Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.

细胞代谢受到机械环境的强烈影响。我们在此表明​​，kindlin-2 的一部分定位于线粒体，并与吡咯啉-5-羧酸还原酶 1 (PYCR1)（脯氨酸合成的关键酶）相互作用。细胞外基质 (ECM) 硬化促进 kindlin-2 易位到线粒体及其与 PYCR1 的相互作用，导致 PYCR1 水平升高，从而增加脯氨酸合成和细胞增殖。 kindlin-2 的耗竭会降低 PYCR1 水平，增加活性氧 (ROS) 的产生和细胞凋亡，并消除 ECM 硬化诱导的脯氨酸合成和细胞增殖的增加。在体内，肺腺癌中 kindlin-2 和 PYCR1 水平均显着升高。消除肺腺癌中的kindlin-2可显着降低PYCR1和脯氨酸水平，并减少体内纤维化，从而显着抑制肿瘤生长并降低死亡率。我们的研究结果揭示了一种机械响应 kindlin-2-PYCR1 复合物，它将机械环境与脯氨酸代谢和信号传导联系起来，并提出了一种抑制肿瘤生长的策略。