Mitochondrial YME1L Restrains GRP75-Dependent ISR Activation to Prevent Podocyte Senescence in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is characterized by progressive podocyte loss and cellular senescence, but the upstream stress pathways that determine podocyte fate are not fully understood. YME1L expression was markedly reduced in experimental models of DKD and was inversely associated with senescence markers. Genetic deletion of YME1L caused sustained eIF2α phosphorylation, enhanced ATF4 signaling, and promoted podocyte hypertrophy and senescence in vitro and in vivo. In contrast, restoration of YME1L suppressed integrated stress response (ISR) activation and alleviated diabetic podocyte senescence. Mechanistically, coimmunoprecipitation and mass spectrometry showed that YME1L interacts with the mitochondrial chaperone GRP75. Loss of YME1L led to abnormal accumulation of GRP75 in mitochondria and was accompanied by persistent ISR activation. Notably, GRP75 knockdown or pharmacological inhibition of ISR with ISR inhibitor reduced stress signaling and improved senescence-related phenotypes. Together, these findings identify a YME1L-GRP75 pathway that links mitochondrial stress to ISR activation and podocyte senescence in DKD. Article Highlights Loss of YME1L promotes podocyte senescence in diabetic kidney disease. YME1L deficiency induces sustained maladaptive integrated stress response activation. YME1L interacts with and regulates mitochondrial GRP75 homeostasis. GRP75 accumulation drives persistent integrated stress response activation and mitochondrial dysfunction.