The PAK5–SIRT5–GLUL axis mediates glutamine deprivation-induced mitophagy in breast cancer

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.