2026-10-12T18:28:15Z https://www.scidb.cn/oai

10.57760/sciencedb.45887 2026-08-12T09:34:57Z

2026-08-12 The PAK5–SIRT5–GLUL axis mediates glutamine deprivation-induced mitophagy in breast cancer doi:10.57760/sciencedb.45887 en Solid tumors frequently experience chronic glutamine starvation, and the adaptive mechanisms underlying this metabolic stress remain poorly defined. In this study, we unveil the molecular mechanisms by which the PAK5‑SIRT5‑GLUL axis regulate mitophagy in breast cancer cells under glutamine deprivation. Glutamine starvation induces elevated PAK5 expression and its translocation to the mitochondria ,where it forms a stable complex with SIRT5 to cooperatively regulate glutamine synthetase (GLUL). Mechanistically, PAK5 phosphorylates GLUL at T301 and S343, while SIRT5 desuccinylates GLUL at K91, establishing coordinated post-translational crosstalk that enhances GLUL stability and activity. Consequently, PAK5 and SIRT5 jointly inhibit mitophagy triggered by glutamine deprivation, thereby promoting breast cancer prolifeation. Importantly, we further validate that elevated protein levels of PAK5, SIRT5, and GLUL are significantly associated with poor clinical outcomes in breast cancer patients. Collectively, our findings reveal a critical role for the PAK5‑SIRT5‑GLUL axis in regulating mitophagy under glutamine deprivation, highlighting this pathway as a promising therapeutic target for breast cancer. PAK5; SIRT5; GLUL; breast cancer; mitophagy; glutamine metabolism Tingting Li Chen Liu Lisha Sun Bing Yu Ke Jin Shourong Xu Jingyi Han Jiabin Li Xue Liu Yan Wang Yiheng Zhang Feng Li EMBARGO https://creativecommons.org/licenses/by/4.0/ dataset Science Data Bank