment of glucose-starved CAFs with oligomycin increased apoptosis by disrupted calcium homeostasis following overactivation of the mPTP. Moreover, oligomycin-induced apoptosis was mitigated by calcium chelation. This study demonstrated that the discriminative calcium influx to mitochondria through MCU coordinated cell growth and apoptosis in glucose-starved CAFs but not in NFs.

癌症相关成纤维细胞 (CAF) 是肿瘤微环境的重要组成部分，具有与正常成纤维细胞 (NF) 不同的特征。然而，在葡萄糖饥饿下异质 CAF 的区分性质仍然未知。在这项研究中，我们研究了葡萄糖缺乏条件下 CAF 中线粒体钙浓度和相关细胞内机制的变化。异种移植的肿瘤块被解剖成多块，并使用磁激活细胞分选 (MACS) 进行 CAF 分离。NFs 与正常肺和皮肤分离。在葡萄糖饥饿下，来自肿瘤块的 CAF 在细胞增殖、ATP 产生和钙浓度方面表现出异质性。与 NF 相比，随着线粒体钙单向转运蛋白 (MCU) 的上调，导致 ATP 产生和细胞生长的增强，葡萄糖缺乏的 CAF 中的线粒体钙浓度显着更高。有趣的是，在 mPTP 过度激活后，用寡霉素处理葡萄糖饥饿的 CAF 会通过破坏钙稳态来增加细胞凋亡。此外，钙螯合减轻了寡霉素诱导的细胞凋亡。这项研究表明，在葡萄糖缺乏的 CAF 中，有区别的钙通过 MCU 流入线粒体协调细胞生长和凋亡，但在 NF 中则不然。在 mPTP 过度激活后，用寡霉素处理葡萄糖饥饿的 CAF 通过破坏钙稳态来增加细胞凋亡。此外，钙螯合可减轻寡霉素诱导的细胞凋亡。这项研究表明，在葡萄糖缺乏的 CAF 中，有区别的钙通过 MCU 流入线粒体协调细胞生长和凋亡，但在 NF 中则不然。在 mPTP 过度激活后，用寡霉素处理葡萄糖饥饿的 CAF 通过破坏钙稳态来增加细胞凋亡。此外，钙螯合可减轻寡霉素诱导的细胞凋亡。这项研究表明，在葡萄糖缺乏的 CAF 中，有区别的钙通过 MCU 流入线粒体协调细胞生长和凋亡，但在 NF 中则不然。